The DOI matches its Crossref record; 290 of the 294 references it cites were found in a registry or an index; 3 of the 301 sources its claims cite were checked for support.
Genetic architecture of Alzheimer's disease
Open accessAbstract
Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit large effects on disease susceptibility, with the remaining risk loci having much smaller effects on AD risk. Notably, common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants are enriched within regulatory elements active in human myeloid cells, and to a lesser extent liver cells, implicating these cell and tissue types as critical to disease etiology. Integrative approaches are emerging as highly effective for identifying the specific target genes through which AD risk variants act and will likely yield important insights related to potential therapeutic targets in the coming years. In the future, additional consideration of sex- and ethnicity-specific contributions to risk as well as the contribution of complex gene-gene and gene-environment interactions will likely be necessary to further improve our understanding of AD genetic architecture.
Overview
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Written from the paper’s full text.
TL;DR
This review synthesizes the genetic architecture of Alzheimer’s disease, covering rare high-effect mutations in APP, PSEN1, and PSEN2, the major risk factor APOE, and many small-effect common variants. It argues that AD risk variants are enriched in regulatory elements active in myeloid immune cells and that integrative functional genomics is needed to identify causal genes and therapeutic targets.
Key findings
- Autosomal dominant AD is rare (<1% of cases) and mostly caused by mutations in APP, PSEN1, or PSEN2; PSEN1 mutations are the most common monogenic cause, with over 350 mutations identified as of April 2020 and an estimated ~80% contribution to monogenic AD, while PSEN2 has only around 30 known ADAD mutations.
- APOE is the strongest common genetic risk factor: APOEε3 is present in almost 80% of individuals, APOEε4 in ~14%; Caucasian APOEε4 homozygotes have on average a 15-fold increased LOAD risk versus non-carriers, one ε4 allele gives ~3-fold risk, and risk estimates differ by ethnicity (e.g., up to 30-fold in Japanese ε4 homozygotes, weaker or absent associations in some African-American, Hispanic, and Nigerian groups).
- GWAS have identified many small-effect LOAD loci beyond APOE; the most recent meta-analysis included over 95,000 individuals across 46 datasets and validated over 20 loci, including BIN1, CD2AP, CLU, ABCA7, and INPP5D, while common variants explain only about 30% of AD heritability.
- AD-associated common variants are not randomly distributed: they are enriched in regulatory elements active in immune/hematopoietic cells, especially monocytes, macrophages, and microglia, and to a lesser extent liver cells, with no enrichment in bulk brain datasets; rare variants such as TREM2 R47H also implicate microglial immune function.
Methods
- Narrative review of genetic and functional genomic studies of Alzheimer’s disease, including monogenic AD, APOE, GWAS, rare variants, polygenic risk scores, endophenotype GWAS, somatic variation, copy number variation, sex-specific architecture, and model systems.
- No primary data collection, sample, or statistical analysis is reported; the paper synthesizes published findings and publicly available annotation resources.
- Key cited analyses include GWAS meta-analyses, rare-variant sequencing studies, functional annotation enrichment analyses, eQTL colocalization, and PRS studies.
Limitations
- The paper states that GWAS cannot identify the causal variant or gene in an associated region, that common variants explain only ~30% of AD heritability, and that over 25% of variance remains unexplained by known genetic factors.
- It notes that most functional annotation data come from healthy donors, that sex- and ethnicity-specific contributions are understudied, and that gene-gene and gene-environment interactions are difficult to identify; disease heterogeneity and mixed pathologies may also reduce GWAS power.
- Evident from the text: as a narrative review, it does not report a systematic search strategy or formal quality assessment of included studies.
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Claims the paper makes
184 Not checked yet · 52 Own interpretation · 12 No basis given · 2 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A majority of ADAD families carry a pathogenic mutation in one of three genes: APP, presenilin 1 (PSEN1), or presenilin 2 (PSEN2) [2, 33].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Partly supportedcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 sourceExperimental — accuracy not yet measured
Section 2.2 identifies APP, PSEN1, and PSEN2 as causal early-onset AD genes. But it reports that, depending on the study, 23% to 88.2% of autosomal dominant patients remain genetically unexplained. The source therefore does not support an unqualified claim that a majority of ADAD families carry a mutation in one of the three genes. (LLM, conf=0.88)
- Partly supportedcites [33] Bekris LM, Yu CE, Bird TD, & Tsuang DW (2010). Genetics of Alzheimer disease. Journal of geriatric psychiatry and neurology, 23(4), 213– 227. 21045163 PMC3044597 sourceExperimental — accuracy not yet measured
The Summary links autosomal-dominant early-onset familial Alzheimer disease to APP, PSEN1, and PSEN2. Genetic Testing and Counseling estimates that 20%–70% of cases have a PSEN1 mutation, 10%–15% an APP mutation, and few a PSEN2 mutation. Those ranges do not establish that a majority of families carry a mutation in one of the three genes. (LLM, conf=0.82)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“common polymorphisms in the gene apolipoprotein E (APOE) are the most significant genetic risk factor for AD [52–54].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [52] Pericak-Vance MA, Bebout JL, Gaskell PC Jr., Yamaoka LH, Hung WY, Alberts MJ, … (1991). Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. American journal of human genetics, 48(6), 1034– 1050. 2035524 PMC1683100
- Not checked yetcites [53] Roses AD, & Saunders AM (1994). APOE is a major susceptibility gene for Alzheimer’s disease. Current opinion in biotechnology, 5(6), 663– 667. 7765750 source
- Not checked yetcites [54] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, … Pericak-Vance MA (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921– 923. 8346443 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“the effect of APOEε4 has been reported to differ across ethnicities [58–61]”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [58] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, … van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the journal of the American Medical Association, 278(16), 1349– 1356. 9343467 source
- Not checked yetcites [59] Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, … Kuwano R (2013). SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PloS one, 8(4), e58618. 23565137 PMC3614978 source
- Not checked yetcites [60] Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, … Farrer LA (2017). Transethnic genome-wide scan identifies novel Alzheimer’s disease loci. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 13(7), 727– 738. PMC5496797 28183528 source
- Not checked yetcites [61] Murrell JR, Price B, Lane KA, Baiyewu O, Gureje O, Ogunniyi A, … Hall KS (2006). Association of apolipoprotein E genotype and Alzheimer disease in African Americans. Archives of neurology, 63(3), 431– 434. 16533971 PMC3203415 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“PSEN2 mutations are much rarer, with only around 30 mutations identified in ADAD families [2].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“To date, more than 50 highly penetrant mutations have been identified in APP [2].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Mutations in the Aβ domain itself alter the hydrophobicity and downstream aggregation propensity of Aβ peptides, leading to an increase in plaque load [36].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [36] Tcw J, & Goate AM (2017). Genetics of beta-Amyloid Precursor Protein in Alzheimer’s Disease. Cold Spring Harbor perspectives in medicine, 7(6). 10.1101/cshperspect.a024539 PMC5453386 28003277 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Estimates of heritability for EOAD are as high as 90–100% [24]”
§ Genetic architecture of Alzheimer’s disease > Introduction to Alzheimer’s disease
What the sources say
- Not checked yetcites [24] Wingo TS, Lah JJ, Levey AI, & Cutler DJ (2012). Autosomal recessive causes likely in early-onset Alzheimer disease. Archives of neurology, 69(1), 59– 64. 21911656 PMC3332307 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“familial EOAD mutations in PSEN1 and PSEN2 typically result in an increased production of longer and more aggregation-prone derivatives of APP such as Aβ1–42 [47–49].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [47] Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, … Selkoe DJ (1997). Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature medicine, 3(1), 67– 72. 8986743 source
- Not checked yetcites [48] Mehta ND, Refolo LM, Eckman C, Sanders S, Yager D, Perez-Tur J, … Hutton M (1998). Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Annals of neurology, 43(2), 256– 258. 9485068 source
- Not checked yetcites [49] Cacquevel M, Aeschbach L, Houacine J, & Fraering PC (2012). Alzheimer’s disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified gamma-secretase complexes. PloS one, 7(4), e35133. 22529981 PMC3329438 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“heritability estimates for LOAD are slightly lower, in the range of 60–80% [25]”
§ Genetic architecture of Alzheimer’s disease > Introduction to Alzheimer’s disease
What the sources say
- Not checked yetcites [25] Gatz M, Pedersen NL, Berg S, Johansson B, Johansson K, Mortimer JA, … Ahlbom A (1997). Heritability for Alzheimer’s disease: the study of dementia in Swedish twins. The journals of gerontology. Series A, Biological sciences and medical sciences, 52(2), M117– 25. 9060980 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“mutations occurring near the βsecretase cleavage site, such as the Swedish mutation (K670N/M671L), appear to result in increased production of total Aβ [34, 35].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [34] Busciglio J, Gabuzda DH, Matsudaira P, & Yankner BA (1993). Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proceedings of the National Academy of Sciences of the United States of America, 90(5), 2092– 2096. 8446635 PMC46027 source
- Not checked yetcites [35] Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, … Selkoe DJ (1994). Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proceedings of the National Academy of Sciences of the United States of America, 91(25), 11993– 11997. 7991571 PMC45362 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 30
- It may state two separate claims as one. 73
- The quote only partly states this claim. 2
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“While microglia exhibit several beneficial functions in the brain such as clearance of cellular debris and orchestration of appropriate immune responses, their chronic activation can lead to toxic neuroinflammation and aberrant pruning of synapses [203, 204].”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
What the sources say
- Not checked yetcites [203] Salter MW, & Stevens B (2017). Microglia emerge as central players in brain disease. Nature medicine, 23(9), 1018– 1027. 28886007 source
- Partly supportedcites [204] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, … Stevens B (2016). Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 352(6286), 712– 716. 27033548 PMC5094372 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Caucasian individuals with two copies of APOEε4 have on average a 15-fold increased risk for LOAD relative to those carrying no APOEε4 alleles, whereas risk for individuals carrying only one APOEε4 allele decreases to ~3 times that of non-carriers [58].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [58] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, … van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the journal of the American Medical Association, 278(16), 1349– 1356. 9343467
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“up to a 30-fold increase in disease risk was observed among Japanese individuals with two ε4 alleles as compared to a 15-fold increased risk in Caucasians [59, 60]”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [59] Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, … Kuwano R (2013). SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PloS one, 8(4), e58618. 23565137 PMC3614978
- Not checked yetcites [60] Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, … Farrer LA (2017). Transethnic genome-wide scan identifies novel Alzheimer’s disease loci. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 13(7), 727– 738. PMC5496797 28183528
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“APOEε4 is less frequent (~14%) among the general population but drastically increases risk for AD in a dose-dependent manner [54, 57]”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [54] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, … Pericak-Vance MA (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921– 923. 8346443 source
- Not checked yetcites [57] Liu CC, Liu CC, Kanekiyo T, Xu H, & Bu G (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature reviews. Neurology, 9(2), 106– 118. 23296339 PMC3726719 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The effect of PSEN2 mutations is more variable than either PSEN1 or APP mutations, with age of onset in PSEN2 mutation carriers ranging from 40 to 85 years of age [50, 51].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [50] Ryan NS, & Rossor MN (2010). Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomarkers in medicine, 4(1), 99– 112. 20387306 PMC3937872
- Not checked yetcites [51] Pilotto A, Padovani A, & Borroni B (2013). Clinical, biological, and imaging features of monogenic Alzheimer’s Disease. BioMed research international, 2013, 689591. 24377094 PMC3860086
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the association between ε4 and disease is reported to be weaker among African-American and Hispanic individuals [58, 61, 62] and nonexistent among Nigerian individuals [63].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [58] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, … van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the journal of the American Medical Association, 278(16), 1349– 1356. 9343467 source
- Not checked yetcites [61] Murrell JR, Price B, Lane KA, Baiyewu O, Gureje O, Ogunniyi A, … Hall KS (2006). Association of apolipoprotein E genotype and Alzheimer disease in African Americans. Archives of neurology, 63(3), 431– 434. 16533971 PMC3203415 source
- Not checked yetcites [62] Rajabli F, Feliciano BE, Celis K, Hamilton-Nelson KL, Whitehead PL, Adams LD, … Pericak-Vance MA (2018). Ancestral origin of ApoE epsilon4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS genetics, 14(12), e1007791. 30517106 PMC6281216 source
- Not checked yetcites [63] Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM, … Murrell JR (2006). APOE epsilon4 is not associated with Alzheimer’s disease in elderly Nigerians. Annals of neurology, 59(1), 182– 185. 16278853 PMC2855121 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the two subsets share common pathological features and are both considered to be highly heritable.”
