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Cited by 126Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Genetic architecture of Alzheimer's disease

Open access
Neuner, Sarah M., TCW, Julia, Goate, Alison M.·2020·Neurobiology of Disease
DOI 10.1016/j.nbd.2020.104976PMC PMC7409822
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Abstract

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.

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.nbd.2020.104976

Cites

290 of 290 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 301 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Common polymorphisms in the gene apolipoprotein E (APOE) are the most significant genetic risk factor for Alzheimer's disease.

    “common polymorphisms in the gene apolipoprotein E (APOE) are the most significant genetic risk factor for AD [52–54].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • Premisecitation

    The effect of APOEε4 on Alzheimer's disease risk differs across ethnicities.

    “the effect of APOEε4 has been reported to differ across ethnicities [58–61]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • Premisecitation

    A majority of ADAD families carry a pathogenic mutation in one of three genes: APP, PSEN1, or PSEN2.

    “A majority of ADAD families carry a pathogenic mutation in one of three genes: APP, presenilin 1 (PSEN1), or presenilin 2 (PSEN2) [2, 33].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • Premisecitation

    PSEN2 mutations are much rarer, with only around 30 mutations identified in ADAD families.

    “PSEN2 mutations are much rarer, with only around 30 mutations identified in ADAD families [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • Premisecitation

    More than 50 highly penetrant mutations have been identified in APP.

    “To date, more than 50 highly penetrant mutations have been identified in APP [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims. 73
  • Classified as probably not a substantial claim. 30
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    Premisecitation

    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 is about 3 times that of non-carriers.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APOEε4 is less frequent (~14%) among the general population but drastically increases risk for Alzheimer's disease in a dose-dependent manner.

    “APOEε4 is less frequent (~14%) among the general population but drastically increases risk for AD in a dose-dependent manner [54, 57]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    The association between APOEε4 and Alzheimer's disease is weaker among African-American and Hispanic individuals and nonexistent among Nigerian individuals.

    “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].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    EOAD and LOAD share common pathological features and are both considered to be highly heritable.

    “the two subsets share common pathological features and are both considered to be highly heritable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mutations in PSEN1 are the most common cause of ADAD; as of April 2020, over 350 mutations (some of unclear pathogenicity) have been identified.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Autosomal dominant Alzheimer's disease (ADAD) is very rare, accounting for less than 1% of all cases of Alzheimer's disease.

    “ADAD is very rare, accounting for less than <1% of all cases of AD [2, 31–33]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    APOEε3 is the most common allele in all human populations, present in almost 80% of individuals.

    “Of the three alleles, APOEε3 is the most common in all human populations, present in almost 80% of individuals [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The amyloid cascade hypothesis posits that amyloid deposition is an initial causative event in a cascade of symptoms resulting in neurodegeneration and cognitive decline.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Hardy JA, & Higgins GA (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science, 256(5054), 184– 185. 1566067

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  • May combine two claims.

    Premisecitation

    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).

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Proxy risk for Alzheimer's disease, defined as a parental history of AD, exhibits strong genetic correlation with AD and can be combined with existing GWAS datasets to enhance statistical power to find true genetic associations with disease.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    APOEε2 appears to reduce risk for Alzheimer's disease, with carriers of even one APOEε2 allele in combination with APOEε3 exhibiting only about half the risk of those carrying two APOEε3 alleles.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    The most recent meta-analysis identified novel variants not previously associated with Alzheimer's disease by standard GWAS, including variants near IQCK.

    “this GWAS identified novel variants not previously associated with the disease by standard GWAS, including variants near IQCK [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Association signals in the MS4A region were stronger in APOEε4− subjects, while variants in the PICALM region exhibit stronger associations in APOEε4+ subjects, suggesting independent mechanisms may partially contribute to Alzheimer's disease across APOE genotypes.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In 2009, the first large-scale GWAS were published and loci outside of APOE were implicated in LOAD risk for the first time.

    “In 2009, the first large-scale GWAS were published and loci outside of APOE were implicated in LOAD risk for the first time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SNPs protective against Alzheimer's disease were associated with increased expression of MAPT exon 3, which has previously been associated with decreased aggregation of tau protein and protection from neurodegeneration.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Interpretationreasoning

    Either APOE genotype interacts with surrounding genetic variants to dictate disease risk, or protective alleles within the African APOE haplotype reduce the effect of APOEε4 on disease.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Genetic variation at the APOE locus is the most significant common genetic risk factor for LOAD, and genetic variation at other loci individually confers only small effects on disease risk.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Several ethnicity-specific loci associated with Alzheimer's disease have been identified, including variants on 18q23 in Caribbean Hispanics and variants near KCHN15 in Chinese.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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

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  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proxy approaches show substantial genetic overlap with previous case-control GWAS and nominate a number of novel loci associated with proxy risk for Alzheimer's disease.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Interpretationcitation

    AD is likely influenced by a large number of susceptibility genes, reflecting a complex set of biological pathways related to the disease.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Polygenic risk scores have been expanded in the context of Alzheimer's disease and used for individualized risk prediction.

