CoChat
Sign Up
Cited by 30Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAmyotrophic Lateral Sclerosis Research

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease

Open access
Langella, Stephanie, Barksdale, N. Gil, Vasquez, Daniel, Aguillon, David, Chen, Yinghua, Su, Yi, Acosta-Baena, Natalia, Acosta-Uribe, Juliana +17 more·2023·Nature Communications
DOI 10.1038/s41467-023-40775-zPMC PMC10447560
Open this paper in CoChat — free accountOpen PDF

Abstract

Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E ( APOE ) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-023-40775-z

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Some studies have suggested an interaction between APOE genotype and modifiable risk factors, whereby carrying the APOEε4 allele would multiply the increased Alzheimer disease risk associated with the risk factor alone or counteract the reduced Alzheimer disease risk conferred by a protective factor, such as education attainment or physical exercise.

    “Indeed, some studies have suggested an interaction between APOE genotype and several of these modifiable risk factors, whereby carrying the APOEε4 allele would multiply the increased AD risk associated with the risk factor alone (for example, cardiovascular risk factors30) or counteract the reduced AD risk conferred by a protective factor, such as education attainment31 or physical exercise32.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [31]

    Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • APOEε4 can accelerate age-related cognitive decline even in genetically determined Alzheimer disease, such as familial autosomal dominant Alzheimer disease and Down syndrome, whereas APOEε2 can delay age of onset even in familial autosomal dominant Alzheimer disease.

    “Remarkably, APOEε4 can accelerate age-related cognitive decline even in genetically determined AD, such as familial autosomal dominant AD31 and Down syndrome82, whereas APOEε2 can delay age of onset even in familial autosomal dominant AD83.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [31]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 48 · Cited by 30

