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Cited by 21Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

Open access
Cochran, Jesse Nicholas, Acosta‐Uribe, Juliana, Esposito, Bianca T., Madrigal, Lucia, Aguillón, David, Giraldo, Margarita M., Taylor, Jared W., Bradley, Joseph +22 more·2023·Alzheimer's & Dementia
DOI 10.1002/alz.13021PMC PMC10514237
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Abstract

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early‐onset AD study and four late‐onset AD studies. RESULTS: 13 variants had p <1×10 −7 or p <1×10 −5 with replication including three independent loci with candidate associations with clusterin including near CLU . Other suggestive associations were identified in or near HS3ST1 , HSPG2 , ACE , LRP1B , TSPAN10 , and TSPAN14 . DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Integrity signals

Registry

Crossref · 10.1002/alz.13021

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

2 of 31 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    APOE ε2 had a protective effect on age at dementia onset in the Colombian E280A population (β=8.2, 95% CI 4.5-12.0, p=3.8x10-5).

    “including a protective effect of APOE ε2 in the Colombian E280A population (β=8.2, 95% CI=4.5-12.0,p=3.8x10 -5 ) [21]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] 21. Velez JI, Lopera F, Sepulveda-Falla D, Patel HR, Johar AS, Chuah A, et al. APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Mol Psychiatry. 2016;21:916-24. [PubMed: 26619808] source
      Experimental — accuracy not yet measured
  • Findingcitation

    rs35980966 falls within a single nucleus multiomics linkage to CLU.

    “The variant falls within a single nucleus multiomics linkage [20] to CLU.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] 20. Anderson AG, Rogers BB, Loupe JM, Rodriguez-Nunez I, Roberts SC, White LM, et al. Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific cis regulatory elements. bioRxiv. 2022. source

      Checked before — its earlier verdict is held back until a new check runs.

  • Findingown data

    No other coding variants in APOE beyond those in Table 2 were observed in either the imputed set or the subset of cases with genomes available.

    “No other coding variants in APOE beyond those described in Table 2 were observed in either the imputed set or the subset of cases with genomes available.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In the PSEN1 E280A cohort, the APOE ε4 variant rs429358-C was associated with an earlier age at dementia onset (β = -2.0 years, p = 0.0025).

    “rs429358-C APOE ε4 (when rs7412 ref.) -2.0 (0.6) 0.0025 8 0.138 0.155 p.(Cys130Arg) 16.7”
    Quote in the paperSubstantial claim
  • Findingown data

    The final cohort had a mean age at dementia onset of 49.3 years (median 48, range 37-75, 10th-90th percentile 43-56).

    “The final cohort had a mean age of dementia onset of 49.3 years (median: 48, range: 37-75, 10 th -90 th percentile: 43-56).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingreasoning

    rs138295139 on chromosome 1 is 4.4 kb from a variant previously associated with plasma clusterin, rs4428865, but the two variants are not in linkage disequilibrium, possibly due to the rarity of rs138295139.

    “In addition, rs138295139 on chromosome 1 is only 4.4kb from a variant previously associated with plasma clusterin, rs4428865 [41], though these variants are not in LD, which could be explained by the rarity of rs138295139.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] 41. Deming Y, Xia J, Cai Y, Lord J, Holmans P, Bertelsen S, et al. A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin. Neurobiol Aging. 2016;37:208 e1-e9. source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Findingown data

    The APOE Christchurch variant (rs121918393) had a nominally significant effect on age at onset in this cohort, but the effect size was modest.

    “A recent case report implicated the APOE Christchurch variant (rs121918393) [5].That individual was also enrolled in this study, and while we do observe a nominally significant effect on age at onset of this variant, we note that the effect size is modest”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] 5. Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25:1680-3. [PubMed: 31686034] source

  • May combine two claims.

    Findingcitation

    rs4942482 on chromosome 13 is near a variant previously associated with CSF clusterin and replicates in three studies and the ADGC EOAD study in progress.