§ Genetic architecture of Alzheimer’s disease > Introduction to Alzheimer’s disease
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Mutations in PSEN1 are the most common cause of ADAD; as of April 2020, over 350 mutations (some of unclear pathogenicity) have been identified (www.Alzforum.org).”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The overall effect of APP mutations is generally increased production and/or aggregation of amyloid, although the precise mechanism differs by mutation type and localization.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“ADAD is very rare, accounting for less than <1% of all cases of AD [2, 31–33]”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source
- Not checked yetcites [31] Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, … Frebourg T (1999). Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. American journal of human genetics, 65(3), 664– 670. 10441572 PMC1377972 source
- Not checked yetcites [32] Brickell KL, Steinbart EJ, Rumbaugh M, Payami H, Schellenberg GD, Van Deerlin V, … Bird TD (2006). Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Archives of neurology, 63(9), 1307– 1311. 16966510 source
- Not checked yetcites [33] Bekris LM, Yu CE, Bird TD, & Tsuang DW (2010). Genetics of Alzheimer disease. Journal of geriatric psychiatry and neurology, 23(4), 213– 227. 21045163 PMC3044597 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Of the three alleles, APOEε3 is the most common in all human populations, present in almost 80% of individuals [57].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [57] Liu CC, Liu CC, Kanekiyo T, Xu H, & Bu G (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature reviews. Neurology, 9(2), 106– 118. 23296339 PMC3726719 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“the “amyloid cascade hypothesis” which posits that amyloid deposition is an initial causative event in a cascade of symptoms resulting in neurodegeneration and cognitive decline [39].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Monogenic causes of AD
What the sources say
- Not checked yetcites [39] Hardy JA, & Higgins GA (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science, 256(5054), 184– 185. 1566067
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A second 2009 GWAS replicated the association of SNPs near CLU with LOAD and identified another locus on chromosome 1 as associated with disease, near the gene encoding the complement receptor 1 (CR1) [92].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Genome-wide association studies (GWAS)
What the sources say
- Not checked yetcites [92] Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, … Amouyel P (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nature genetics, 41(10), 1094– 1099. 19734903
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Proxy risk for AD, defined as a parental history of AD, exhibits strong genetic correlation with AD [113] and can thus be combined with existing GWAS datasets to enhance statistical power to find true genetic associations with disease.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Variations on traditional GWAS
What the sources say
- Not checked yetcites [113] Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, … Posthuma D (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature genetics, 51(3), 404– 413. 30617256 PMC6836675 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“APOEε2 appears to reduce risk for AD, with carriers of even one APOEε2 allele in combination with APOEε3 exhibiting only about half the risk of those carrying two APOEε3 alleles [58].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > APOE as a major genetic risk factor for AD
What the sources say
- Not checked yetcites [58] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, … van Duijn CM (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA: the journal of the American Medical Association, 278(16), 1349– 1356. 9343467
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“this GWAS identified novel variants not previously associated with the disease by standard GWAS, including variants near IQCK [97].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Genome-wide association studies (GWAS)
What the sources say
- Not checked yetcites [97] Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, … Environmental Risk for Alzheimer’s Disease, Consortium. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics, 51(3), 414– 430. 30820047 PMC6463297
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“association signals in the MS4A region were also stronger in APOEε4− subjects [107], while variants in the PICALM region exhibit stronger associations in APOEε4+ subjects [111], further suggesting independent mechanisms may partially contribute to AD across APOE genotypes.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Variations on traditional GWAS
What the sources say
- Not checked yetcites [107] Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert J-C, Chung J, Naj AC, … Farrer LA (2016). A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular psychiatry, 21(1), 108– 117. 25778476 PMC4573764
- Not checked yetcites [111] Jun G, Naj AC, Beecham GW, Wang L-S, Buros J, Gallins PJ, … Schellenberg GD (2010). Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Archives of neurology, 67(12), 1473– 1484. 20697030 PMC3048805
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In 2009, the first large-scale GWAS were published and loci outside of APOE were implicated in LOAD risk for the first time.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Genome-wide association studies (GWAS)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SNPs protective against AD were associated with increased expression of MAPT exon 3, which has previously been associated with decreased aggregation of tau protein [108, 109] and protection from neurodegeneration [110].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Variations on traditional GWAS
What the sources say
- Not checked yetcites [108] Trabzuni D, Wray S, Vandrovcova J, Ramasamy A, Walker R, Smith C, … Ryten M (2012). MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Human molecular genetics, 21(18), 4094– 4103. 22723018 PMC3428157
- Not checked yetcites [109] Zhong Q, Congdon EE, Nagaraja HN, & Kuret J (2012). Tau isoform composition influences rate and extent of filament formation. The Journal of biological chemistry, 287(24), 20711– 20719. 22539343 PMC3370253
- Not checked yetcites [110] Caffrey TM, Joachim C, & Wade-Martins R (2008). Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. Neurobiology of aging, 29(12), 1923– 1929. 17602795 PMC2801070
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This finding suggests either 1) APOE genotype interacts with some surrounding genetic variants to dictate disease risk, or 2) protective alleles within the African APOE haplotype reduce the effect of APOEε4 on disease, providing hypotheses to test in future studies.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Genome-wide association studies (GWAS)
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The identification of APOE as the sole risk factor in small GWAS demonstrates that genetic variation at this locus is the most significant common genetic risk factor for LOAD, and genetic variation at other loci individually confer only small effects on disease risk.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Genome-wide association studies (GWAS)
boostedcorrelationaln = 2,000- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“several ethnicity-specific loci associated with disease have been identified, including variants on 18q23 in Caribbean Hispanics [99] and variants near KCHN15 in Chinese [100].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Genome-wide association studies (GWAS)
What the sources say
- Not checked yetcites [99] Lee JH, Cheng R, Barral S, Reitz C, Medrano M, Lantigua R, … Mayeux R (2011). Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Archives of neurology, 68(3), 320– 328. 21059989 PMC3268783
- Not checked yetcites [100] Zhou X, Chen Y, Mok KY, Zhao Q, Chen K, Chen Y, … Alzheimer’s Disease Neuroimaging, Initiative. (2018). Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis. Proceedings of the National Academy of Sciences of the United States of America, 115(8), 1697– 1706. 29432188 PMC5828602
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The most recent meta-analysis of LOAD risk included data from over 95,000 individuals across 46 datasets and validated over 20 loci previously associated with disease, including well-replicated variants located near genes including BIN1, CD2AP, CLU, ABCA7, and INPP5D, among others [97] (Table S1).”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Genome-wide association studies (GWAS)
What the sources say
- Not checked yetcites [97] Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, … Environmental Risk for Alzheimer’s Disease, Consortium. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics, 51(3), 414– 430. 30820047 PMC6463297
plaincorrelationaln = 95,000- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“these approaches show substantial genetic overlap with previous case-control GWAS and nominate a number of novel loci associated with proxy risk for AD [112–114].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Variations on traditional GWAS
What the sources say
- Not checked yetcites [112] Liu JZ, Erlich Y, & Pickrell JK (2017). Case-control association mapping by proxy using family history of disease. Nature genetics, 49(3), 325– 331. 28092683 source
- Not checked yetcites [113] Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, … Posthuma D (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature genetics, 51(3), 404– 413. 30617256 PMC6836675 source
- Not checked yetcites [114] Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD, … Visscher PM (2018). GWAS on family history of Alzheimer’s disease. Translational psychiatry, 8(1), 99. 29777097 PMC5959890 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This supports the notion that AD is likely influenced by a large number of susceptibility genes, reflecting a complex set of biological pathways related to the disease [123].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Polygenic risk scores
What the sources say
- Not checked yetcites [123] Escott-Price V, Shoai M, Pither R, Williams J, & Hardy J (2017). Polygenic score prediction captures nearly all common genetic risk for Alzheimer’s disease. Neurobiology of aging, 49, 214 e7– 214 e11. 27595457 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These “polygenic risk scores” (PRS) have since been expanded upon in the context of AD and used for individualized risk prediction [118]”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Polygenic risk scores
What the sources say
- Not checked yetcites [118] Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, … Dale AM (2017). Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS medicine, 14(3), e1002258. 28323831 PMC5360219
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Many of these genes containing coding variants are highly expressed in microglia and function within the immune system, highlighting this pathway as critical for disease risk.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Variations on traditional GWAS
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Together, these results suggest shared genetic architecture exists between both EOAD and LOAD, with some of the same loci influencing risk for disease in both cases.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Polygenic risk scores
What the sources say
- Not checked yetcites [26] Cruchaga C, Del-Aguila JL, Saef B, Black K, Fernandez MV, Budde J, … Harari O (2018). Polygenic risk score of sporadic late-onset Alzheimer’s disease reveals a shared architecture with the familial and early-onset forms. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 14(2), 205– 214. PMC5803427 28943286
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“and decreases the stability of the protein, potentially conferring reduced functionality [136].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [136] Sudom A, Talreja S, Danao J, Bragg E, Kegel R, Min X, … Wang Z (2018). Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2. The Journal of biological chemistry, 293(32), 12634– 12646. 29794134 PMC6093241
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It was found that the burden (PRS) of LOAD GWAS variants significantly predicted disease risk and age at onset in both familial LOAD and sporadic EOAD [26].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Polygenic risk scores
What the sources say
- Not checked yetcites [26] Cruchaga C, Del-Aguila JL, Saef B, Black K, Fernandez MV, Budde J, … Harari O (2018). Polygenic risk score of sporadic late-onset Alzheimer’s disease reveals a shared architecture with the familial and early-onset forms. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 14(2), 205– 214. PMC5803427 28943286
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Since its identification, the R47H variant has been associated not only with AD risk but also neuropathology, brain atrophy, and additional behavioral symptoms such as anxiety in AD patients [133–135].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [133] Luis EO, Ortega-Cubero S, Lamet I, Razquin C, Cruchaga C, Benitez BA, … Pastor P (2014). Frontobasal gray matter loss is associated with the TREM2 p.R47H variant. Neurobiology of aging, 35(12), 2681– 2690. 25027412 PMC4253600
- Not checked yetcites [134] Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, … Cruchaga C (2019). The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Science translational medicine, 11(505). 10.1126/scitranslmed.aau2291 PMC6697053 31413141
- Not checked yetcites [135] Guerreiro R, Bilgic B, Guven G, Bras J, Rohrer J, Lohmann E, … Emre M (2013). Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiology of aging, 34(12), 2890 e1– 5. PMC3898264 23870839
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“risk and seems to provide an improved method for risk prediction over more selective PRS or standard predictors such as APOEε4 alleles, age, and sex [118, 122, 123].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Polygenic risk scores
What the sources say
- Not checked yetcites [118] Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, … Dale AM (2017). Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS medicine, 14(3), e1002258. 28323831 PMC5360219 source
- Not checked yetcites [122] Escott-Price V, Sims R, Bannister C, Harold D, Vronskaya M, Majounie E, … Williams J (2015). Common polygenic variation enhances risk prediction for Alzheimer’s disease. Brain: a journal of neurology, 138(Pt 12), 3673– 3684. 26490334 PMC5006219 source
- Not checked yetcites [123] Escott-Price V, Shoai M, Pither R, Williams J, & Hardy J (2017). Polygenic score prediction captures nearly all common genetic risk for Alzheimer’s disease. Neurobiology of aging, 49, 214 e7– 214 e11. 27595457 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Additional genes identified to harbor rare variants associated with AD risk include AKAP9, UNC5, and ADAM10, although the strength of these associations and the role of these genes in disease etiology remains less well-established [145, 146].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [145] Lord J, Lu AJ, & Cruchaga C (2014). Identification of rare variants in Alzheimer’s disease. Frontiers in genetics, 5, 369. 25389433 PMC4211559
- Not checked yetcites [146] Del-Aguila JL, Koboldt DC, Black K, Chasse R, Norton J, Wilson RK, & Cruchaga C (2015). Alzheimer’s disease: rare variants with large effect sizes. Current opinion in genetics & development, 33, 49– 55. 26311074
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“PLGC2, which harbors a protective variant, encodes a transmembrane signaling enzyme implicated in lipid metabolism, calcium homeostasis, and immune response [130, 142].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [130] Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, … Schellenberg GD (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nature genetics, 49(9), 1373– 1384. 28714976 PMC5669039
- Not checked yetcites [142] Milner JD (2015). PLAID: a Syndrome of Complex Patterns of Disease and Unique Phenotypes. Journal of clinical immunology, 35(6), 527– 530. 26206677 PMC4575258
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“ABI3 has similarly been implicated in regulation of the immune response through interferon signaling [143] and also plays a role in actin cytoskeletal organization [144].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [143] Fairfax BP, Humburg P, Makino S, Naranbhai V, Wong D, Lau E, … Knight JC (2014). Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression. Science, 343(6175), 1118– +. PMC4064786 24604202 source
- Not checked yetcites [144] Sekino S, Kashiwagi Y, Kanazawa H, Takada K, Baba T, Sato S, … Tani K (2015). The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell communication and signaling: CCS, 13, 41. 26428302 PMC4589964 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Although GWAS variants were not associated with risk for familial EOAD inherited in an autosomal dominant fashion, the researchers noted that the sample size was small and that variant burden may have been associated with age at symptom onset in these families [26].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Polygenic risk scores
What the sources say
- Not checked yetcites [26] Cruchaga C, Del-Aguila JL, Saef B, Black K, Fernandez MV, Budde J, … Harari O (2018). Polygenic risk score of sporadic late-onset Alzheimer’s disease reveals a shared architecture with the familial and early-onset forms. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 14(2), 205– 214. PMC5803427 28943286
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In addition to overt disease risk, PRS scores derived from large numbers of common variants have been used to significantly predict age at onset of AD as well as likelihood of longitudinal progression from mild cognitive impairment to AD [118].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Polygenic risk scores
What the sources say
- Not checked yetcites [118] Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, … Dale AM (2017). Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS medicine, 14(3), e1002258. 28323831 PMC5360219
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Histone modifications can reliably be measured across the genome using chromatin immunoprecipitation followed by sequencing (ChIP-seq), while chromatin accessibility is typically measured by either DNase hypersensitivity analysis (DNase-seq) [168] or assay for transposase-accessible chromatin using sequencing”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [168] Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, … Stamatoyannopoulos JA (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science, 337(6099), 1190– 1195. 22955828 PMC3771521 source
- Not checked yetcites [177] Buenrostro JD, Wu B, Chang HY, & Greenleaf WJ (2015). ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide. Current protocols in molecular biology / edited by Frederick M. Ausubel... [et al.], 109, 21 29 1– 9. PMC4374986 25559105 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“However, regulatory elements can act on downstream target genes located a long distance away and have diverse effects depending on the context in which they are activated [169], making the specific genes impacted by GWAS SNPs difficult to identify.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [169] Jowett JB, Curran JE, Johnson MP, Carless MA, Goring HH, Dyer TD, … Blangero J (2010). Genetic variation at the FTO locus influences RBL2 gene expression. Diabetes, 59(3), 726– 732. 20009087 PMC2828652 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, rare variants in SORL1 and ABCA7 have been identified in family-based studies of LOAD [147–150], each of which have been associated with alterations in APP processing.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [147] Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, … Mayeux R (2015). Coding mutations in SORL1 and Alzheimer disease. Annals of neurology, 77(2), 215– 227. 25382023 PMC4367199 source
- Not checked yetcites [148] Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, … Alzheimer’s Disease Sequencing, Project. (2018). Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer’s disease. Ann Clin Transl Neurol, 5(7), 832– 842. 30009200 PMC6043775 source
- Not checked yetcites [149] Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, … Goate AM (2014). Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature, 505(7484), 550– 554. 24336208 PMC4050701 source
- Not checked yetcites [150] Le Guennec K, Nicolas G, Quenez O, Charbonnier C, Wallon D, Bellenguez C, … Cnr-Maj collaborators. (2016). ABCA7 rare variants and Alzheimer disease risk. Neurology, 86(23), 2134– 2137. 27037229 PMC4898320 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the overlap between EOAD and LOAD as discussed above, these modifiers may provide potential therapeutic targets for a more general population.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“Enhancers are difficult to confidently identify from DNA sequence alone, but are instead defined by the presence of several functional marks including specific histone modifications that promote transcription [176] and by accessibility of local chromatin.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [176] Catarino RR, & Stark A (2018). Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation. Genes & development, 32(3–4), 202– 223. 29491135 PMC5859963
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Rare variants typically have a more deleterious impact on protein structure and/or function than common variants [166, 167] and thus have a larger effect on disease susceptibility than those identified by GWAS.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [166] Park JH, Gail MH, Weinberg CR, Carroll RJ, Chung CC, Wang Z, … Chatterjee N (2011). Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants. Proceedings of the National Academy of Sciences of the United States of America, 108(44), 18026– 18031. 22003128 PMC3207674
- Not checked yetcites [167] Eyre-Walker A (2010). Evolution in health and medicine Sackler colloquium: Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proceedings of the National Academy of Sciences of the United States of America, 107 Suppl 1, 1752– 1756. 20133822 PMC2868283
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This, combined with the effect that the gene impacted by the identified variant is often immediately apparent, makes it possible to more easily model the effect of the variant in cell-based assays or model organisms.”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“A variety of assays now exist to capture this three-dimensional architecture, including various adaptations of chromosome conformation capture (3C) [179].”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [179] Gavrilov A, Eivazova E, Priozhkova I, Lipinski M, Razin S, & Vassetzky Y (2009). Chromosome conformation capture (from 3C to 5C) and its ChIP-based modification. Methods in molecular biology, 567, 171– 188. 19588093 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Disease-associated mutations in SORL1 have been linked with altered levels of APP at the cell surface and increased production of toxic Aβ species [147].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [147] Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, … Mayeux R (2015). Coding mutations in SORL1 and Alzheimer disease. Annals of neurology, 77(2), 215– 227. 25382023 PMC4367199
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Interestingly, there is evidence that groups of genes close together in chromosomal space function in similar biological pathways [172], suggesting this approach may be valid to identify overall pathways and functions perturbed by GWAS variants, although the specific genes investigated may not be direct targets of the causal variants in the region.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [172] Thevenin A, Ein-Dor L, Ozery-Flato M, & Shamir R (2014). Functional gene groups are concentrated within chromosomes, among chromosomes and in the nuclear space of the human genome. Nucleic acids research, 42(15), 9854– 9861. 25056310 PMC4150778
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SORL1, a sorting receptor located in neurons [152], astrocytes, and microglia [153] is known to direct APP toward non-amyloidogenic processing in the trans-Golgi network [148, 154].”