    “These “polygenic risk scores” (PRS) have since been expanded upon in the context of AD and used for individualized risk prediction [118]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Many of the genes containing coding variants are highly expressed in microglia and function within the immune system, highlighting this pathway as critical for Alzheimer's disease risk.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Shared genetic architecture exists between EOAD and LOAD, with some of the same loci influencing risk for disease in both cases.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The R47H variant decreases the stability of the TREM2 protein, potentially conferring reduced functionality.

    “and decreases the stability of the protein, potentially conferring reduced functionality [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The burden (PRS) of LOAD GWAS variants significantly predicted disease risk and age at onset in both familial LOAD and sporadic EOAD.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The R47H variant has been associated with AD risk, neuropathology, brain atrophy, and additional behavioral symptoms such as anxiety in AD patients.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expanding PRS to include variants below the genome-wide statistical cutoff allows for a more complete view of the genetic contribution to disease 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.

    “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].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PLGC2 harbors a protective variant and encodes a transmembrane signaling enzyme implicated in lipid metabolism, calcium homeostasis, and immune response.

    “PLGC2, which harbors a protective variant, encodes a transmembrane signaling enzyme implicated in lipid metabolism, calcium homeostasis, and immune response [130, 142].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ABI3 has been implicated in regulation of the immune response through interferon signaling and plays a role in actin cytoskeletal organization.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the familial EOAD study, the sample size was small and variant burden may have been associated with age at symptom onset in these families.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Histone modifications can reliably be measured across the genome using ChIP-seq, while chromatin accessibility is typically measured by either DNase-seq or ATAC-seq.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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, making the specific genes impacted by GWAS SNPs difficult to identify.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rare variants in SORL1 and ABCA7 have been identified in family-based studies of LOAD, each associated with alterations in APP processing.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Given the overlap between EOAD and LOAD, these modifiers may provide potential therapeutic targets for a more general population.

    “Given the overlap between EOAD and LOAD as discussed above, these modifiers may provide potential therapeutic targets for a more general population.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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 and by accessibility of local chromatin.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rare variants typically have a more deleterious impact on protein structure and/or function than common variants and thus have a larger effect on disease susceptibility than those identified by GWAS.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The gene impacted by the identified rare variant is often immediately apparent, making it possible to more easily model the effect of the variant in cell-based assays or model organisms.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A variety of assays now exist to capture three-dimensional architecture, including various adaptations of chromosome conformation capture (3C).

    “A variety of assays now exist to capture this three-dimensional architecture, including various adaptations of chromosome conformation capture (3C) [179].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disease-associated mutations in SORL1 have been linked with altered levels of APP at the cell surface and increased production of toxic Aβ species.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is evidence that groups of genes close together in chromosomal space function in similar biological pathways, 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SORL1 is a sorting receptor located in neurons, astrocytes, and microglia and is known to direct APP toward non-amyloidogenic processing in the trans-Golgi network.

    “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].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Enhancers, short genomic sequences distally located from their target genes, confer additional cell- and tissue-type specificity to the regulation of gene expression.

    “Enhancers, short genomic sequences distally located from their target genes, confer additional cell- and tissue-type specificity to the regulation of gene expression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Promoters proximal to the transcription start site of protein coding genes can recruit the binding of specific transcription factors, activators, or repressors.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Enhancers are often located at a considerable distance from their target genes, and 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Altered methylation at the promoters of APP, PSEN1, and APOE could modify risk for disease.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisereasoning

    Bulk datasets do not provide specific information about the cell types through which AD variants act, but they still provide useful information as to which genes may be targeted by GWAS SNPs.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The case/control approach does not provide information about other aspects of the disease such as age of onset or disease progression, or biological mechanisms involved in disease pathogenesis.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    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 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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gagliano et al. 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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The liver is the principal site responsible for maintaining cholesterol homeostasis in the body.

    “The identification of enrichment among “liver” datasets is particularly notable given that the liver is the principal site responsible for maintaining”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Most of the currently available functional annotation data is derived from healthy donors.