    “Finally, rs4942482 on chromosome 13 is near a variant previously associated with CSF clusterin [41] and replicates in three studies [17,19] and ADGC EOAD study in progress.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] 17. Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nat Neurosci. 2017;20:1052-61. [PubMed: 28628103] source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [19] 19. Bellenguez C, Kucukali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022;54:412- 36. [PubMed: 35379992] source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Findingcitation

    rs35980966 (p=5.5x10-8) is a rare variant (gnomAD v3.1.2 MAF=0.35%) that tags the CLU locus on chromosome 8 and replicates in three studies and the ADGC EOAD study in progress.

    “One of the most significant variants was rs35980966 (p=5.5x10-8 ), which is a rare variant (gnomAD v3.1.2MAF=0.35%) that tags the CLU locus on chromosome 8 and exhibits replication in three studies [18,19] and ADGC EOAD study in progress.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] 18. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51:414-30. [PubMed: 30820047] source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [19] 19. Bellenguez C, Kucukali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022;54:412- 36. [PubMed: 35379992] source

      Checked before — its earlier verdict is held back until a new check runs.

  • May combine two claims.

    Findingown data

    Of the 184 prior index variants, 151 were genotyped in this cohort; nine had p<0.05, but only six had a consistent effect direction.

    “Of these variants, 151 were genotyped in this cohort, nine with p<0.05, but only six of these were in a consistent direction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study identified 13 loci with p<1x10-5 and replication or p<1x10-7 with a nearby GWAS hit associated with AD phenotypes, as well as more speculative signals from replication of previous GWAS or coding variants.

    “We identified 13 loci with p<1x10 -5 and replication or p<1x10 -7 with a nearby GWAS hit associated with AD phenotypes as well as more speculative signals when considering replication of previous GWAS in this cohort or important coding variants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    rs4942482 is linked via single nucleus multiomics measurements to nearby genes including ZC3H13 and SIAH3, with the SIAH3 linkage being AD-specific.

    “This variant is linked via single nucleus multiomics measurements to nearby genes including ZC3H13 and SIAH3 (the linkage to SIAH3 is particularly interesting as it is AD-specific).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TSPAN14 and TSPAN10, which are involved in scaffolding ADAM10, had a GWAS variant and a coding variant, respectively, in this study.

    “First, TSPAN14 and TSPAN10 are involved in scaffolding ADAM10 and had GWAS and coding variants respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HS3ST1 had a GWAS variant and HSPG2 had a coding variant, with both genes involved in heparin sulfate biology.

    “Third, HS3ST1 had a GWAS variant, and HSPG2 had a coding variant, with both involved in heparin sulfate biology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The chip heritability of age at dementia onset calculated by GEMMA was 0.74 ± 0.14, with a Vg estimate of 24.6 and Ve estimate of 8.5.

    “The chip heritability calculated by GEMMA was 0.74+/-0.14 with a Vg estimate of of 24.6 and Ve estimate of 8.5.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Previously established APOE variants important for AD association in late-onset AD showed effects in the expected direction in this cohort, but with modest magnitude.

    “Effects of previously established APOE variants important for AD association in LOAD are in the expected direction based on previous studies, but modest in magnitude (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A common variant in TSPAN14, rs6586028, replicated in this cohort, and a coding variant in TSPAN10 was also identified.

    “A common variant in TSPAN14, rs6586028 (recently newly implicated in LOAD [19]), replicated in this cohort, and we also identified a coding variant in TSPAN10 (Table 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 19. Bellenguez C, Kucukali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022;54:412- 36. [PubMed: 35379992] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Two variants were identified in or near heparin sulfate associated genes: rs6448453, a common variant near HS3ST1, and rs143543800, a rare variant in HSPG2.

    “Two variants were identified in or near heparin sulfate associated genes including rs6448453, a common variant near HS3ST1, and rs143543800, a rare variant in HSPG2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    ACE had both a GWAS variant and a coding variant in this study.

    “Second, ACE had a GWAS and coding variant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Six of the 13 highlighted top candidate associations had allele counts between 3 and 7 and were driven by a small number of individuals with a late age of onset.

    “In particular, 6 of the 13 associations highlighted as top candidate associations are observed with an allele count of between 3-7, and thus these associations are driven by a small number of individuals with a late age of onset.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Previously identified genome-wide significant variants for AD-associated phenotypes showed p < 0.05 and consistent direction of effect in this cohort.