§ Genetic architecture of Alzheimer’s disease > Genetics of AD > Rare variants
What the sources say
- Not checked yetcites [152] Grear KE, Ling IF, Simpson JF, Furman JL, Simmons CR, Peterson SL, … Estus S (2009). Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain. Molecular neurodegeneration, 4, 46. 19889229 PMC2776013 source
- Not checked yetcites [153] Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, … Barres BA (2016). Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron, 89(1), 37– 53. 26687838 PMC4707064 source
- Not checked yetcites [148] Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, … Alzheimer’s Disease Sequencing, Project. (2018). Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer’s disease. Ann Clin Transl Neurol, 5(7), 832– 842. 30009200 PMC6043775 source
- Not checked yetcites [154] Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, … St George-Hyslop P (2007). The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature genetics, 39(2), 168– 177. 17220890 PMC2657343 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Enhancers, short genomic sequences distally located from their target genes, confer additional cell- and tissue-type specificity to the regulation of gene expression.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For example, promoters proximal to the transcription start site of protein coding genes can recruit the binding of specific transcription factors, activators, or repressors [175].”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [175] Fuda NJ, Ardehali MB, & Lis JT (2009). Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature, 461(7261), 186– 192. 19741698 PMC2833331
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“As enhancers are often located at a considerable distance from their target genes, it is believed they function by recruiting specific chromatin remodeling factors that promote the formation of chromatin loops, bringing the enhancer and promoter into close proximity [178].”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [178] Krivega I, & Dean A (2012). Enhancer and promoter interactions-long distance calls. Current opinion in genetics & development, 22(2), 79– 85. 22169023 PMC3342482 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Much of the non-coding genome has regulatory functions, suggesting a majority of GWAS variants act by perturbing gene expression, presumably in a subset of disease-relevant cell or tissue types.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SPI1 is particularly important for myeloid cell differentiation and function, and has been linked to the ability of microglia to clear pathogens and cellular debris [173, 194].”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
What the sources say
- Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334
- Not checked yetcites [194] Smith AM, Gibbons HM, Oldfield RL, Bergin PM, Mee EW, Faull RL, & Dragunow M (2013). The transcription factor PU.1 is critical for viability and function of human brain microglia. Glia, 61(6), 929– 942. 23483680
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the critical role of regulatory elements in regulating gene expression, it can be hypothesized based on the above findings that AD variants likely modify risk for AD by having a functional impact on gene expression in immune cells, particularly myeloid cells such as monocytes, macrophages, and microglia.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The GWAS discussed above were primarily performed on case/control datasets and provide information regarding the genetic architecture of disease risk.”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Early clues to the involvement of epigenetic modifications in AD came from observations that altered methylation at the promoters of APP, PSEN1, and APOE could modify risk for disease.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Instead, it was shown that variants in high LD with the lead SNP were significantly associated with regulation of SPI1 levels in myeloid cells, likely causally modifying disease through this mechanism [173].”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
What the sources say
- Not checked yetcites [173] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, … Goate AM (2017). A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nature neuroscience, 20(8), 1052– 1061. 28628103 PMC5759334
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“While the use of bulk datasets does not provide specific information about the cell types through which AD variants act, they still provide useful information as to which genes may be targeted by GWAS SNPs.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, this approach does not provide information about other aspects of the disease such as age of onset or disease progression, or as discussed, biological mechanisms involved in disease pathogenesis.”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In addition, the case/control design can be complicated by pre-symptomatic AD patients who are misclassified as “controls” due to a current absence of clinical symptoms and non-AD dementias misclassified as probable AD.”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Regulatory elements across the genome exhibit a high degree of cell-type specificity, enabling the existence of diverse cell and tissue types as well as carefully orchestrated transcriptional responses to stimuli from a single genome.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Identification of the precise cells and tissues in which regulatory elements containing AD risk variants are active would provide critical insight into where these variants may be acting to perturb gene expression and mediate functional effects that translate into modified risk for disease.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“In combination with additional annotation information including chromatin accessibility as measured by DNase hypersensitivity, Gagliano et al. [183] identified a significant enrichment for AD-associated variants in functional annotations active in the “immune/hematopoietic cell” and “liver” categories, but not in other categories such as brain, cardiovascular, kidney, etc.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
What the sources say
- Not checked yetcites [183] Gagliano SA, Pouget JG, Hardy J, Knight J, Barnes MR, Ryten M, & Weale ME (2016). Genomics implicates adaptive and innate immunity in Alzheimer’s and Parkinson’s diseases. Ann Clin Transl Neurol, 3(12), 924– 933. 28097204 PMC5224821 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The identification of enrichment among “liver” datasets is particularly notable given that the liver is the principal site responsible for maintaining”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
What the sources say
- Not checked yetcites [187] Trapani L, Segatto M, & Pallottini V (2012). Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic “power station.” World journal of hepatology, 4(6), 184– 190. 22761969 PMC3388116
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It should be noted that most of the currently available functional annotation data is derived from healthy donors.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“This search has been facilitated by large-scale annotation projects such as the Roadmap Epigenomics Project [180], the Blueprint Project [181], and PsychENCODE [182]. These projects aim to generate, and make publicly available, high-quality reference annotation maps across a wide variety of human cell and tissue types.”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Understanding the regulatory function of non-coding risk variants
What the sources say
- Not checked yetcites [180] Roadmap Epigenomics, Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, … Kellis M (2015). Integrative analysis of 111 reference human epigenomes. Nature, 518(7539), 317– 330. 25693563 PMC4530010 source
- Not checked yetcites [181] Fernandez JM, de la Torre V, Richardson D, Royo R, Puiggros M, Moncunill V, … Valencia A (2016). The BLUEPRINT Data Analysis Portal. Cell Syst, 3(5), 491– 495 e5. 27863955 PMC5919098 source
- Not checked yetcites [182] Psych, Encode Consortium, Akbarian S, Liu C, Knowles JA, Vaccarino FM, Farnham PJ, … Sestan N (2015). The PsychENCODE project. Nature neuroscience, 18(12), 1707– 1712. 26605881 PMC4675669 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“These associations were observed whether APOE was included or not, confirming the enrichment was not driven by a single moderate-effect variant [183].”
§ Genetic architecture of Alzheimer’s disease > Functional genomic architecture > Cell-type specificity of AD risk
What the sources say
- Not checked yetcites [183] Gagliano SA, Pouget JG, Hardy J, Knight J, Barnes MR, Ryten M, & Weale ME (2016). Genomics implicates adaptive and innate immunity in Alzheimer’s and Parkinson’s diseases. Ann Clin Transl Neurol, 3(12), 924– 933. 28097204 PMC5224821 source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CSF levels of APOE protein have also been suggested to act as a valuable endophenotype for AD [215], along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated [216–218].”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
What the sources say
- Not checked yetcites [215] Cruchaga C, Kauwe JS, Nowotny P, Bales K, Pickering EH, Mayo K, … Goate AM (2012). Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer’s disease. Human molecular genetics, 21(20), 4558– 4571. 22821396 PMC3459471 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Notably, several of these novel variants, including those near GLIS1 and within SERPINB1, were associated with additional aspects of disease including risk, age at”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
What the sources say
- Not checked yetcites [211] Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, … Cruchaga C (2017). Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta neuropathologica, 133(5), 839– 856. 28247064 PMC5613285
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“sTREM2 is thought to be produced in one of two ways; either by cleavage of TREM2 by proteases such as ADAM10, ADAM17, and γ-secretase, or by alternative splicing which generates a short isoform lacking a transmembrane domain (~25% of TREM2 transcripts) [134].”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
What the sources say
- Not checked yetcites [134] Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, … Cruchaga C (2019). The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Science translational medicine, 11(505). 10.1126/scitranslmed.aau2291 PMC6697053 31413141
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“sTREM2 is then released into the CSF where it can be measured, and has been shown to correlate with CSF levels of tau [213, 214], suggesting it may be a relevant secondary biomarker of disease progression.”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
What the sources say
- Not checked yetcites [213] Henjum K, Almdahl IS, Årskog V, Minthon L, Hansson O, Fladby T, & Nilsson LNG (2016). Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease. Alzheimer’s research & therapy, 8(1), 17. PMC4848774 27121148
- Not checked yetcites [214] Suárez-Calvet M, Kleinberger G, Araque Caballero MÁ, Brendel M, Rominger A, Alcolea D, … Haass C (2016). sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s disease and associate with neuronal injury markers. EMBO molecular medicine, 8(5), 466– 476. 26941262 PMC5120370
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, this approach greatly facilitates interpretation of the downstream functional consequences of the prioritized loci.”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
None of the sources cited for this claim have been checked yet.
In the paper
“along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated [216–218].”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
What the sources say
- Not checked yetcites [216] Hampel H, Toschi N, Baldacci F, Zetterberg H, Blennow K, Kilimann I, … Alzheimer Precision Medicine, Initiative. (2018). Alzheimer’s disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Abeta1–42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 14(4), 492– 501. 29328927 source
- Not checked yetcites [217] Blennow K (2017). A Review of Fluid Biomarkers for Alzheimer’s Disease: Moving from CSF to Blood. Neurol Ther, 6(Suppl 1), 15– 24. 28733960 PMC5520819 source
- Not checked yetcites [218] Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, … Zetterberg H (2016). CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet neurology, 15(7), 673– 684. 27068280 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As the quantitative nature of endophenotypes results in improved phenotype definition beyond traditional case-control analyses”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“PET imaging can also be used to measure glucose metabolism in the brain through the utilization of a radiolabeled alternate form of glucose, 18F-fluorodeoxyglucose (FDG) [220].”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
What the sources say
- Not checked yetcites [220] Ou YN, Xu W, Li JQ, Guo Y, Cui M, Chen KL, … Alzheimer’s Disease Neuroimaging, Initiative. (2019). FDG-PET as an independent biomarker for Alzheimer’s biological diagnosis: a longitudinal study. Alzheimer’s research & therapy, 11(1), 57. PMC6599313 31253185 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“These analyses have identified variants in the TREM2 cluster as associated with these quantitative endophenotypes, as well as variants in the ABCA7 and FERMT2 gene regions [23, 211].”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD endophenotypes
What the sources say
- Not checked yetcites [23] Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, … Goate AM (2013). GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron, 78(2), 256– 268. 23562540 PMC3664945
- Not checked yetcites [211] Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, … Cruchaga C (2017). Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta neuropathologica, 133(5), 839– 856. 28247064 PMC5613285
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“studies have reported more rapid cognitive decline in women, increased susceptibility to neuropathology such that each unit increase of AD pathology confers a 22-fold increase in risk for AD in women compared to a 3-fold increase in males”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Sex-specific genetic architecture
What the sources say
- Not checked yetcites [262] Koran MEI, Wagener M, Hohman TJ, & Alzheimer’s Neuroimaging, Initiative. (2017). Sex differences in the association between AD biomarkers and cognitive decline. Brain imaging and behavior, 11(1), 205– 213. 26843008 PMC4972701
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“with aging, the efficacy of these systems is known to be reduced, providing a genomic environment in which TEs may become activated and contribute to somatic mutagenesis [244, 245]”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Somatic variation
What the sources say
- Not checked yetcites [244] Maxwell PH, Burhans WC, & Curcio MJ (2011). Retrotransposition is associated with genome instability during chronological aging. Proceedings of the National Academy of Sciences of the United States of America, 108(51), 20376– 20381. 22021441 PMC3251071 source
- Not checked yetcites [245] Li W, Prazak L, Chatterjee N, Gruninger S, Krug L, Theodorou D, & Dubnau J (2013). Activation of transposable elements during aging and neuronal decline in Drosophila. Nature neuroscience, 16(5), 529– 531. 23563579 PMC3821974 source
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A recent sex-stratified GWAS identified a male-specific protective variant located on chromosome 7 that conferred specific protection from tau pathology and was associated with delayed age at onset [263]”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Sex-specific genetic architecture
What the sources say
- Not checked yetcites [263] Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Bush WS, … Hohman TJ (2019). Sex differences in the genetic predictors of Alzheimer’s pathology. Brain: a journal of neurology, 142(9), 2581– 2589. 31497858 PMC6736148
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“APP gene duplications that result from trisomy of chromosome 21 (Down’s Syndrome) result in near-complete penetrance of AD neuropathology and increased incidence of dementia by age 30–40y [250, 251]”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Copy number variation
What the sources say
- Not checked yetcites [250] Wisniewski KE, Wisniewski HM, & Wen GY (1985). Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Annals of neurology, 17(3), 278– 282. 3158266 source
- Not checked yetcites [251] Menendez M (2005). Down syndrome, Alzheimer’s disease and seizures. Brain & development, 27(4), 246– 252. 15862185 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“APOE has been associated with sex-specific alterations in CSF tau levels and disease progression but not robustly with CSF Aβ1–42”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Sex-specific genetic architecture
What the sources say
- Not checked yetcites [258] Dumitrescu L, Mayeda ER, Sharman K, Moore AM, & Hohman TJ (2019). Sex Differences in the Genetic Architecture of Alzheimer’s Disease. Current genetic medicine reports, 7(1), 13– 21. 31360619 PMC6662731 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CNVs may alter gene dosage and have a profound impact on both gene and protein function.”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Copy number variation
What the sources say
- Not checked yetcites [247] Li W, & Olivier M (2013). Current analysis platforms and methods for detecting copy number variation. Physiological genomics, 45(1), 1– 16. 23132758 PMC3544484
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“One offspring of the affected patient inherited the PSEN1 mutation in all cells of her body and exhibited signs of dementia by age 27”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Somatic variation
What the sources say
- Not checked yetcites [236] Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF, … Tabrizi SJ (2004). Somatic and germline mosaicism in sporadic early-onset Alzheimer’s disease. Human molecular genetics, 13(12), 1219– 1224. 15115757
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Gene duplications of APP are well-known to cause AD, with as many as 25 duplications of variable length associated with AD in EOAD families [2]”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Copy number variation
What the sources say
- Not checked yetcites [2] Cacace R, Sleegers K, & Van Broeckhoven C (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 12(6), 733– 748. 27016693 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The patient was originally classified as negative for PSEN1 mutations after peripheral blood was drawn and blood DNA sequenced, but after DNA was obtained from the cerebral cortex, evidence of a cell-type specific mutation was observed.”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Somatic variation
What the sources say
- Not checked yetcites [236] Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF, … Tabrizi SJ (2004). Somatic and germline mosaicism in sporadic early-onset Alzheimer’s disease. Human molecular genetics, 13(12), 1219– 1224. 15115757
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“AD is well-known to be more prevalent among elderly females”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Sex-specific genetic architecture
What the sources say
- Not checked yetcites [1] Alzheimer’s Association. (2019). 2019 Alzheimer’s disease facts and figures. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 15(3), 321– 387.
- Not checked yetcites [257] Arias E, Xu J, & Kochanek KD (2019). United States Life Tables, 2016. National vital statistics reports: from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System, 68(4), 1– 66. 31112121
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“CNVs may span multiple genes and have a measurable impact on more than one target [247]”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Copy number variation
What the sources say
- Not checked yetcites [247] Li W, & Olivier M (2013). Current analysis platforms and methods for detecting copy number variation. Physiological genomics, 45(1), 1– 16. 23132758 PMC3544484
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“When TEs, especially retrotransposons, are activated, they mobilize through an RNA intermediate and can cause somatic mutations or large genomic rearrangements via their insertion into random segments of the genome [241, 242]”
§ Genetic architecture of Alzheimer’s disease > Genetic architecture of AD: beyond SNPs > Somatic variation
What the sources say
- Not checked yetcites [241] Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, De Sapio F, … Faulkner GJ (2011). Somatic retrotransposition alters the genetic landscape of the human brain. Nature, 479(7374), 534– 537. 22037309 PMC3224101 source
- Not checked yetcites [242] Upton KR, Gerhardt DJ, Jesuadian JS, Richardson SR, Sanchez-Luque FJ, Bodea GO, … Faulkner GJ (2015). Ubiquitous L1 mosaicism in hippocampal neurons. Cell, 161(2), 228– 239. 25860606 PMC4398972 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Hohman et al. [268] performed the most extensive analysis of gene-gene interactions in AD to date and identified three gene-gene combinations which significantly interact to determine an individual’s risk for AD”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Missing heritability of AD
What the sources say
- Not checked yetcites [268] Hohman TJ, Bush WS, Jiang L, Brown-Gentry KD, Torstenson ES, Dudek SM, … Alzheimer’s Disease Genetics, Consortium. (2016). Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiology of aging, 38, 141– 150. 26827652 PMC4735733 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Current estimates suggest only about 30–40% of the heritability of AD is explained by identified GWAS variants, leaving over 25% of the variance unexplained by known genetic factors [76]”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Missing heritability of AD
What the sources say
- Not checked yetcites [76] Ridge PG, Mukherjee S, Crane PK, Kauwe JS, & Alzheimer’s Disease Genetics, Consortium. (2013). Alzheimer’s disease: analyzing the missing heritability. PloS one, 8(11), e79771. 24244562 PMC3820606 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It has been shown that an individual’s genetics affects the impact of many of these risk factors on AD; for example, APOEε4 carriers with low self-reported exercise levels exhibited an increased risk for disease beyond those with either APOEε4 or low exercise alone [271]”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Missing heritability of AD
What the sources say
- Not checked yetcites [271] Luck T, Riedel-Heller SG, Luppa M, Wiese B, Kohler M, Jessen F, … Maier W (2014). Apolipoprotein E epsilon 4 genotype and a physically active lifestyle in late life: analysis of gene-environment interaction for the risk of dementia and Alzheimer’s disease dementia. Psychological medicine, 44(6), 1319– 1329. 23883793 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Some of this “missing heritability” can be attributed to low frequency variants not evaluated in the general population or to variations in the epigenetic profile of patients not captured by standard genetic evaluation”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Missing heritability of AD
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“innovative transplantation methods have been established to implant hematopoietic stem cells (microglia precursors) or microglia themselves directly into the brains of mouse models, where they have been shown to fully integrate and differentiate into mature microglia [278, 279, 283]”
§ Genetic architecture of Alzheimer’s disease > Additional Considerations > Use of model systems that reflect the genetic architecture of disease
What the sources say
- Not checked yetcites [278] McQuade A, Coburn M, Tu CH, Hasselmann J, Davtyan H, & Blurton-Jones M (2018). Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Molecular neurodegeneration, 13(1), 67. 30577865 PMC6303871
- Not checked yetcites [279] Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, … Blurton-Jones M (2017). iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron, 94(2), 278– 293 e9. 28426964 PMC5482419
- Not checked yetcites [283] Hasselmann J, Coburn MA, England W, Figueroa Velez DX, Kiani Shabestari S, Tu CH, … Blurton-Jones M (2019). Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo. Neuron, 103(6), 1016– 1033 e10. 31375314 PMC7138101
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit relatively large effects on disease susceptibility, with the remaining implicated loci having a much smaller individual impact on AD risk.”