    “It should be noted that most of the currently available functional annotation data is derived from healthy donors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microglia exhibit several beneficial functions in the brain such as clearance of cellular debris and orchestration of appropriate immune responses, but their chronic activation can lead to toxic neuroinflammation and aberrant pruning of synapses.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [203] Salter MW, & Stevens B (2017). Microglia emerge as central players in brain disease. Nature medicine, 23(9), 1018– 1027. 28886007 source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Large-scale annotation projects such as the Roadmap Epigenomics Project, the Blueprint Project, and PsychENCODE aim to generate, and make publicly available, high-quality reference annotation maps across a wide variety of human cell and tissue types.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These associations were observed whether APOE was included or not, confirming the enrichment was not driven by a single moderate-effect variant.

    “These associations were observed whether APOE was included or not, confirming the enrichment was not driven by a single moderate-effect variant [183].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CSF levels of APOE protein have been suggested to act as a valuable endophenotype for AD.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Several of these novel variants, including those near GLIS1 and within SERPINB1, were associated with additional aspects of disease including risk, age at onset, and progression.

    “Notably, several of these novel variants, including those near GLIS1 and within SERPINB1, were associated with additional aspects of disease including risk, age at”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    sTREM2 is thought to be produced 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).

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    sTREM2 is released into the CSF where it can be measured, and has been shown to correlate with CSF levels of tau.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    This approach greatly facilitates interpretation of the downstream functional consequences of the prioritized loci.

    “In addition, this approach greatly facilitates interpretation of the downstream functional consequences of the prioritized loci.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Levels of various additional proteins have been suggested as endophenotypes for AD, the clinical and biological relevance of which remain to be elucidated.

    “along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated [216–218].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The quantitative nature of endophenotypes results in improved phenotype definition beyond traditional case-control analyses.

    “As the quantitative nature of endophenotypes results in improved phenotype definition beyond traditional case-control analyses”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    PET imaging can measure glucose metabolism in the brain through the utilization of a radiolabeled alternate form of glucose, 18F-fluorodeoxyglucose (FDG).

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Large GWAS using CSF Aβ1-42 and/or tau levels as the trait of interest have identified variants in the TREM2 cluster as associated with these quantitative endophenotypes, as well as variants in the ABCA7 and FERMT2 gene regions.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies have reported more rapid cognitive decline in women and 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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With aging, the efficacy of these surveillance systems is reduced, providing a genomic environment in which TEs may become activated and contribute to somatic mutagenesis.

    “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]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP gene duplications resulting 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.

    “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]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [251] Menendez M (2005). Down syndrome, Alzheimer’s disease and seizures. Brain & development, 27(4), 246– 252. 15862185 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APOE has been associated with sex-specific alterations in CSF tau levels and disease progression but not robustly with CSF Aβ1-42.

    “APOE has been associated with sex-specific alterations in CSF tau levels and disease progression but not robustly with CSF Aβ1–42”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “CNVs may alter gene dosage and have a profound impact on both gene and protein function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Li W, & Olivier M (2013). Current analysis platforms and methods for detecting copy number variation. Physiological genomics, 45(1), 1– 16. 23132758 PMC3544484

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One offspring of the affected patient inherited the PSEN1 mutation in all cells of her body and exhibited signs of dementia by age 27.

    “One offspring of the affected patient inherited the PSEN1 mutation in all cells of her body and exhibited signs of dementia by age 27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    The patient was originally classified as negative for PSEN1 mutations after peripheral blood DNA sequencing, but after DNA from the cerebral cortex, evidence of a cell-type specific mutation was observed.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AD is more prevalent among elderly females.

    “AD is well-known to be more prevalent among elderly females”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CNVs may span multiple genes and have a measurable impact on more than one target.

    “CNVs may span multiple genes and have a measurable impact on more than one target [247]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [247] Li W, & Olivier M (2013). Current analysis platforms and methods for detecting copy number variation. Physiological genomics, 45(1), 1– 16. 23132758 PMC3544484

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When transposable elements, 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.

    “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]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hohman et al. 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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Some of the missing heritability of AD 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.

    “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”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim
94 of 94

  • 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”
6 of 6

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Authors
Neuner, S. M., TCW, J., & Goate, A. M.
Affiliations
Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Goate, Alison M.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2020-09
Volume
143
Pages
104976
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2020.104976
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 · 2019: 1
FWCI
2.45
Type
journal article
Language
en
Open access
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
  • Health Sciences › Medicine › Physiology › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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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