    “Hits with genome-wide significance for AD-associated phenotypes from previous studies with p<0.05 and consistent direction of effect in this cohort.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The variants presented in the study should be viewed as speculative, especially those where a small number of alleles account for the association, including 6 of the 13 loci in Table 1 with allele counts of 3-7.

    “Because of this, the variants presented throughout should be viewed as speculative, particularly variants where a small number of alleles account for the association (including 6 out of the 13 loci presented in Table 1 where allele count ranges from 3-7).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Imputation quality for variants presented in the tables averaged 0.95 ± 0.09, with only one variant having R2 below 0.85 (rs11705431, R2=0.671).

    “This table also includes imputation quality (R2) for variants presented in all tables, including those in Table 1 (average +/-standard deviation = 0.95 +/-0.09), with only one variant with an R2 < 0.85 (rs11705431, R2=0.671)).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The nominal associations identified in this study are speculative.

    “Still, we recognize the speculative nature of the nominal associations identified in this study.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Genetic relatedness was assessed using KING 2.2.

    “Genetic relatedness was assessed using KING 2.2 [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] 14. Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010;26:2867-73. [PubMed: 20926424] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is a strong correlation between age at onset and the specific autosomal dominant Alzheimer's disease mutation (r2 = 0.52), but substantial variability remains unexplained.

    “There is a strong correlation between age at onset (AAO) and a particular ADAD mutation (r 2 = 0.52) [2], but there still remains substantial unexplained variability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] 2. Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014;83:253-60. [PubMed: 24928124] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because of the nature of the analysis, alleles present in a small number of individuals with particularly late age at onset can produce a low p-value and large effect size (winner's curse), so large effect sizes in this study should be interpreted with caution.

    “However, we note that due to the nature of the analysis, it is possible for the presence of alleles in a small number of individuals with a particularly late age at onset to result in a low p value and large effect size (”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The modest effect size of APOE Christchurch could be because the model does not consider homozygosity effects.

    “which could be because our model does not consider homozygosity effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SIAH3 has been associated through another GWAS with rate of ventricular enlargement in the ADNI cohort, and this association has also been observed separately with variants near CLU.

    “In addition, SIAH3 has been associated through another GWAS to rate of ventricular enlargement in the ADNI cohort [42], an association that has also been separately observed with variants near CLU [43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] 42. Li X, Chu SG, Shen XN, Hou XH, Xu W, Ou YN, et al. Genome-wide association study identifies SIAH3 locus influencing the rate of ventricular enlargement in non-demented elders. Aging (Albany NY). 2019;11:9862-74. [PubMed: 31711042] source

      Not checked in the free run.

    • cites [43] 43. Roussotte FF, Gutman BA, Madsen SK, Colby JB, Thompson PM, Alzheimer's Disease Neuroimaging I. Combined effects of Alzheimer risk variants in the CLU and ApoE genes on ventricular expansion patterns in the elderly. J Neurosci. 2014;34:6537-45. [PubMed: 24806679] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TSPAN14 and TSPAN10 code for tetraspanins in the TspanC8 subgroup, which promote ADAM10 maturation.

    “These two genes code for tetraspanins that are a part of the TspanC8 subgroup of tetraspanins which promote ADAM10 maturation [47].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] 47. Haining EJ, Yang J, Bailey RL, Khan K, Collier R, Tsai S, et al. The TspanC8 subgroup of tetraspanins interacts with A disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression. J Biol Chem. 2012;287:39753-65. [PubMed: 23035126] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The number of replicated prior GWAS hits with nominal significance and consistent direction (six observed) is close to the number expected by random sampling (about four expected), so this table should be interpreted with caution.

    “This table should be interpreted with caution, as it is close to the number of variants that would be expected based on random sampling of this set of GWAS hits (six observed versus ~four expected)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    While age at dementia onset in ADAD has a strong heritable component, it is likely that many different genetic contributors sum to determine an individual's age at dementia onset, as with LOAD.