§ Genetic architecture of Alzheimer’s disease > Conclusions and future directions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
The paper relies on this without support.
GWAS SNPs simply act as tagging variants for a given risk locus and are often not themselves the causal variants.
“GWAS SNPs simply act as tagging variants for a given risk locus and are often not themselves the causal variants.”
The paper relies on this without support.
Standard GWAS often suffer from being under-powered to identify true associations and may miss variants modifying disease risk.
“standard GWAS often suffer from being under-powered to identify true associations and as such, may miss variants modifying disease risk.”
The paper relies on this without support.
Aβ-targeting strategies have largely failed to produce disease-modifying therapeutics.
“Aβ-targeting strategies have largely failed to produce disease-modifying therapeutics”
The paper relies on this without support.
GWAS variants often fall within regions of high LD such that multiple non-causal variants are inherited together with putative causal variant(s).
“GWAS variants often fall within regions of high LD such that multiple non-causal variants are inherited together with putative causal variant(s).”
The paper relies on this without support.
The brain is the organ most affected in AD, and regulation of gene expression in this tissue is important for disease pathogenesis.
“the brain is still the organ most affected in AD, and the regulation of gene expression in this critical tissue is undoubtedly important for disease pathogenesis.”
The paper relies on this without support.
Mouse and human share strong biochemical, developmental, physiological, and genetic similarities sufficient for mouse models to inform AD research.
“Due to the strong biochemical, developmental, physiological, and genetic similarities between the mouse and human, the mouse represents an incredible resource for neuroscience research”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“According to studies, having these gene mutations practically guarantees that a person will develop the sickness [39,40,41].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [40]
Citations
Cites
McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Kawas, C. H., Klunk, W. E., Koroshetz, W. J., Manly, J. J., Mayeux, R., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.005 · Cited by 18,657 · cited 1×
“AD usually presents with deficits in short-term memory formation and disturbance of additional cognitive functions including word-finding, spatial orientation, reasoning, judgement, and problem-solving (Karantzoulis and Galvin, 2011; McKhann et al., 2011).”
BackgroundCorder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484 · cited 1×
“Together, this evidence has led to the development of the “amyloid cascade hypothesis” which posits that amyloid deposition is an initial causative event in a cascade of symptoms resulting in neurodegeneration and cognitive decline (Hardy and Higgins, 1992).”
BackgroundIntegrative analysis of 111 reference human epigenomes
Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. (2015) · Nature · doi:10.1038/nature14248 · Cited by 6,368 · cited 2×
“This search has been facilitated by large-scale annotation projects such as the Roadmap Epigenomics Project (Roadmap Epigenomics, Consortium, et al., 2015), the Blueprint Project (Fernandez et al., 2016), and PsychENCODE (Psych, Encode Consortium, et al., 2015).”
MethodDementia prevention, intervention, and care
Livingston, G., Sommerlad, A., Orgeta, V., Costafreda, S. G., Huntley, J., Ames, D., Ballard, C., Banerjee, S., Burns, A., Cohen-Mansfield, J., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31363-6 · Cited by 6,072 · cited 1×
“Several modifiable risk factors have been associated with AD risk across populations, including educational attainment, obesity, cholesterol levels, social isolation, alcohol consumption, and exposure to pesticides (Eid et al., 2019; Livingston et al., 2017).”
BackgroundCommon polygenic variation contributes to risk of schizophrenia and bipolar disorder
The International Schizophrenia Consortium (2009) · Nature · doi:10.1038/nature08185 · Cited by 4,821 · cited 1×
“Approaches to better understand how many associated variants may act together to predict risk of disease were first developed by the International Schizophrenia Consortium in 2009 [117].”
BackgroundMeta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · cited 3×
“These studies have since been expanded and many loci replicated across studies and sample sets (Naj et al., 2011; Hollingworth et al., 2011; Seshadri et al., 2010; Lambert et al., 2013), see Fig.”
BackgroundSelf-citationCloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) · Nature · doi:10.1038/375754a0 · Cited by 4,051
Systematic Localization of Common Disease-Associated Variation in Regulatory DNA
Maurano, M. T., Humbert, R., Rynes, E., Thurman, R. E., Haugen, E., Wang, H., Reynolds, A. P., Sandstrom, R., Qu, H., Brody, J., et al. (2012) · Science · doi:10.1126/science.1222794 · Cited by 3,716 · cited 2×
“Histone modifications can reliably be measured across the genome using chromatin immunoprecipitation followed by sequencing (ChIP-seq), while chromatin accessibility is typically measured by either DNase hypersensitivity analysis (DNase-seq) (Maurano et al., 2012) or assay for transposaseaccessible chromatin using seq…”
BackgroundMethodApolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · cited 8×
“Of the three alleles, APOEε3 is the most common in all human populations, present in almost 80% of individuals (Liu et al., 2013).”
BackgroundInfluentialNeuropathological alterations in Alzheimer disease
Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006189 · Cited by 3,345
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · cited 2×
“beneficial functions in the brain such as clearance of cellular debris and orchestration of appropriate immune responses, their chronic activation can lead to toxic neuroinflammation and aberrant pruning of synapses [203, 204].”
BackgroundThe neuropathological diagnosis of Alzheimer's disease
DeTure, M. A., & Dickson, D. W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0333-5 · Cited by 3,329 · cited 2×
“the onset, duration, and severity of symptoms across multiple functional domains and may experience deficits in cognitive function, speech, mood regulation and psychosis, motor function, and regulation of circadian rhythms [275].”
BackgroundHarold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326 · cited 1×
“The larger of these, involving over 16,000 individuals, identified SNPs on chromosomes 8 and 11 as significantly associated with disease risk (Harold et al., 2009).”
BackgroundSelf-citationATAC-seq: a method for assaying chromatin accessibility genome-wide
Buenrostro, J. D., Wu, B., Chang, H. Y., & Greenleaf, W. J. (2015) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb2129s109 · Cited by 3,289 · cited 1×
“…using chromatin immunoprecipitation followed by sequencing (ChIP-seq), while chromatin accessibility is typically measured by either DNase hypersensitivity analysis (DNase-seq) (Maurano et al., 2012) or assay for transposaseaccessible chromatin using sequencing (ATAC-seq) (Buenrostro et al., 2015).”
MethodTREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Self-citationAlzheimer Disease Genetics Consortium (ADGC), Kunkle, B. W., The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0358-2 · Cited by 2,946
The molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708 · cited 2×
“In addition to clinical symptoms, AD is characterized by specific pathological features (Selkoe, 1991).”
BackgroundPartitioning heritability by functional annotation using genome-wide association summary statistics
ReproGen Consortium, Finucane, H. K., Schizophrenia Working Group of the Psychiatric Genomics Consortium, The RACI Consortium, Bulik-Sullivan, B., Gusev, A., Trynka, G., Reshef, Y., Loh, P.-R., Anttila, V., et al. (2015) · Nature Genetics · doi:10.1038/ng.3404 · Cited by 2,604 · cited 1×
“(Finucane et al., 2015) for partitioning the genome into functional categories based on publicly available annotation data.”
BackgroundVariant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · cited 24×
“Common variants in the MS4A gene cluster were shown to significantly regulate sTREM2 levels in CSF (Deming et al., 2019), demonstrating regulation of this endophenotype is orchestrated by genetic variants that also modify risk for disease.”
BackgroundInfluential2019 Alzheimer’s disease facts and figures.
Alzheimer's Association (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.01.010 · Cited by 2,461 · cited 2×
“Sex-specific genetic architecture AD is well-known to be more prevalent among elderly females, although it has been difficult to elucidate whether this is simply attributable to the longer lifespan of women (Alzheimer's Association, 2019; Arias et al., 2019).”
BackgroundZhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S. B., Li, G., et al. (2016) · Neuron · doi:10.1016/j.neuron.2015.11.013 · Cited by 2,295 · cited 1×
“SORL1, a sorting receptor located in neurons [152], astrocytes, and microglia [153] is known to direct APP toward non-amyloidogenic processing in the trans-Golgi network [148, 154].”
Jansen, I. E., Savage, J. E., Watanabe, K., Bryois, J., Williams, D. M., Steinberg, S., Sealock, J., Karlsson, I. K., Hägg, S., Athanasiu, L., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0311-9 · Cited by 2,277 · cited 5×
“Interpretation of GWAS hits is made more straightforward when GWAS SNPs themselves or nearby variants in high LD are located within coding regions of the genome, although this happens relatively infrequently (Kunkle et al., 2019; Jansen et al., 2019).”
BackgroundResultInfluentialGenome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234 · cited 6×
“CNVs have also been identified as modifying risk for LOAD; a functional CNV in the gene CR1 modifying isoform production was shown to increase risk for LOAD in two populations (Brouwers et al., 2012), among others (Swaminathan et al., 2012; Szigeti et al., 2013; Heinzen et al., 2010).”
BackgroundInfluentialRogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., et al. (1995) · Nature · doi:10.1038/376775a0 · Cited by 2,052 · cited 1×
“The first disease-causative mutations in these genes were identified in 1995 [42, 43], although it”
BackgroundOlsson, B., Lautner, R., Andreasson, U., Öhrfelt, A., Portelius, E., Bjerke, M., Hölttä, M., Rosén, C., Olsson, C., Strobel, G., et al. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00070-3 · Cited by 2,049
Initiative, T. A. D. N., Hollingworth, P., CHARGE consortium, EADI1 consortium, Harold, D., Sims, R., Gerrish, A., Lambert, J.-C., Carrasquillo, M. M., Abraham, R., et al. (2011) · Nature Genetics · doi:10.1038/ng.803 · Cited by 1,997 · cited 1×
“These studies have since been expanded and many loci replicated across studies and sample sets (Naj et al., 2011; Hollingworth et al., 2011; Seshadri et al., 2010; Lambert et al., 2013), see Fig.”
BackgroundSelf-citationNaj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · cited 1×
“These studies have since been expanded and many loci replicated across studies and sample sets (Naj et al., 2011; Hollingworth et al., 2011; Seshadri et al., 2010; Lambert et al., 2013), see Fig.”
BackgroundSelf-citationApolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836
Microglia emerge as central players in brain disease
Salter, M. W., & Stevens, B. (2017) · Nature Medicine · doi:10.1038/nm.4397 · Cited by 1,767 · cited 1×
“beneficial functions in the brain such as clearance of cellular debris and orchestration of appropriate immune responses, their chronic activation can lead to toxic neuroinflammation and aberrant pruning of synapses [203, 204].”
A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012) · Nature · doi:10.1038/nature11283 · Cited by 1,738 · cited 1×
“In contrast, a protective mutation in APP (A673T) identified in the Icelandic population (Jonsson et al., 2012) results in approximately a 40% reduction in the formation of amyloidogenic peptides.”
BackgroundGene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
Escott-Price, V., Bellenguez, C., Wang, L.-S., Choi, S.-H., Harold, D., Jones, L., Holmans, P., Gerrish, A., Vedernikov, A., Richards, A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094661 · Cited by 1,398
Self-citationArnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., & Van Hoesen, G. W. (1991) · Cerebral Cortex · doi:10.1093/cercor/1.1.103 · Cited by 1,380 · cited 1×
“Intracellular aggregates composed of hyperphosphorylated forms of the microtubule-associated protein tau (encoded by the MAPT gene), often referred to as neurofibrillary tangles, also accumulate primarily in neurons, although they have been reported in other cell types of the brain (Braak and Braak, 1998; Arnold et al…”
BackgroundAmyloid, the presenilins and Alzheimer’s disease
Hardy, J. (1997) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)01030-2 · Cited by 1,370 · cited 2×
“First described by Alois Alzheimer in 1906 (Hippius and Neundorfer, 2003), AD is a neurodegenerative disease defined by the presence of extracellular plaques primarily composed of beta-amyloid (Aβ) protein, a byproduct of sequential cleavage of the amyloid precursor protein (APP) by the enzymatic complexes beta (β) an…”
BackgroundAlzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357 · cited 1×
“This approach has prioritized genes enriched for several major biological pathways including lipid metabolism, immune response, regulation of endocytosis, and protein ubiquitination, implicating these pathways in disease pathogenesis (Karch et al., 2014; Karch and Goate, 2015).”
BackgroundSelf-citationCitron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-wood, K., Lee, M., Seubert, P., Davis, A., et al. (1997) · Nature Medicine · doi:10.1038/nm0197-67 · Cited by 1,271
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,242
Self-citationMueller, S. G., Weiner, M. W., Thal, L. J., Petersen, R. C., Jack, C. R., Jagust, W., Trojanowski, J. Q., Toga, A. W., & Beckett, L. (2005) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2005.06.003 · Cited by 1,233 · cited 1×
“clinicians to obtain accurate estimates of these features in living patients (Mueller et al., 2005), which has aided in the clinical diagnosis of AD.”
BackgroundGenome-wide Analysis of Genetic Loci Associated With Alzheimer Disease
Seshadri, S. (2010) · JAMA · doi:10.1001/jama.2010.574 · Cited by 1,219 · cited 1×
“Seshadri, S., Fitzpatrick, A.L., Ikram, M.A., DeStefano, A.L., Gudnason, V., Boada, M, ... Eadi Consortium, 2010.”
Chapter 11: Genome-wide association studies
Bush, W. S., & Moore, J. H. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002822 · Cited by 1,171
The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease
Rogaeva, E., Meng, Y., Lee, J. H., Gu, Y., Kawarai, T., Zou, F., Katayama, T., Baldwin, C. T., Cheng, R., Hasegawa, H., et al. (2007) · Nature Genetics · doi:10.1038/ng1943 · Cited by 1,167
Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome
Wisniewski, K. E., Wisniewski, H. M., & Wen, G. Y. (1985) · Annals of Neurology · doi:10.1002/ana.410170310 · Cited by 1,159 · cited 1×
“In addition, APP gene duplications that result from trisomy of chromosome 21 (Down's Syndrome) result in nearcomplete penetrance of AD neuropathology and increased incidence of dementia by age 30-40 years (Wisniewski et al., 1985; Menendez, 2005).”