Research works printed but not linked: 40

  1. [1]Roses AD Apolipoprotein E alleles as risk factors in Alzheimer’s disease Annu. Rev. Med. 1996 47 387 400 8712790
  2. [2]Corder EH Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families Science 1993 261 921 923 8346443
  3. [3]Bagyinszky E Youn YC An S Kim S The genetics of Alzheimer’s disease Clin. Interv. Aging 2014 9 535 24729694 PMC3979693
  4. [7]Almkvist O Johansson C Laffita‐Mesa J Thordardottir S Graff C APOE ε4 influences cognitive decline positively in APP and negatively in PSEN1 mutation carriers with autosomal‐dominant Alzheimer’s disease Eur. J. Neurol. 2022 29 3580 3589 36039401 PMC9826049
  5. [8]Almkvist O Graff C The APOE ε4 allele affects cognitive functions differently in carriers of APP mutations compared to carriers of PSEN1 mutations in autosomal-dominant Alzheimer’s disease Genes 2021 12 1954 34946903 PMC8701239
  6. [9]Van Duijn CM Interaction between genetic and environmental risk factors for Alzheimer’s disease: A reanalysis of case-control studies Genet. Epidemiol. 1994 11 539 551 7713394
  7. [10]Majoka MA Schimming C Effect of social determinants of health on cognition and risk of Alzheimer disease and related dementias Clin. Ther. 2021 43 922 929 34103175
  8. [11]Edwards III, G. A., Gamez, N., Escobedo Jr., G., Calderon, O. & Moreno-Gonzalez, I. Modifiable risk factors for Alzheimer’s disease. Front. Aging Neurosci. 11, 10.3389/fnagi.2019.00146 (2019). PMC6601685 31293412 · DOI · Paper page
  9. [13]Christensen H Education and decline in cognitive performance: compensatory but not protective Int. J. Geriatr. Psychiatry 1997 12 323 330 9152716
  10. [14]Meng X D’Arcy C Education and dementia in the context of the cognitive reserve hypothesis: a systematic review with meta-analyses and qualitative analyses PLoS ONE 2012 7 e38268 22675535 PMC3366926
  11. [16]Aguirre-Acevedo DC Cognitive decline in a colombian kindred with autosomal dominant Alzheimer disease JAMA Neurol. 2016 73 431 26902171 PMC5505685
  12. [17]William Rebeck G Reiter JS Strickland DK Hyman BT Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions Neuron 1993 11 575 580 8398148
  13. [18]Poirier J Apolipoprotein E polymorphism and Alzheimer’s disease Lancet 1993 342 697 699 8103819
  14. [19]Ashford JW APOE genotype effects on Alzheimer’s disease onset and epidemiology J. Mol. Neurosci. 2004 23 157 166 15181244
  15. [20]Reiman EM Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study Nat. Commun. 2020 11 667 32015339 PMC6997393
  16. [21]Arboleda-Velasquez JF Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report Nat. Med. 2019 25 1680 1683 31686034 PMC6898984
  17. [22]Van Broeckhoven C APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer’s disease Neurosci. Lett. 1994 169 179 80 8047278
  18. [25]Lemere CA The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology Nat. Med. 1996 2 1146 1150 8837617
  19. [26]Wildsmith, K. R., Holley, M., Savage, J. C., Skerrett, R. & Landreth, G. E. Evidence for impaired amyloid β clearance in Alzheimer’s disease. Alzheimer’s Res. Ther. 5, 33 (2013). PMC3978761 23849219
  20. [27]Ye S Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target Proc. Natl Acad. Sci. USA 2005 102 18700 18705 16344478 PMC1311738
  21. [28]Sorbi S Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer’s disease Ann. Neurol. 1995 38 124 127 7611715
  22. [29]Polsinelli, A. J. et al. APOE ε4 carrier status and sex differentiate rates of cognitive decline in early‐ and late‐onset Alzheimer’s disease. Alzheimer’s Dement. 10.1002/alz.12831 (2022). PMC10182251 36394443 · DOI
  23. [30]Evans S Cognitive and neural signatures of the APOE E4 allele in mid-aged adults Neurobiol. Aging 2014 35 1615 1623 24582638 PMC4001126
  24. [31]Rusted JM APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures Neuroimage 2013 65 364 373 23063453
  25. [33]Tuminello ER Han SD The apolipoprotein e antagonistic pleiotropy hypothesis: review and recommendations Int. J. Alzheimers Dis. 2011 2011 726197 21423560 PMC3056453
  26. [34]Gharbi-Meliani A The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study Alzheimers Res. Ther. 2021 13 5 33397450 PMC7784268
  27. [35]Dowell NG Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE-e4 carriers compared with non-APOE-e4 carriers NMR Biomed. 2016 29 614 624 26929040
  28. [36]Dowell NG MRI of carriers of the apolipoprotein E e4 allele-evidence for structural differences in normal-appearing brain tissue in e4+ relative to e4- young adults NMR Biomed. 2013 26 674 82 23364916
  29. [37]Fox‐Fuller JT Cortical thickness across the lifespan in a Colombian cohort with autosomal‐dominant Alzheimer’s disease: a cross‐sectional study Alzheimer’s Dement. 2021 13 e12233 PMC8438687 34541287
  30. [38]Wilson RS Education and cognitive reserve in old age Neurology 2019 92 e1041 e1050 30728309 PMC6442015
  31. [39]Sharp ES Gatz M Relationship between education and dementia Alzheimer Dis. Assoc. Disord. 2011 25 289 304 21750453 PMC3193875
  32. [40]Gonneaud J Association of education with Aβ burden in preclinical familial and sporadic Alzheimer disease Neurology 2020 95 e1554 e1564 32759192 PMC7713743
  33. [41]Leuzy A Cullen NC Mattsson-Carlgren N Hansson O Current advances in plasma and cerebrospinal fluid biomarkers in Alzheimer’s disease Curr. Opin. Neurol. 2021 34 266 274 33470669
  34. [42]Telser J Risch L Saely CH Grossmann K Werner P P-tau217 in Alzheimer’s disease Clin. Chim. Acta 2022 531 100 111 35341762
  35. [43]Aguillon, D. et al. Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer’s disease. Alzheimers Dement. 10.1002/alz.12906 (2022). PMC10271963 36571821 · DOI · Paper page
  36. [44]Wisniewski T Drummond E APOE-amyloid interaction: therapeutic targets Neurobiol. Dis. 2020 138 104784 32027932 PMC7118587
  37. [45]Williams T Borchelt DR Chakrabarty P Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease Mol. Neurodegener. 2020 15 8 32005122 PMC6995170
  38. [46]Reiman EM Alzheimer’s prevention initiative: a plan to accelerate the evaluation of presymptomatic treatments J. Alzheimer’s Dis. 2011 26 321 329 21971471 PMC3343739
  39. [47]Lendon CL E280A PS-1 mutation causes Alzheimer’s disease but age of onset is not modified by ApoE alleles Hum. Mutat. 1997 10 186 195 9298817
  40. [48]He, C., Holme, J. & Anthony, J. SNP genotyping: the KASP Assay BT - crop breeding: methods and protocols. in Methods in Molecular Biology (eds. Fleury, D. & Whitford, R.) 75–86 (Springer New York, 2014). 24816661

Authors
Langella, S., Barksdale, N. G., Vasquez, D., Aguillon, D., Chen, Y., Su, Y., Acosta-Baena, N., Acosta-Uribe, J., Baena, A. Y., Garcia-Ospina, G., Giraldo-Chica, M., Tirado, V., Muñoz, C., Ríos-Romenets, S., Guzman-Martínez, C., Oliveira, G., Yang, H.-S., Vila-Castelar, C., Pruzin, J. J., Ghisays, V., Arboleda-Velasquez, J. F., Kosik, K. S., Reiman, E. M., Lopera, F., & Quiroz, Y. T.
Affiliations
  • Harvard University (US)
  • Universidad de Antioquia (CO)
  • Banner Alzheimer’s Institute (US)
  • Brigham and Women's Hospital (US)
  • University of California, Santa Barbara (US)
Corresponding author
Quiroz, Yakeel T.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-08-23
Volume
14
Issue
1
Pages
5120-5120
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-40775-z
PMC
PMC10447560
OpenAlex
W4386097474
Cited by
30
References
48
Citations by year
2026: 8 · 2025: 11 · 2024: 9 · 2023: 2
FWCI
5.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01 AG054671)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
autosomal dominant Alzheimer's disease, apolipoprotein E, APOE ε4, APOE e2 allele, educational attainment, cognitive decline, cognitive trajectories, presenilin-1 E280A mutation, mutation carriers, dementia onset, genetic risk factors, environmental factors
MeSH terms
Alzheimer Disease, Apolipoproteins, Apolipoproteins E, Cognition, Educational Status, Genotype, Humans

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.

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 ›

Are you an author, or do you see a problem with this page? Request a review