    “An important overarching theme from this analysis is that while age at dementia onset in ADAD has a strong heritable component, it is likely that, as with LOAD, there are many different genetic contributors that sum to determine an individual's age at dementia onset for ADAD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Participants were evaluated with a standard protocol that included physical and neurological examination and population-validated neuropsychological assessment.

    “Participants were evaluated following a standard protocol including physical and neurological examination, as well as population-validated neuropsychological assessment [10,11].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] 10. Aguirre-Acevedo DC, Gomez RD, Moreno S, Henao-Arboleda E, Motta M, Munoz C, et al. [Validity and reliability of the CERAD-Col neuropsychological battery]. Rev Neurol. 2007;45:655-60. [PubMed: 18050096]

      Not checked in the free run.

    • cites [11] 11. Ardila A, Lopera F, Rosselli M, Moreno S, Madrigal L, Arango-Lasprilla JC, et al. Neuropsychological profile of a large kindred with familial Alzheimer's disease caused by the E280A single presenilin-1 mutation. Arch Clin Neuropsychol. 2000;15:515-28. [PubMed: 14590205] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The main association analysis used GEMMA, a linear mixed model likelihood ratio test that adjusts for relatedness between individuals.

    “We employed GEMMA, a package that performs a likelihood ratio test using a linear mixed model to adjust for relatedness between individuals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 13. Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012;44:821-4. [PubMed: 22706312] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Colombian PSEN1 E280A kindred is the world's largest autosomal dominant Alzheimer's disease founder population and has a comprehensive family tree of thousands of individuals.

    “Large ADAD families such as the kindred harboring the Colombian PSEN1 NM_000021:c.839A>C,p. (Glu280Ala) (canonically known as PSEN1 E280A) mutation, the world's largest ADAD founder population with a comprehensive family tree of thousands of individuals [3], provide an opportunity to assess the contribution of genetic variation to unexplained variability in age of dementia onset.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] 3. Lopera F, Ardilla A, Martinez A, Madrigal L, Arango-Viana JC, Lemere CA, et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997;277:793-9. [PubMed: 9052708] source

      Not checked in the free run.

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

    Study design and conductown data

    Patients had extensive follow-up, with a mean of 6.7 medical evaluations (range 1-27) and 4.8 neuropsychological evaluations (range 1-18).

    “The patients had extensive follow up data; the mean number of medical evaluations was 6.7 (1-27), and 4.8 (1-18) for neuropsychological evaluations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Heparin sulfate has been implicated in cell-to-cell spread of tau and other AD-associated processes.

    “Heparin sulfate has been implicated in cell-to-cell spread of tau [45] as well as other AD-associated processes [46], pointing to potential importance of this pathway for dominant AD.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] 45. Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013;110:E3138-47. [PubMed: 23898162] source

      Not checked in the free run.

    • cites [46] 46. Snow AD, Cummings JA, Lake T. The Unifying Hypothesis of Alzheimer's Disease: Heparan Sulfate Proteoglycans/Glycosaminoglycans Are Key as First Hypothesized Over 30 Years Ago. Front Aging Neurosci. 2021;13:710683. [PubMed: 34671250] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because the three largest available ADAD datasets were analyzed, it is not possible to further increase sample size or replication in ADAD, so the findings are presented in light of replication with available ADAD, sporadic EOAD, and LOAD cohorts.

    “However, because we analyzed the three largest ADAD datasets available in the field, it is not possible to further increase sample size or replication in ADAD, and we therefore present these findings in light of replication with these available ADAD cohorts as well as sporadic EOAD and LOAD cohorts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    As the largest age at onset modifier study in ADAD to date, this study has nominated several new candidate genetic associations with age of dementia onset in ADAD.

    “As the largest age at onset modifier study in ADAD to date (to our knowledge), this study has nominated several new candidate genetic associations with age of dementia onset in ADAD.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    As an additional quality control measure, only variants called in the genomes of the 26 individuals sequenced at HudsonAlpha were considered.

    “As an additional quality control measure, note that we also only considered variants called in the genomes of the 26 individuals sequenced at HudsonAlpha (see methods).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Dementia was diagnosed according to the most recent DSM criteria at the time of diagnosis.