BackgroundiPSC-derived human microglia-like cells to study neurological diseases
Abud, E. M., Ramirez, R. N., Martinez, E. S., Healy, L. M., Nguyen, C. H. H., Newman, S. A., Yeromin, A. V., Scarfone, V. M., Marsh, S. E., Fimbres, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.03.042 · Cited by 1,154 · cited 2×
“To this end, innovative transplantation methods have been established to implant hematopoietic precursor cells or microglia themselves directly into the brains of mouse models, where they have been shown to fully integrate and differentiate into mature microglia (McQuade et al., 2018; Abud et al., 2017; Hasselmann et…”
BackgroundMethodPatterns of linkage disequilibrium in the human genome
Ardlie, K., Kruglyak, L., & Seielstad, M. T. (2002) · Nature Reviews Genetics · doi:10.1038/nrg777 · Cited by 1,133 · cited 2×
“GWAS take advantage of the linkage disequilibrium (LD) structure across the human genome, where large blocks of the genome are inherited together [77].”
BackgroundReview Article: Genetics of Alzheimer Disease
Bekris, L. M., Yu, C.-E., Bird, T. D., & Tsuang, D. W. (2010) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988710383571 · Cited by 1,029 · cited 6×
“The first disease-causative mutations in these genes were identified in 1995 (Rogaev et al., 1995; Sherrington et al., 1995), although it wasn't until 2000 that it was discovered these proteins are critical subunits of the γ-secretase complex responsible for processing of APP (Kopan and Goate, 2000; Esler et al., 2000…”
BackgroundInfluentialClinical epidemiology of Alzheimer’s disease: assessing sex and gender differences
Mielke, M., Vemuri, P., & Rocca, W. (2014) · Clinical Epidemiology · doi:10.2147/clep.s37929 · Cited by 1,021 · cited 1×
“Notable sex differences in the clinical and pathological presentation between the sexes exist, each of which have been extensively reviewed previously (Dumitrescu et al., 2019a; Mielke et al., 2014; Laws et al., 2018; Laws et al., 2016).”
BackgroundARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,012
Li, Y., Willer, C., Sanna, S., & Abecasis, G. (2009) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.9.081307.164242 · Cited by 990 · cited 2×
“to be captured by standard SNP genotyping or imputation using the publicly available reference resources [79].”
BackgroundMethodMurray, M. E., Graff-Radford, N. R., Ross, O. A., Petersen, R. C., Duara, R., & Dickson, D. W. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70156-9 · Cited by 972 · cited 2×
“This has led many to attempt to identify distinct subtypes of AD (Murray et al., 2011; Petersen, 1998).”
BackgroundAlzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
De Jager, P. L., Srivastava, G., Lunnon, K., Burgess, J., Schalkwyk, L. C., Yu, L., Eaton, M. L., Keenan, B. T., Ernst, J., McCabe, C., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3786 · Cited by 956 · cited 1×
“gene as associated with the burden of AD pathology [198, 199].”
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943
Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
Li, Y.-M., Xu, M., Lai, M.-T., Huang, Q., Castro, J. L., DiMuzio-Mower, J., Harrison, T., Lellis, C., Nadin, A., Neduvelil, J. G., et al. (2000) · Nature · doi:10.1038/35015085 · Cited by 866 · cited 1×
“…et al., 1995), although it wasn't until 2000 that it was discovered these proteins are critical subunits of the γ-secretase complex responsible for processing of APP (Kopan and Goate, 2000; Esler et al., 2000; Li et al., 2000) and other membrane-bound proteins such as NOTCH (Bekris et al., 2010).”
BackgroundThe genetic landscape of Alzheimer disease: clinical implications and perspectives
Van Cauwenberghe, C., Van Broeckhoven, C., & Sleegers, K. (2016) · Genetics in Medicine · doi:10.1038/gim.2015.117 · Cited by 863 · cited 1×
“expressed; high expression is observed in the liver, brain, and peripheral immune cells including monocytes and macrophages [55].”
BackgroundCampion, D., Dumanchin, C., Hannequin, D., Dubois, B., Belliard, S., Puel, M., Thomas-Anterion, C., Michon, A., Martin, C., Charbonnier, F., et al. (1999) · The American Journal of Human Genetics · doi:10.1086/302553 · Cited by 785
Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression
Fairfax, B. P., Humburg, P., Makino, S., Naranbhai, V., Wong, D., Lau, E., Jostins, L., Plant, K., Andrews, R., McGee, C., et al. (2014) · Science · doi:10.1126/science.1246949 · Cited by 764
Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage.
(1991) · Europe PMC (PubMed Central) · Cited by 758
Brain cell type–specific enhancer–promoter interactome maps and disease - risk association
Nott, A., Holtman, I. R., Coufal, N. G., Schlachetzki, J. C. M., Yu, M., Hu, R., Han, C. Z., Pena, M., Xiao, J., Wu, Y., et al. (2019) · Science · doi:10.1126/science.aay0793 · Cited by 699 · cited 2×
“This is supported by a recent identification of the enrichment of AD-associated variants in enhancers active in primary human microglia [192].”
Somatic retrotransposition alters the genetic landscape of the human brain
Baillie, J. K., Barnett, M. W., Upton, K. R., Gerhardt, D. J., Richmond, T. A., De Sapio, F., Brennan, P. M., Rizzu, P., Smith, S., Fell, M., et al. (2011) · Nature · doi:10.1038/nature10531 · Cited by 684 · cited 1×
“When TEs, especially retrotransposons, are activated, they mobilize through an RNA intermediate and can cause somatic mutations or large genomic rearrangements via their insertion into random segments of the genome (Baillie et al., 2011; Upton et al., 2015).”
BackgroundEarly Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain
Ingelsson, M., Fukumoto, H., Newell, K. L., Growdon, J. H., Hedley–Whyte, E. T., Frosch, M. P., Albert, M. S., Hyman, B. T., & Irizarry, M. C. (2004) · Neurology · doi:10.1212/01.wnl.0000115115.98960.37 · Cited by 666 · cited 1×
“Interestingly, markers of gliosis seem to linearly increase across the course of disease despite a plateau in plaque pathology, suggesting independent mechanisms drive each cellular phenotype (Ingelsson et al., 2004).”
Sunderland, T., Linker, G., Mirza, N., Putnam, K. T., Friedman, D. L., Kimmel, L. H., Bergeson, J., Manetti, G. J., Zimmermann, M., Tang, B., et al. (2003) · JAMA · doi:10.1001/jama.289.16.2094 · Cited by 656 · cited 1×
“Research has shown that measurements of Aβ and tau in cerebrospinal fluid (CSF) exhibit high diagnostic sensitivity, with low levels of CSF Aβ42 and high levels of total tau or phosphorylated tau (particularly p-tau181) capable of differentiating AD from mild cognitive impairment and other dementias such as frontotemp…”
BackgroundA 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease
Park, J., Wetzel, I., Marriott, I., Dréau, D., D’Avanzo, C., Kim, D. Y., Tanzi, R. E., & Cho, H. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0175-4 · Cited by 644 · cited 1×
“culture [280] and the development of brain organoids is likely to greatly contribute to our understanding of how these cells contribute to disease [281].”
BackgroundStrategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
Frisoni, G. B., Boccardi, M., Barkhof, F., Blennow, K., Cappa, S., Chiotis, K., Démonet, J.-F., Garibotto, V., Giannakopoulos, P., Gietl, A., et al. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30159-x · Cited by 626
Dynamic interactions between transposable elements and their hosts
Levin, H. L., & Moran, J. V. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3030 · Cited by 621 · cited 1×
“Under normal conditions, surveillance mechanisms including those associated with DNA repair and chromatin remodeling function to repress TE activity and largely maintain genomic stability (Levin and Moran, 2011).”
BackgroundMolecular genetics of early-onset Alzheimer’s disease revisited
Cacace, R., Sleegers, K., & Van Broeckhoven, C. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.01.012 · Cited by 617
Lanoiselée, H.-M., Nicolas, G., Wallon, D., Rovelet-Lecrux, A., Lacour, M., Rousseau, S., Richard, A.-C., Pasquier, F., Rollin-Sillaire, A., Martinaud, O., et al. (2017) · PLOS Medicine · doi:10.1371/journal.pmed.1002270 · Cited by 616 · cited 1×
“…in these genes are typically thought to be inherited in an autosomal dominant fashion, de novo variants in APP, PSEN1, and PSEN2 have also been identified by sequencing in sporadic cases of EOAD that occur with no family history of disease (Lanoiselee et al., 2017; Rovelet-Lecrux et al., 2015).”
BackgroundApolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800069-jlr200 · Cited by 580
Defining mechanisms that regulate RNA polymerase II transcription in vivo
Fuda, N. J., Ardehali, M. B., & Lis, J. T. (2009) · Nature · doi:10.1038/nature08449 · Cited by 576 · cited 1×
“For example, promoters proximal to the transcription start site of protein coding genes can recruit the binding of specific transcription factors, activators, or repressors (Fuda et al., 2009).”
BackgroundMethylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease
Lunnon, K., Smith, R., Hannon, E., De Jager, P. L., Srivastava, G., Volta, M., Troakes, C., Al-Sarraj, S., Burrage, J., Macdonald, R., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3782 · Cited by 574 · cited 1×
“, 2015), and two independent genome-wide studies recently identified a differentially methylated region in the ANK1 gene as associated with the burden of AD pathology (Lunnon et al., 2014; De Jager et al., 2014).”
Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.
Busciglio, J., Gabuzda, D. H., Matsudaira, P., & Yankner, B. A. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.2092 · Cited by 569 · cited 1×
“For example, mutations occurring near the β-secretase cleavage site, such as the Swedish mutation (K670N/ M671L), appear to result in increased production of total Aβ (Busciglio et al., 1993; Citron et al., 1994).”
BackgroundCoon, K. D., Myers, A. J., Craig, D. W., Webster, J. A., Pearson, J. V., Lince, D. H., Zismann, V. L., Beach, T. G., Leung, D., Bryden, L., et al. (2007) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v68n0419 · Cited by 569 · cited 1×
“The first association studies covering most of the genome were published in 2007 [81, 82].”
BackgroundHopperton, K. E., Mohammad, D., Trépanier, M. O., Giuliano, V, & Bazinet, R. P. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.246 · Cited by 567 · cited 1×
“gliosis) has been described, especially in close proximity to plaques (Beach et al., 1989; Serrano-Pozo et al., 2011; Hopperton et al., 2018) .”
BackgroundGWAS on family history of Alzheimer’s disease
Marioni, R. E., Harris, S. E., Zhang, Q., McRae, A. F., Hagenaars, S. P., Hill, W. D., Davies, G., Ritchie, C. W., Gale, C. R., Starr, J. M., et al. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0150-6 · Cited by 564 · cited 5×
“Together, these approaches show substantial genetic overlap with previous case-control GWAS and nominate a number of novel loci associated with proxy risk for AD (Liu et al., 2017; Jansen et al., 2019; Marioni et al., 2018).”
BackgroundResultInfluentialSelf-citationEllis, R. J., Olichney, J. M., Thal, L. J., Mirra, S. S., Morris, J. C., Beekly, D., & Heyman, A. (1996) · Neurology · doi:10.1212/wnl.46.6.1592 · Cited by 561
Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort
Risacher, S., Saykin, A., Wes, J., Shen, L., Firpi, H., & McDonald, B. (2009) · Current Alzheimer Research · doi:10.2174/156720509788929273 · Cited by 538 · cited 1×
“they reliably predict cognitive decline [222], are heritable [223, 224], and are readily quantifiable by magnetic resonance imaging (MRI).”
Suárez‐Calvet, M., Kleinberger, G., Araque Caballero, M. Á., Brendel, M., Rominger, A., Alcolea, D., Fortea, J., Lleó, A., Blesa, R., Gispert, J. D., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201506123 · Cited by 522
Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism
Mahley, R. W. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.307023 · Cited by 516 · cited 1×
“Several factors implicate cholesterol metabolism in the pathogenesis of AD; a major role of APOE is to facilitate the transport of cholesterol from astrocytes to neurons in the CNS (Mahley, 2016).”
BackgroundThe discovery of Alzheimer's disease
Hippius, H., & Neundörfer, G. (2003) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2003.5.1/hhippius · Cited by 516 · cited 1×
“First described by Alois Alzheimer in 1906 (Hippius and Neundorfer, 2003), AD is a neurodegenerative disease defined by the presence of extracellular plaques primarily composed of beta-amyloid (Aβ) protein, a byproduct of sequential cleavage of the amyloid precursor protein (APP) by the enzymatic complexes beta (β) an…”
BackgroundTransition-state analogue inhibitors of γ-secretase bind directly to presenilin-1
Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Diehl, T. S., Moore, C. L., Tsai, J.-Y., Rahmati, T., Xia, W., Selkoe, D. J., & Wolfe, M. S. (2000) · Nature Cell Biology · doi:10.1038/35017062 · Cited by 514
Bertram, L., Lange, C., Mullin, K., Parkinson, M., Hsiao, M., Hogan, M. F., Schjeide, B. M. M., Hooli, B., DiVito, J., Ionita, I., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.10.008 · Cited by 511 · cited 1×
“In fact, seven of the earliest GWAS, each of which used less than 2000 cases, identified only APOE as significantly associated with AD (Feulner et al., 2010; Carrasquillo et al., 2009; Beecham et al., 2009; Bertram et al., 2008; Li et al., 2008; Abraham et al., 2008; Liu et al., 2007).”
BackgroundPolarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes
Raj, T., Rothamel, K., Mostafavi, S., Ye, C., Lee, M. N., Replogle, J. M., Feng, T., Lee, M., Asinovski, N., Frohlich, I., et al. (2014) · Science · doi:10.1126/science.1249547 · Cited by 506
Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis
Ryman, D. C., Acosta-Baena, N., Aisen, P. S., Bird, T., Danek, A., Fox, N. C., Goate, A., Frommelt, P., Ghetti, B., Langbaum, J. B. S., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000596 · Cited by 502 · cited 1×
“PSEN mutations [276], suggesting additional factors such as background genetic modifiers or even non-genetic lifestyle factors play a substantial role in dictating disease risk and severity.”
Self-citationCandidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease
Li, H., Wetten, S., Li, L., St. Jean, P. L., Upmanyu, R., Surh, L., Hosford, D., Barnes, M. R., Briley, J. D., Borrie, M., et al. (2008) · Archives of Neurology · doi:10.1001/archneurol.2007.3 · Cited by 499 · cited 1×
“In fact, seven of the earliest GWAS, each of which used less than 2000 cases, identified only APOE as significantly associated with AD (Feulner et al., 2010; Carrasquillo et al., 2009; Beecham et al., 2009; Bertram et al., 2008; Li et al., 2008; Abraham et al., 2008; Liu et al., 2007).”
BackgroundEvolution of neuronal changes in the course of Alzheimer’s disease
Braak, H., & Braak, E. (1998) · Journal of neural transmission. Supplementum · doi:10.1007/978-3-7091-6467-9_11 · Cited by 493 · cited 2×
“…of hyperphosphorylated forms of the microtubule-associated protein tau (encoded by the MAPT gene), often referred to as neurofibrillary tangles, also accumulate primarily in neurons, although they have been reported in other cell types of the brain (Braak and Braak, 1998; Arnold et al., 1991).”
BackgroundGAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers
Reiman, E. M., Webster, J. A., Myers, A. J., Hardy, J., Dunckley, T., Zismann, V. L., Joshipura, K. D., Pearson, J. V., Hu-Lince, D., Huentelman, M. J., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.022 · Cited by 487 · cited 1×
“The first association studies covering most of the genome were published in 2007 (Coon et al., 2007; Reiman et al., 2007).”
BackgroundThe endophenotype concept in psychiatric genetics
FLINT, J., & MUNAFÒ, M. R. (2007) · Psychological Medicine · doi:10.1017/s0033291706008750 · Cited by 477
Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., Chen, Y., Su, Y., Myers, A. J., Hardy, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14279-8 · Cited by 473
Self-citationAlzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473 · cited 1×
“This approach has prioritized genes enriched for several major biological pathways including lipid metabolism, immune response, regulation of endocytosis, and protein ubiquitination, implicating these pathways in disease pathogenesis (Karch et al., 2014; Karch and Goate, 2015).”
