Genetic architecture of Alzheimer's disease

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].”

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

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]”

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

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]”

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

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].”

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

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].”

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

In the paper

“the two subsets share common pathological features and are both considered to be highly heritable.”

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).”

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.”

In the paper

“ADAD is very rare, accounting for less than <1% of all cases of AD [2, 31–33]”

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

In the paper

“Of the three alleles, APOEε3 is the most common in all human populations, present in almost 80% of individuals [57].”

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

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].”

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

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].”

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

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.”

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

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].”

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

In the paper

“this GWAS identified novel variants not previously associated with the disease by standard GWAS, including variants near IQCK [97].”

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

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.”

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

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.”

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].”

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

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.”

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.”

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].”

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

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).”

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

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].”

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

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].”

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

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]”

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

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.”

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.”

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

In the paper

“and decreases the stability of the protein, potentially conferring reduced functionality [136].”

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

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].”

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

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].”

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

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].”

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

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].”

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

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].”

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

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].”

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

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].”

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

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].”

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

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”

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

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.”

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

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.”

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

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.”

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.”

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

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.”

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

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.”

In the paper

“A variety of assays now exist to capture this three-dimensional architecture, including various adaptations of chromosome conformation capture (3C) [179].”

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

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].”

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

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.”

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

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].”

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

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.”

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].”

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

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].”

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

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.”

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].”

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

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.”

In the paper

“The GWAS discussed above were primarily performed on case/control datasets and provide information regarding the genetic architecture of disease risk.”

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.”

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].”

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

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.”

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.”

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.”

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.”

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.”

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.”

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

In the paper

“The identification of enrichment among “liver” datasets is particularly notable given that the liver is the principal site responsible for maintaining”

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

In the paper

“It should be noted that most of the currently available functional annotation data is derived from healthy donors.”

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].”

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
• Not checked yetcites [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 source

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.”

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

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].”

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

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].”

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

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”

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

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].”

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

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.”

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

In the paper

“In addition, this approach greatly facilitates interpretation of the downstream functional consequences of the prioritized loci.”

In the paper

“along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated [216–218].”

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

In the paper

“As the quantitative nature of endophenotypes results in improved phenotype definition beyond traditional case-control analyses”

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].”

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

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].”

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

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”

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

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]”

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

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]”

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

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]”

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

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”

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

In the paper

“CNVs may alter gene dosage and have a profound impact on both gene and protein function.”

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

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”

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

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]”

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

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.”

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

In the paper

“AD is well-known to be more prevalent among elderly females”

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

In the paper

“CNVs may span multiple genes and have a measurable impact on more than one target [247]”

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

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]”

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

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”

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

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]”

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

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]”

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

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”

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]”

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

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.”