    “Dementia was diagnosed according to most recent DSM criteria at the time of diagnosis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The association analysis adjusted for genetic sex, the first ten principal components, and batch.

    “We adjusted for genetic sex, the first ten principal components (calculated from the set of 540,753 high quality variants used as imputation input using PLINK v2.00aLM) because this was an admixed population, and batch.”
    Quote in the paperSubstantial claim
37 of 37

  • The paper relies on this without support.

    Autosomal dominant Alzheimer's disease closely resembles late-onset Alzheimer's disease clinically and neuropathologically but lacks the aging confound, so it provides a less heterogeneous view of underlying AD processes.

    “Autosomal dominant Alzheimer's disease (ADAD) closely resembles the clinical and neuropathological features of LOAD, but without the confound of aging, and thus provides a less heterogeneous view of underlying AD-associated processes.”

  • The paper relies on this without support.

    The Colombian PSEN1 E280A population has a relatively homogeneous set of environmental influences.

    “While environmental influences will always be present, this population has a relatively homogeneous set of environmental influences.”

  • The paper relies on this without support.

    The late-onset AD polygenic risk score, derived from late-onset AD, is informative for age at dementia onset in carriers of the PSEN1 E280A mutation.

    “Late onset AD polygenic risk score applied to the PSEN1 E280A cohort.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The original report of four APOE3Ch heterozygotes did not describe delayed cognitive impairment onset, leading the authors and others to first conclude that APOE3Ch heterozygosity was not protective.

    “Our original report about one person in this population who was homozygous for APOE3Ch7 also discussed four persons with the PSEN1E280A variant who were heterozygous for APOE3Ch, and we did not describe a delay in the age at onset of cognitive impairment. This finding led us7 and others18 to initially conclude that APOE3Ch heterozygosity was not protective.”

    From <i>APOE3</i> Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease (2024) · cites this paper as [18]

    The Results at key APOE variants discuss a Christchurch case report and find a modest, nominally significant association with later age at onset. Our copy does not say that this paper initially concluded heterozygosity was not protective, or describe the original report’s four heterozygotes and their cognitive-impairment onset (searched: four heterozygotes, initial conclusion, protective effect). The paper’s current finding does not establish what its authors concluded initially. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Cochran, J. N., Acosta‐Uribe, J., Esposito, B. T., Madrigal, L., Aguillón, D., Giraldo, M. M., Taylor, J. W., Bradley, J., Fulton‐Howard, B., Andrews, S. J., Acosta‐Baena, N., Alzate, D., Garcia, G. P., Piedrahita, F., Lopez, H. E., Anderson, A. G., Rodriguez‐Nunez, I., Roberts, K., Dominantly Inherited Alzheimer Network, Absher, D., Myers, R. M., Beecham, G. W., Reitz, C., Rizzardi, L. F., Fernandez, M. V., Goate, A. M., Cruchaga, C., Renton, A. E., Lopera, F., & Kosik, K. S.
Affiliations
  • HudsonAlpha Institute for Biotechnology (US)
  • University of California, Santa Barbara (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Grupo de Neurociencias de Antioquia. School of Medicine. Universidad de Antioquia Medellín Antioquia Colombia
  • Universidad de Antioquia (CO)
  • Washington University in St. Louis (US)
  • HudsonAlpha Institute for Biotechnology Huntsville Alabama USA
  • University of Miami (US)
  • Columbia University (US)
  • Washington University School of Medicine St. Louis Missouri USA
Corresponding author
Cochran, Jesse Nicholas
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2023-03-23
Volume
19
Issue
9
Pages
3835-3847
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.13021
PMC
PMC10514237
OpenAlex
W4360601157
Cited by
21
References
55
Citations by year
2026: 5 · 2025: 4 · 2024: 8 · 2023: 3
FWCI
3.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Larry L. Hillblom Foundation
  • National Institute on Aging (4R00AG068271, 1R56AG062479)
  • Michael J. Fox Foundation for Parkinson's Research
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, age of onset
MeSH terms
Alzheimer Disease, Amyloid, Colombia, Humans, Mutation, Age of Onset, Clusterin, Presenilin-1

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 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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