BackgroundSelf-citationRare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease
Cruchaga, C., Karch, C. M., Jin, S. C., Benitez, B. A., Cai, Y., Guerreiro, R., Harari, O., Norton, J., Budde, J., Bertelsen, S., et al. (2014) · Nature · doi:10.1038/nature12825 · Cited by 461
Self-citationEarly-Versus Late-Onset Alzheimer's Disease: More than Age Alone
Koedam, E. L. G. E., Lauffer, V., van der Vlies, A. E., van der Flier, W. M., Scheltens, P., & Pijnenburg, Y. A. L. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1337 · Cited by 452 · cited 1×
“While EOAD and LOAD have traditionally been considered distinct (Smits et al., 2012; Koedam et al., 2010), this review will consider the underlying genetic architecture of both forms of the disease, which in recent years has come to highlight a significant overlap between the subtypes.”
BackgroundAkbarian, S., Liu, C., Knowles, J. A., Vaccarino, F. M., Farnham, P. J., Crawford, G. E., Jaffe, A. E., Pinto, D., Dracheva, S., Geschwind, D. H., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4156 · Cited by 451
Practical considerations for choosing a mouse model of Alzheimer’s disease
Jankowsky, J. L., & Zheng, H. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0231-7 · Cited by 449 · cited 1×
“Due to the strong biochemical, developmental, physiological, and genetic similarities between the mouse and human, the mouse represents an incredible resource for neuroscience research and has been used for decades to gain insight into mechanisms underlying the development of AD in vivo (Esquerda-Canals et al., 2017;…”
BackgroundMcQuade, A., Coburn, M., Tu, C. H., Hasselmann, J., Davtyan, H., & Blurton-Jones, M. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0297-x · Cited by 449 · cited 2×
“To this end, innovative transplantation methods have been established to implant hematopoietic precursor cells or microglia themselves directly into the brains of mouse models, where they have been shown to fully integrate and differentiate into mature microglia (McQuade et al., 2018; Abud et al., 2017; Hasselmann et…”
BackgroundMethodSaykin, A. J., Shen, L., Foroud, T. M., Potkin, S. G., Swaminathan, S., Kim, S., Risacher, S. L., Nho, K., Huentelman, M. J., Craig, D. W., et al. (2010) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2010.03.013 · Cited by 442
A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease
The International Genomics of Alzheimer's Project, Huang, K.-L., Initiative, T. A. D. N., Marcora, E., Pimenova, A. A., Di Narzo, A. F., Kapoor, M., Jin, S. C., Harari, O., Bertelsen, S., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4587 · Cited by 423
Self-citationJun, G. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.201 · Cited by 422 · cited 1×
“, 2016), while variants in the PICALM region exhibit stronger associations in APOE ε4+ subjects (Jun et al., 2010), further suggesting independent mechanisms may partially contribute to AD across APOE genotypes.”
BackgroundCommon polygenic variation enhances risk prediction for Alzheimer’s disease
Escott-Price, V., Sims, R., Bannister, C., Harold, D., Vronskaya, M., Majounie, E., Badarinarayan, N., GERAD/PERADES, consortia, I., Morgan, K., et al. (2015) · Brain · doi:10.1093/brain/awv268 · Cited by 414
Self-citationHeritability for Alzheimer’s disease: the study of dementia in Swedish twins
Gatz, M., Pedersen, N. L., Berg, S., Johansson, B., Johansson, K., Mortimer, J. A., Posner, S. F., Viitanen, M., Winblad, B., & Ahlbom, A. (1997) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/52a.2.m117 · Cited by 413 · cited 2×
“Estimates of heritability for EOAD are as high as 90–100% (Wingo et al., 2012), while heritability estimates for LOAD are slightly lower, in the range of 60–80% (Gatz et al., 1997).”
BackgroundDesikan, R. S., Fan, C. C., Wang, Y., Schork, A. J., Cabral, H. J., Cupples, L. A., Thompson, W. K., Besser, L., Kukull, W. A., Holland, D., et al. (2017) · PLoS Medicine · doi:10.1371/journal.pmed.1002258 · Cited by 395
Distinguishing Alzheimer’s disease from other major forms of dementia
Karantzoulis, S., & Galvin, J. E. (2011) · Expert Review of Neurotherapeutics · doi:10.1586/ern.11.155 · Cited by 385 · cited 1×
“AD usually presents with deficits in short-term memory formation and disturbance of additional cognitive functions including word-finding, spatial orientation, reasoning, judgement, and problem-solving (Karantzoulis and Galvin, 2011; McKhann et al., 2011).”
BackgroundGWAS of Cerebrospinal Fluid Tau Levels Identifies Risk Variants for Alzheimer’s Disease
Cruchaga, C., Kauwe, J. S. K., Harari, O., Jin, S. C., Cai, Y., Karch, C. M., Benitez, B. A., Jeng, A. T., Skorupa, T., Carrell, D., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.026 · Cited by 383
Self-citationDevelopment of a Chimeric Model to Study and Manipulate Human Microglia In Vivo
Hasselmann, J., Coburn, M. A., England, W., Figueroa Velez, D. X., Kiani Shabestari, S., Tu, C. H., McQuade, A., Kolahdouzan, M., Echeverria, K., Claes, C., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.07.002 · Cited by 380 · cited 2×
“…methods have been established to implant hematopoietic precursor cells or microglia themselves directly into the brains of mouse models, where they have been shown to fully integrate and differentiate into mature microglia (McQuade et al., 2018; Abud et al., 2017; Hasselmann et al., 2019).”
Potkin, S. G., Guffanti, G., Lakatos, A., Turner, J. A., Kruggel, F., Fallon, J. H., Saykin, A. J., Orro, A., Lupoli, S., Salvi, E., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006501 · Cited by 376 · cited 1×
“…previously implicated in AD (including APOE and PICALM (Furney et al., 2011)) have been associated with imaging endophenotypes, a large number of novel loci and genes have been nominated by these analyses (Risacher et al., 2009; Furney et al., 2011; Potkin et al., 2009; Stein et al., 2010) (Fig.”
BackgroundThe impact of rare and low-frequency genetic variants in common disease
Bomba, L., Walter, K., & Soranzo, N. (2017) · Genome biology · doi:10.1186/s13059-017-1212-4 · Cited by 369 · cited 1×
“However, if variants are rare (minor allele occurs in less than 1% of the general population (Bomba et al., 2017)), they are unlikely to be captured by standard SNP genotyping or imputation using the publicly available reference resources [79].”
BackgroundCitron, M., Vigo-Pelfrey, C., Teplow, D. B., Miller, C., Schenk, D., Johnston, J., Winblad, B., Venizelos, N., Lannfelt, L., & Selkoe, D. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.25.11993 · Cited by 366
Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors
Zelcer, N., Khanlou, N., Clare, R., Jiang, Q., Reed-Geaghan, E. G., Landreth, G. E., Vinters, H. V., & Tontonoz, P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701096104 · Cited by 358
Weiner, M. W., Veitch, D. P., Aisen, P. S., Beckett, L. A., Cairns, N. J., Cedarbaum, J., Green, R. C., Harvey, D., Jack, C. R., Jagust, W., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.11.001 · Cited by 348
Activation of transposable elements during aging and neuronal decline in Drosophila
Li, W., Prazak, L., Chatterjee, N., Grüninger, S., Krug, L., Theodorou, D., & Dubnau, J. (2013) · Nature Neuroscience · doi:10.1038/nn.3368 · Cited by 346 · cited 2×
“However, with aging, the efficacy of these systems is known to be reduced, providing a genomic environment in which TEs may become activated and contribute to somatic mutagenesis (Maxwell et al., 2011; Li et al., 2013).”
BackgroundSex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau
Hohman, T. J., Dumitrescu, L., Barnes, L. L., Thambisetty, M., Beecham, G., Kunkle, B., Gifford, K. A., Bush, W. S., Chibnik, L. B., Mukherjee, S., et al. (2018) · JAMA Neurology · doi:10.1001/jamaneurol.2018.0821 · Cited by 340 · cited 1×
“Several additional loci, including APOE (Hohman et al., 2018), have been identified as exhibiting sexspecific association with AD endophenotypes, providing insight into biological mechanisms by which females may be at increased risk for AD (Dumitrescu et al.”
BackgroundPatterns of gliosis in alzheimer's disease and aging cerebrum
Beach, T. G., Walker, R., & McGeer, E. G. (1989) · Glia · doi:10.1002/glia.440020605 · Cited by 339 · cited 1×
“For example, an increase in the number of reactive astrocytes and activated microglia (i.e. gliosis) has been described, especially in close proximity to plaques (Beach et al., 1989; Serrano-Pozo et al., 2011; Hopperton et al., 2018) .”
BackgroundSex differences in the association between AD biomarkers and cognitive decline
Initiative, F. T. A. N., Koran, M. E. I., Wagener, M., & Hohman, T. J. (2017) · Brain Imaging and Behavior · doi:10.1007/s11682-016-9523-8 · Cited by 339 · cited 1×
“cognitive decline in women, increased susceptibility to neuropathology such that each unit increase of AD pathology confers a 22-fold increase in risk for AD in women compared to a 3-fold increase in males, as well as important differences in clinical and pathological disease presentation [262].”
BackgroundAlzheimer’s disease: analyzing the missing heritability
Ridge, P. G., Mukherjee, S., Crane, P. K., Kauwe, J. S. K., & Alzheimer’s Disease Genetics Consortium (2013) · PLoS ONE · doi:10.1371/journal.pone.0079771 · Cited by 328
Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease
DemGene, Steinberg, S., Stefansson, H., Jonsson, T., Johannsdottir, H., Ingason, A., Helgason, H., Sulem, P., Magnusson, O. T., Gudjonsson, S. A., et al. (2015) · Nature Genetics · doi:10.1038/ng.3246 · Cited by 324
Cruchaga, C., Chakraverty, S., Mayo, K., Vallania, F. L. M., Mitra, R. D., Faber, K., Williamson, J., Bird, T., Diaz-Arrastia, R., Foroud, T. M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031039 · Cited by 320 · cited 30×
“Given the overlap between EOAD and LOAD as discussed above, these modifiers may provide potential therapeutic targets for a more general population.”
BackgroundInfluentialSelf-citationUbiquitous L1 Mosaicism in Hippocampal Neurons
Upton, K. R., Gerhardt, D. J., Jesuadian, J. S., Richardson, S. R., Sánchez-Luque, F. J., Bodea, G. O., Ewing, A. D., Salvador-Palomeque, C., van der Knaap, M. S., Brennan, P. M., et al. (2015) · Cell · doi:10.1016/j.cell.2015.03.026 · Cited by 320
Chang, S., Ma, T. R., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508254102 · Cited by 319 · cited 2×
“nervous system, APOEε4 has been linked to impaired Aβ clearance [71, 72], disruption of lysosomes and neuronal apoptosis [73, 74], as well as mitochondrial dysfunction [75].”
BackgroundCoding variants in TREM2 increase risk for Alzheimer's disease
Jin, S. C., Benitez, B. A., Karch, C. M., Cooper, B., Skorupa, T., Carrell, D., Norton, J. B., Hsu, S., Harari, O., Cai, Y., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu277 · Cited by 314
Self-citationSex differences in cognitive impairment in Alzheimer’s disease
Laws, K. R., Irvine, K., & Gale, T. M. (2016) · World Journal of Psychiatry · doi:10.5498/wjp.v6.i1.54 · Cited by 307 · cited 1×
“Notable sex differences in the clinical and pathological presentation between the sexes exist, each of which have been extensively reviewed previously (Dumitrescu et al., 2019a; Mielke et al., 2014; Laws et al., 2018; Laws et al., 2016).”
BackgroundPottier, C., Hannequin, D., Coutant, S., Rovelet-Lecrux, A., Wallon, D., Rousseau, S., Legallic, S., Paquet, C., Bombois, S., Pariente, J., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.15 · Cited by 305 · cited 1×
“Pottier, C., Hannequin, D., Coutant, S., Rovelet-Lecrux, A., Wallon, D., Rousseau, S., ... Phrc Gmaj Collaborators, 2012.”
A novel Alzheimer disease locus located near the gene encoding tau protein
Jun, G., Ibrahim-Verbaas, C. A., Vronskaya, M., Lambert, J.-C., Chung, J., Naj, A. C., Kunkle, B. W., Wang, L.-S., Bis, J. C., Bellenguez, C., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.23 · Cited by 297 · cited 2×
“To test this hypothesis, researchers have re-analyzed data from the International Genomics of Alzheimer's Project (IGAP) following separation of APOE ε4+ and APOE ε4- subjects (Jun et al., 2016).”
BackgroundMethodGenetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease
Carrasquillo, M. M., Zou, F., Pankratz, V. S., Wilcox, S. L., Ma, L., Walker, L. P., Younkin, S. G., Younkin, C. S., Younkin, L. H., Bisceglio, G. D., et al. (2009) · Nature Genetics · doi:10.1038/ng.305 · Cited by 296 · cited 1×
“In fact, seven of the earliest GWAS, each of which used less than 2000 cases, identified only APOE as significantly associated with AD (Feulner et al., 2010; Carrasquillo et al., 2009; Beecham et al., 2009; Bertram et al., 2008; Li et al., 2008; Abraham et al., 2008; Liu et al., 2007).”
BackgroundA Review of Fluid Biomarkers for Alzheimer’s Disease: Moving from CSF to Blood
Blennow, K. (2017) · Neurology and Therapy · doi:10.1007/s40120-017-0073-9 · Cited by 295 · cited 3×
“CSF levels of APOE protein have also been suggested to act as a valuable endophenotype for AD (Cruchaga et al., 2012b), along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated (Hampel et al., 2018; Blennow, 2017; Olsson et al., 2016).”
BackgroundYu, L., Chibnik, L. B., Srivastava, G. P., Pochet, N., Yang, J., Xu, J., Kozubek, J., Obholzer, N., Leurgans, S. E., Schneider, J. A., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3049 · Cited by 290 · cited 1×
“Targeted studies have revealed methylation alterations at additional loci associated with disease (Lunnon and Mill, 2013; Yu et al., 2015; Chibnik et al., 2015), and two independent genome-wide studies recently identified a differentially methylated region in the ANK1 gene as associated with the burden of AD pathology…”
BackgroundMouse models of Alzheimer’s disease
Esquerda-Canals, G., Montoliu-Gaya, L., Güell-Bosch, J., & Villegas, S. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170045 · Cited by 288 · cited 1×
“neuroscience research and has been used for decades to gain insight into mechanisms underlying the development of AD in vivo [284, 285].”
BackgroundThe genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE
Guerreiro, R. J., Gustafson, D. R., & Hardy, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.03.025 · Cited by 285 · cited 2×
“Besides mutations in SORL1 described above, mutations in NOTCH3 were identified in a Turkish family with AD (Guerreiro et al., 2012b).”
BackgroundPark, J.-H., Gail, M. H., Weinberg, C. R., Carroll, R. J., Chung, C. C., Wang, Z., Chanock, S. J., Fraumeni, J. F., & Chatterjee, N. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1114759108 · Cited by 280
Koldamova, R. P., Lefterov, I. M., Staufenbiel, M., Wolfe, D., Huang, S., Glorioso, J. C., Walter, M., Roth, M. G., & Lazo, J. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411420200 · Cited by 279 · cited 1×
“Interestingly, several genes expressed in the liver including liver X receptors (LXRs) have been suggested as potential therapeutic targets for AD (Sodhi and Singh, 2013; Zelcer et al., 2007; Koldamova et al., 2005).”
BackgroundSuárez-Calvet, M., Araque Caballero, M. Á., Kleinberger, G., Bateman, R. J., Fagan, A. M., Morris, J. C., Levin, J., Danek, A., Ewers, M., Haass, C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1767 · Cited by 272 · cited 1×
“soluble TREM2 (sTREM2) have been shown to increase five years before symptom onset in autosomal dominant forms of AD [212].”
The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Deming, Y., Filipello, F., Cignarella, F., Cantoni, C., Hsu, S., Mikesell, R., Li, Z., Del-Aguila, J. L., Dube, U., Farias, F. G., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau2291 · Cited by 271 · cited 20×
“Common variants in the MS4A gene cluster were shown to significantly regulate sTREM2 levels in CSF (Deming et al., 2019), demonstrating regulation of this endophenotype is orchestrated by genetic variants that also modify risk for disease.”
BackgroundInfluentialAutosomal Recessive Causes Likely in Early-Onset Alzheimer Disease
Wingo, T. S. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.221 · Cited by 265 · cited 2×
“Estimates of heritability for EOAD are as high as 90–100% (Wingo et al., 2012), while heritability estimates for LOAD are slightly lower, in the range of 60–80% (Gatz et al.”
BackgroundGenome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease
Beecham, G. W., Martin, E. R., Li, Y.-J., Slifer, M. A., Gilbert, J. R., Haines, J. L., & Pericak-Vance, M. A. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.12.008 · Cited by 260 · cited 1×
“In fact, seven of the earliest GWAS, each of which used less than 2000 cases, identified only APOE as significantly associated with AD (Feulner et al., 2010; Carrasquillo et al., 2009; Beecham et al., 2009; Bertram et al., 2008; Li et al., 2008; Abraham et al., 2008; Liu et al., 2007).”
BackgroundTrabzuni, D., Wray, S., Vandrovcova, J., Ramasamy, A., Walker, R., Smith, C., Luk, C., Gibbs, J. R., Dillman, A., Hernandez, D. G., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds238 · Cited by 252 · cited 1×
“Specifically, SNPs protective against AD were associated with increased expression of MAPT exon 3, which has previously been associated with decreased aggregation of tau protein (Trabzuni et al., 2012; Zhong et al., 2012) and protection from neurodegeneration (Caffrey et al.”
BackgroundEvidence for impaired amyloid β clearance in Alzheimer's disease
Wildsmith, K. R., Holley, M., Savage, J. C., Skerrett, R., & Landreth, G. E. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt187 · Cited by 249 · cited 1×
“In the context of the central nervous system, APOE ε4 has been linked to impaired Aβ clearance (Castellano et al., 2011; Wildsmith et al., 2013), disruption of lysosomes and neuronal apoptosis (Ji et al., 2002; Ji et al., 2006), as well as mitochondrial dysfunction (Chang et al., 2005).”
BackgroundGenetics of β-Amyloid Precursor Protein in Alzheimer's Disease
TCW, J., & Goate, A. M. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024539 · Cited by 242 · cited 2×
“Mutations in the Aβ domain itself alter the hydrophobicity and downstream aggregation propensity of Aβ peptides, leading to an increase in plaque load (TCW and Goate, 2017).”
BackgroundSelf-citationCase–control association mapping by proxy using family history of disease
Liu, J. Z., Erlich, Y., & Pickrell, J. K. (2017) · Nature Genetics · doi:10.1038/ng.3766 · Cited by 238 · cited 2×
“Together, these approaches show substantial genetic overlap with previous case-control GWAS and nominate a number of novel loci associated with proxy risk for AD (Liu et al., 2017; Jansen et al., 2019; Marioni et al., 2018).”
MethodResultCorneveaux, J. J., Myers, A. J., Allen, A. N., Pruzin, J. J., Ramirez, M., Engel, A., Nalls, M. A., Chen, K., Lee, W., Chewning, K., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq221 · Cited by 237
(ADNI), A. D. N. I., Deming, Y., The Alzheimer Disease Genetic Consortium (ADGC), Li, Z., Kapoor, M., Harari, O., Del-Aguila, J. L., Black, K., Carrell, D., Cai, Y., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1685-y · Cited by 231
Self-citationEyre‐Walker, A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906182107 · Cited by 230 · cited 2×
“Rare variants typically have a more deleterious impact on protein structure and/or function than common variants [166, 167] and thus have a larger effect on disease susceptibility than those identified by GWAS.”
Wijsman, E. M., Pankratz, N., Choi, Y., Rothstein, J. H., Faber, K. M., Cheng, R., Lee, J. H., Bird, T. D., Bennett, D. A., Diaz-Arrastia, R. R., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001308 · Cited by 229 · cited 1×
“Likewise, familial inheritance of AD is typically associated with early-onset forms of the disease, but large families with multiple individuals affected by LOAD are prevalent (Wijsman et al., 2011; Vardarajan et al., 2014).”
BackgroundSelf-citationBrouwers, N., Van Cauwenberghe, C., Engelborghs, S., Lambert, J.-C., Bettens, K., Le Bastard, N., Pasquier, F., Montoya, A. G., Peeters, K., Mattheijssens, M., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.24 · Cited by 227 · cited 1×
“CNVs have also been identified as modifying risk for LOAD; a functional CNV in the gene CR1 modifying isoform production was shown to increase risk for LOAD in two populations (Brouwers et al., 2012), among others (Swaminathan et al.”
BackgroundMendelian Randomization: Methods for Using Genetic Variants in Causal Estimation
Burgess, S., & Thompson, S. G. (2015) · Cited by 226
Enhancer and promoter interactions—long distance calls
Krivega, I., & Dean, A. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.11.001 · Cited by 225 · cited 1×
“As enhancers are often located at a considerable distance from their target genes, it is believed they function by recruiting specific chromatin remodeling factors that promote the formation of chromatin loops, bringing the enhancer and promoter into close proximity (Krivega and Dean, 2012).”
BackgroundClinical subtypes of Alzheimer’s disease
Petersen, R. C. (1998) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051199 · Cited by 223 · cited 2×
“This has led many to attempt to identify distinct subtypes of AD (Murray et al., 2011; Petersen, 1998).”
Dysregulation of lipids in Alzheimer’s disease and their role as potential biomarkers
Wong, M. W., Braidy, N., Poljak, A., Pickford, R., Thambisetty, M., & Sachdev, P. S. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.01.008 · Cited by 223 · cited 1×
“Lipid accumulation in AD has been under-studied relative to other pathologies, but alterations in lipid metabolism and homeostasis are now emerging as a hallmark of AD brains (Liu and Zhang, 2014; Farmer et al., 2019; Wong et al., 2017).”
BackgroundGenetic Variation and Neuroimaging Measures in Alzheimer Disease
Biffi, A. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.108 · Cited by 222
Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Pagnotta, S., Biferi, M.-G., Barkats, M., Lacor, P., Klein, W., Bauer, C., & Checler, F. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1577-6 · Cited by 219 · cited 1×
“Indeed, there is evidence that alternative APP-derived fragments as well as APP itself play important roles in the modulation of immune cell activation (Sondag and Combs, 2004), protein clearance (Lauritzen et al., 2016), and lipid homeostasis (Grimm et al., 2017).”
BackgroundA common enzyme connects Notch signaling and Alzheimer's diseasePreprint
Kopan, R., & Goate, A. (2000) · Genes & Development · doi:10.1101/gad.836900 · Cited by 217 · cited 1×
“, 1995), although it wasn't until 2000 that it was discovered these proteins are critical subunits of the γ-secretase complex responsible for processing of APP (Kopan and Goate, 2000; Esler et al., 2000; Li et al., 2000) and other membrane-bound proteins such as NOTCH (Bekris et al.”
BackgroundSelf-citationSex differences in Alzheimer's disease
Laws, K. R., Irvine, K., & Gale, T. M. (2018) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000401 · Cited by 216 · cited 1×
“Notable sex differences in the clinical and pathological presentation between the sexes exist, each of which have been extensively reviewed previously (Dumitrescu et al., 2019a; Mielke et al., 2014; Laws et al., 2018; Laws et al., 2016).”
BackgroundCatarino, R. R., & Stark, A. (2018) · Genes & Development · doi:10.1101/gad.310367.117 · Cited by 215 · cited 1×
“Enhancers are difficult to confidently identify from DNA sequence alone, but are instead defined by the presence of several functional marks including specific histone modifications that promote transcription (Catarino and Stark, 2018) and by accessibility of local chromatin.”
BackgroundLi, Y. R., & Keating, B. J. (2014) · Genome Medicine · doi:10.1186/s13073-014-0091-5 · Cited by 214 · cited 3×
“For example, a large transethnic GWAS utilizing samples from Caucasians, African Americans, Japanese, and IsraeliArabs identified several loci contributing to disease risk in all populations (Li and Keating, 2014).”
BackgroundCerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease
Cruchaga, C., Kauwe, J. S. K., Nowotny, P., Bales, K., Pickering, E. H., Mayo, K., Bertelsen, S., Hinrichs, A., Fagan, A. M., Holtzman, D. M., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds296 · Cited by 207 · cited 1×
“CSF levels of APOE protein have also been suggested to act as a valuable endophenotype for AD [215], along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated [216–218].”
BackgroundSelf-citationAncestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations
Rajabli, F., Feliciano, B. E., Celis, K., Hamilton-Nelson, K. L., Whitehead, P. L., Adams, L. D., Bussies, P. L., Manrique, C. P., Rodriguez, A., Rodriguez, V., et al. (2018) · PLOS Genetics · doi:10.1371/journal.pgen.1007791 · Cited by 206 · cited 2×
“the association between ε4 and disease is reported to be weaker among African-American and Hispanic individuals [58, 61, 62] and nonexistent among Nigerian individuals [63].”
Neuner, S. M., Heuer, S. E., Huentelman, M. J., O’Connell, K. M. S., & Kaczorowski, C. C. (2019) · Neuron · doi:10.1016/j.neuron.2018.11.040 · Cited by 202 · cited 3×
“In addition, efforts to expand existing AD mouse models through the inclusion of genetic diversity (Neuner et al., 2019; Onos et al., 2019) have resulted in resources that show a more sig-”
BackgroundInfluentialBiochemical markers in persons with preclinical familial Alzheimer disease
Ringman, J. M., Younkin, S. G., Pratico, D., Seltzer, W., Cole, G. M., Geschwind, D. H., Rodriguez-Agudelo, Y., Schaffer, B., Fein, J., Sokolow, S., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000303973.71803.81 · Cited by 198 · cited 1×
“In targeted analyses, it has been shown that genetic variants that increase risk for AD also influence CSF Aβ1–42 levels, including pathogenic mutations in APP, PSEN1, and PSEN2, as well as APOE (Ringman et al., 2008; Kauwe et al., 2009; Kauwe et al., 2007).”
BackgroundTransethnic genome‐wide scan identifies novel Alzheimer's disease loci
Jun, G. R., Chung, J., Mez, J., Barber, R., Beecham, G. W., Bennett, D. A., Buxbaum, J. D., Byrd, G. S., Carrasquillo, M. M., Crane, P. K., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.12.012 · Cited by 197 · cited 7×
“Interestingly, the effect of APOE ε4 has been reported to differ across ethnicities (Farrer et al., 1997; Miyashita et al., 2013; Jun et al., 2017; Murrell et al., 2006), suggesting additional variants may interact with APOE to mediate its effect on AD risk.”
InfluentialSelf-citationMiyashita, A., Koike, A., Jun, G., Wang, L.-S., Takahashi, S., Matsubara, E., Kawarabayashi, T., Shoji, M., Tomita, N., Arai, H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058618 · Cited by 196
A genome-wide association study for late-onset Alzheimer's disease using DNA pooling
Abraham, R., Moskvina, V., Sims, R., Hollingworth, P., Morgan, A., Georgieva, L., Dowzell, K., Cichon, S., Hillmer, A. M., O'Donovan, M. C., et al. (2008) · BMC Medical Genomics · doi:10.1186/1755-8794-1-44 · Cited by 195
The Alzheimer's Disease Sequencing Project: Study design and sample selection
Beecham, G. W., Bis, J. C., Martin, E. R., Choi, S.-H., DeStefano, A. L., van Duijn, C. M., Fornage, M., Gabriel, S. B., Koboldt, D. C., Larson, D. E., et al. (2017) · Neurology Genetics · doi:10.1212/nxg.0000000000000194 · Cited by 195 · cited 2×
“Fortunately, significant resources have been directed toward this effort in large populations of AD cases and controls through initiatives such as the Alzheimer's Disease Sequencing Project (ADSP) (Beecham et al., 2017).”
BackgroundSelf-citationCoding mutations in SORL1 and Alzheimer disease
Vardarajan, B. N., Zhang, Y., Lee, J. H., Cheng, R., Bohm, C., Ghani, M., Reitz, C., Reyes‐Dumeyer, D., Shen, Y., Rogaeva, E., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24305 · Cited by 191
Lee, J. H., Cheng, R., Barral, S., Reitz, C., Medrano, M., Lantigua, R., Jiménez-Velazquez, I. Z., Rogaeva, E., St. George-Hyslop, P. H., & Mayeux, R. (2011) · Archives of Neurology · doi:10.1001/archneurol.2010.292 · Cited by 190
Lipids in Alzheimer’s disease: A century-old story
Foley, P. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.05.004 · Cited by 186 · cited 1×
“In his original report, Alois Alzheimer also described “adipose inclusions”, now recognized as likely lipid deposits, in glial cells of the brain (Foley, 2010).”
BackgroundDown syndrome, Alzheimer’s disease and seizures
Menéndez, M. (2005) · Brain and Development · doi:10.1016/j.braindev.2004.07.008 · Cited by 186 · cited 1×
“In addition, APP gene duplications that result from trisomy of chromosome 21 (Down's Syndrome) result in nearcomplete penetrance of AD neuropathology and increased incidence of dementia by age 30-40 years (Wisniewski et al., 1985; Menendez, 2005).”
BackgroundPolygenic score prediction captures nearly all common genetic risk for Alzheimer's disease
Escott-Price, V., Shoai, M., Pither, R., Williams, J., & Hardy, J. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.07.018 · Cited by 183 · cited 2×
“biological pathways related to the disease [123].”
MethodEarly onset Alzheimer’s disease is associated with a distinct neuropsychological profile
Smits, L. L., Pijnenburg, Y. A. L., Koedam, E. L. G. E., van der Vlies, A. E., Reuling, I. E. W., Koene, T., Teunissen, C. E., Scheltens, P., & van der Flier, W. M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-111934 · Cited by 182 · cited 1×
“have traditionally been considered distinct [29, 30], this review will consider the underlying genetic architecture of both forms of the disease, which in recent years has come to highlight a significant overlap between the subtypes.”
Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic “power station”
Trapani, L. (2012) · World Journal of Hepatology · doi:10.4254/wjh.v4.i6.184 · Cited by 178 · cited 1×
“The identification of enrichment among “liver” datasets is particularly notable given that the liver is the principal site responsible for maintaining cholesterol homeostasis in the body (Trapani et al., 2012).”
BackgroundJi, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112109200 · Cited by 177 · cited 1×
“In the context of the central nervous system, APOE ε4 has been linked to impaired Aβ clearance (Castellano et al., 2011; Wildsmith et al., 2013), disruption of lysosomes and neuronal apoptosis (Ji et al., 2002; Ji et al., 2006), as well as mitochondrial dysfunction (Chang et al., 2005).”
BackgroundCorrelating familial Alzheimer’s disease gene mutations with clinical phenotype
Ryan, N. S., & Rossor, M. N. (2010) · Biomarkers in Medicine · doi:10.2217/bmm.09.92 · Cited by 176 · cited 1×
“The effect of PSEN2 mutations is more variable than either PSEN1 or APP mutations, with age of onset in PSEN2 mutation carriers ranging from 40 to 85 years of age [50, 51].”
Association between genetic traits for immune-mediated diseases and Alzheimer disease
Yokoyama, J. S., Wang, Y., Schork, A. J., Thompson, W. K., Karch, C. M., Cruchaga, C., McEvoy, L. K., Witoelar, A., Chen, C.-H., Holland, D., et al. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.0150 · Cited by 176
How far from the SNP may the causative genes be?
Brodie, A., Azaria, J. R., & Ofran, Y. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw500 · Cited by 172 · cited 1×
“There has been a growing appreciation in recent years that simply assigning a GWAS-identified SNP to the nearest gene in linear genomic space may lead to false associations (Brodie et al., 2016).”
BackgroundApolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
Farmer, B., Kluemper, J., & Johnson, L. (2019) · Cells · doi:10.3390/cells8020182 · Cited by 164 · cited 1×
“Lipid accumulation in AD has been under-studied relative to other pathologies, but alterations in lipid metabolism and homeostasis are now emerging as a hallmark of AD brains (Liu and Zhang, 2014; Farmer et al., 2019; Wong et al., 2017).”
BackgroundGene-environment interactions in Alzheimer's disease: A potential path to precision medicine
Eid, A., Mhatre, I., & Richardson, J. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.03.005 · Cited by 164 · cited 2×
“across populations, including educational attainment, obesity, cholesterol levels, social isolation, alcohol consumption, and exposure to pesticides [269, 270].”
BackgroundTREM2 is associated with the risk of Alzheimer's disease in Spanish population
Benitez, B. A., Cooper, B., Pastor, P., Jin, S.-C., Lorenzo, E., Cervantes, S., & Cruchaga, C. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.018 · Cited by 163 · cited 1×
“Since the identification of R47H, additional rare variants in TREM2 have been associated with AD risk (Benitez et al., 2013; Jin et al., 2014; Jin et al., 2015), highlighting the critical role of this pro-”
BackgroundThe presenilin genes: a new gene family involved in Alzheimer disease pathology
Cruts, M., Hendriks, L., & Van Broeckhoven, C. (1996) · Human Molecular Genetics · doi:10.1093/hmg/5.supplement_1.1449 · Cited by 163 · cited 1×
“The other EOAD-causative genes are highly homologous members of the presenilin gene family (Cruts et al., 1996).”
BackgroundGene-by-environment interactions in Alzheimer’s disease and Parkinson’s disease
Dunn, A. R., O’Connell, K. M. S., & Kaczorowski, C. C. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.06.018 · Cited by 160 · cited 1×
“dose, timing, and duration of exposure, and/or additional confounds produced by unreported exposures [272].”
BackgroundUnderstanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure
Zhong, N., & Weisgraber, K. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r800009200 · Cited by 159 · cited 1×
“Despite the long-standing recognition of the impact of APOEε4 on AD risk, the precise mechanism by which APOEε4 confers elevated risk for AD remains unclear [69].”
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.005 · Cited by 158 · cited 2×
“Since its identification, the R47H variant has been associated not only with AD risk but also neuropathology, brain atrophy, and additional behavioral symptoms such as anxiety in AD patients (Luis et al., 2014; Deming et al., 2019; Guerreiro et al., 2013b).”
BackgroundFurney, S. J., Simmons, A., Breen, G., Pedroso, I., Lunnon, K., Proitsi, P., Hodges, A., Powell, J., Wahlund, L.-O., Kloszewska, I., et al. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.123 · Cited by 157 · cited 8×
“Interestingly, while several genes previously implicated in AD (including APOE and PICALM (Furney et al., 2011)) have been associated with imaging endophenotypes, a large number of novel loci and genes have been nominated by these analyses (Risacher et al., 2009; Furney et al., 2011; Potkin et al., 2009; Stein et al.,…”
BackgroundInfluentialA Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population
Liu, F., Arias-Vásquez, A., Sleegers, K., Aulchenko, Y. S., Kayser, M., Sanchez-Juan, P., Feng, B.-J., Bertoli-Avella, A. M., van Swieten, J., Axenovich, T. I., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/518720 · Cited by 156 · cited 1×
“In fact, seven of the earliest GWAS, each of which used less than 2000 cases, identified only APOE as significantly associated with AD (Feulner et al., 2010; Carrasquillo et al., 2009; Beecham et al., 2009; Bertram et al., 2008; Li et al., 2008; Abraham et al., 2008; Liu et al., 2007).”
BackgroundToward more predictive genetic mouse models of Alzheimer’s disease
Onos, K. D., Sukoff Rizzo, S. J., Howell, G. R., & Sasner, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2015.12.003 · Cited by 156 · cited 1×
“However, traditional models created by incorporating a highly penetrant mutation in APP, PSEN1, or PSEN2 onto a single inbred background strain have largely failed to yield successful results in human clinical trials [286, 287].”
BackgroundFDG-PET as an independent biomarker for Alzheimer’s biological diagnosis: A longitudinal study
Initiative, O. B. O. A. D. N., Ou, Y.-N., Xu, W., Li, J.-Q., Guo, Y., Cui, M., Chen, K.-L., Huang, Y.-Y., Dong, Q., Tan, L., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0512-1 · Cited by 155
Ferreira, D., Perestelo‐Pérez, L., Westman, E., Wahlund, L., Sarría‐Santamera, A., & Serrano‐Aguilar, P. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00047 · Cited by 153 · cited 1×
“For example, “core” biomarkers and endophenotypes of AD include low CSF levels of Aβ1–42, shown to indicate reduced clearance of Aβ1–42 from the brain, and elevated CSF tau (both total tau and phosphorylated tau), thought to indicate neuronal degeneration or injury (Ferreira et al., 2014).”
BackgroundTREM2 is associated with increased risk for Alzheimer’s disease in African Americans
Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., Lincoln, S., Krishnan, S., Kachadoorian, M., Reitz, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0016-9 · Cited by 153 · cited 1×
“Since the identification of R47H, additional rare variants in TREM2 have been associated with AD risk (Benitez et al., 2013; Jin et al., 2014; Jin et al., 2015), highlighting the critical role of this protein in the etiology of AD.”
BackgroundSelf-citationHardy, J. (2017) · The FEBS Journal · doi:10.1111/febs.14004 · Cited by 153 · cited 3×
“V717L, V717I) influence the activity of g-secretase altering APP processing so that longer Aβ peptides more prone to aggregation are generated, including species 42–43 amino acids in length (Aβ1–42 and Aβ1–43) (Hardy, 2017).”
BackgroundCombined CSF tau, p-tau181 and amyloid-β 38/40/42 for diagnosing Alzheimer’s disease
Welge, V., Fiege, O., Lewczuk, P., Mollenhauer, B., Esselmann, H., Klafki, H.-W., Wolf, S., Trenkwalder, C., Otto, M., Kornhuber, J., et al. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-008-0177-6 · Cited by 152 · cited 1×
“…levels of CSF Aβ42 and high levels of total tau or phosphorylated tau (particularly p-tau181) capable of differentiating AD from mild cognitive impairment and other dementias such as frontotemporal dementia and Lewy body dementia (Sunderland et al., 2003; Welge et al., 2009; Cruchaga et al., 2013).”
BackgroundCuyvers, E., De Roeck, A., Van den Bossche, T., Van Cauwenberghe, C., Bettens, K., Vermeulen, S., Mattheijssens, M., Peeters, K., Engelborghs, S., Vandenbulcke, M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00133-7 · Cited by 152
The BLUEPRINT Data Analysis Portal
Fernández, J. M., de la Torre, V., Richardson, D., Royo, R., Puiggròs, M., Moncunill, V., Fragkogianni, S., Clarke, L., Flicek, P., Rico, D., et al. (2016) · Cell Systems · doi:10.1016/j.cels.2016.10.021 · Cited by 151
Sudom, A., Talreja, S., Danao, J., Bragg, E., Kegel, R., Min, X., Richardson, J., Zhang, Z., Sharkov, N., Marcora, E., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002352 · Cited by 149
Vardarajan, B. N., Ghani, M., Kahn, A., Sheikh, S., Sato, C., Barral, S., Lee, J. H., Cheng, R., Reitz, C., Lantigua, R., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24466 · Cited by 148 · cited 31×
“Given the overlap between EOAD and LOAD as discussed above, these modifiers may provide potential therapeutic targets for a more general population.”
BackgroundInfluentialApplications of Human Brain Organoids to Clinical Problems
Chen, H.-C. I., Song, H., & Ming, G. (2018) · Developmental Dynamics · doi:10.1002/dvdy.24662 · Cited by 147 · cited 1×
“…engineered by genome editing to express disease-relevant mutations to established protocols for neuron/astrocyte co-culture (Park et al., 2018) and the development of brain organoids is likely to greatly contribute to our understanding of how these cells contribute to disease (Chen et al., 2019).”
BackgroundStein, J. L., Hua, X., Morra, J. H., Lee, S., Hibar, D. P., Ho, A. J., Leow, A. D., Toga, A. W., Sul, J. H., Kang, H. M., et al. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.02.068 · Cited by 145
Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease
Henjum, K., Almdahl, I. S., Årskog, V., Minthon, L., Hansson, O., Fladby, T., & Nilsson, L. N. G. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0182-1 · Cited by 145 · cited 1×
“…(~25% of TREM2 transcripts) (Deming et al., 2019). sTREM2 is then released into the CSF where it can be measured, and has been shown to correlate with CSF levels of tau (Henjum et al., 2016; Suárez-Calvet et al., 2016), suggesting it may be a relevant secondary biomarker of disease progression.”
BackgroundThe transcription factor PU.1 is critical for viability and function of human brain microglia
Smith, A. M., Gibbons, H. M., Oldfield, R. L., Bergin, P. M., Mee, E. W., Faull, R. L. M., & Dragunow, M. (2013) · Glia · doi:10.1002/glia.22486 · Cited by 141
Whole‐exome sequencing in 20,197 persons for rare variants in Alzheimer's disease
Raghavan, N. S., Brickman, A. M., Andrews, H., Manly, J. J., Schupf, N., Lantigua, R., Wolock, C. J., Kamalakaran, S., Petrovski, S., Tosto, G., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.582 · Cited by 141
APOE ε4 is not associated with Alzheimer's disease in elderly Nigerians
Gureje, O., Ogunniyi, A., Baiyewu, O., Price, B., Unverzagt, F. W., Evans, R. M., Smith‐Gamble, V., Lane, K. A., Gao, S., Hall, K. S., et al. (2006) · Annals of Neurology · doi:10.1002/ana.20694 · Cited by 139 · cited 1×
“…(Miyashita et al., 2013; Jun et al., 2017), whereas the association between ε4 and disease is reported to be weaker among African-American and Hispanic individuals (Farrer et al., 1997; Murrell et al., 2006; Rajabli et al., 2018) and nonexistent among Nigerian individuals (Gureje et al., 2006).”
BackgroundCruchaga, C., Del‐Aguila, J. L., Saef, B., Black, K., Fernandez, M. V., Budde, J., Ibanez, L., Deming, Y., Kapoor, M., Tosto, G., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.08.013 · Cited by 138 · cited 28×
“Given the overlap between EOAD and LOAD as discussed above, these modifiers may provide potential therapeutic targets for a more general population.”
BackgroundMethodInfluentialSelf-citationBiochemistry and Molecular Biology of Amyloid β‐Protein and the Mechanism of Alzheimer's Disease
(2008) · Handbook of Clinical Neurology · doi:10.1016/s0072-9752(07)01223-7 · Cited by 137 · cited 1×
“…AD is a neurodegenerative disease defined by the presence of extracellular plaques primarily composed of beta-amyloid (Aβ) protein, a byproduct of sequential cleavage of the amyloid precursor protein (APP) by the enzymatic complexes beta (β) and gamma (γ) secretase (Selkoe, 2008; Hardy, 1997).”
Bushman, D. M., Kaeser, G. E., Siddoway, B., Westra, J. W., Rivera, R. R., Rehen, S. K., Yung, Y. C., & Chun, J. (2015) · eLife · doi:10.7554/elife.05116 · Cited by 136 · cited 2×
“Additional somatic mutations in genes known to confer risk for AD such as APP and SORL1 (Nicolas et al., 2018) have been identified in the brains of both EOAD and LOAD patients (Bushman et al., 2015; Sala Frigerio et al., 2015).”
BackgroundDukart, J., Mueller, K., Horstmann, A., Vogt, B., Frisch, S., Barthel, H., Becker, G., Möller, H. E., Villringer, A., Sabri, O., et al. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2009.09.017 · Cited by 134 · cited 4×
“Notable sex differences in the clinical and pathological presentation between the sexes exist, each of which have been extensively reviewed previously (Dumitrescu et al., 2019a; Mielke et al., 2014; Laws et al., 2018; Laws et al., 2016).”
InfluentialRetrotransposition is associated with genome instability during chronological aging
Maxwell, P. H., Burhans, W. C., & Curcio, M. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100271108 · Cited by 132 · cited 1×
“However, with aging, the efficacy of these systems is known to be reduced, providing a genomic environment in which TEs may become activated and contribute to somatic mutagenesis (Maxwell et al., 2011; Li et al., 2013).”
BackgroundGenome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer's Disease
Heinzen, E. L., Need, A. C., Hayden, K. M., Chiba‐Falek, O., Roses, A. D., Strittmatter, W. J., Burke, J. R., Hulette, C. M., Welsh-Bohmer, K. A., & Goldstein, D. B. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1212 · Cited by 131
SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease
Nicolas, G., Charbonnier, C., Wallon, D., Quenez, O., Bellenguez, C., Grenier-Boley, B., Rousseau, S., Richard, A.-C., Rovelet-Lecrux, A., Le Guennec, K., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.121 · Cited by 129 · cited 1×
“Notably, an enrichment for rare disruptive and putatively damaging variants in SORL1 were also identified among EOAD cases (Pottier et al., 2012; Nicolas et al., 2016).”
Background
Cited by
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Ferroptosis Mechanisms Involved in Neurodegenerative Diseases
Reichert, C. O., de Freitas, F. A., Sampaio‐Silva, J., Rokita-Rosa, L., Barros, P. D. L., Levy, D., & Bydlowski, S. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228765 · Cited by 431
The role of innate immune genes in Alzheimer's disease
Griciuc, A., & Tanzi, R. E. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000911 · Cited by 192
“Autosomal dominant mutations in APP and PSEN1/2 accelerate the rate of cognitive decline leading to early-onset dementia [2,3].”
BackgroundThe foundation and architecture of precision medicine in neurology and psychiatry
Hampel, H. J., Gao, P., Cummings, J. L., Toschi, N., Thompson, P. M., Hu, Y., Cho, M., & Vergallo, A. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2022.12.004 · Cited by 163
“This includes monogenic forms of AD or frontotemporal dementia [27], PD and other movement disorders [28,29], ALS and other motoneuron disorders, schizophrenia”
Functional regulatory variants implicate distinct transcriptional networks in dementia
Cooper, Y. A., Teyssier, N., Dräger, N. M., Guo, Q., Davis, J. E., Sattler, S. M., Yang, Z., Patel, A. M., Wu, S. J., Kosuri, S., et al. (2022) · Science · doi:10.1126/science.abi8654 · Cited by 121
“Shown are the locus lead SNPs and annotated genes as described in the listed GWASs.”
BackgroundXia, D., Lianoglou, S., Sandmann, T., Calvert, M., Suh, J. H., Thomsen, E., Dugas, J., Pizzo, M. E., DeVos, S. L., Earr, T. K., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00547-7 · Cited by 124
Metadata
- Authors
- Neuner, S. M., TCW, J., & Goate, A. M.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Goate, Alison M.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 143
- Pages
- 104976
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC7409822
- OpenAlex
- W3036672623
- Semantic Scholar
- e8cdbd032f24aa8300cd48223447f05ebe6d8746
- Cited by
- 126
- References
- 294
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 21 · 2023: 24 · 2022: 21 · 2021: 27 · 2020: 4
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- JPB Foundation
- National Institute on Aging (U01AG058635, U01AG052411, K01AG062683)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, genetic architecture, genetic susceptibility, APP, presenilin 1, presenilin 2, apolipoprotein E, genetic susceptibility loci, regulatory elements, myeloid cells, hepatocytes, cell type enrichment, gene-environment interaction, sex differences, ethnicity, therapeutic target
- MeSH terms
- Alzheimer Disease, Humans, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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