CoChat
Sign Up
Cited by 17Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsGenetic Associations and Epidemiology

Polygenic score modifies risk for Alzheimer's disease in APOE ε4 homozygotes at phenotypic extremes

Open access
Huq, Aamira J., Fulton‐Howard, Brian, Riaz, Moeen, Laws, Simon, Sebra, Robert, Ryan, Joanne, Alzheimer's Disease Genetics Consortium, Renton, Alan E. +9 more·2021·Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
DOI 10.1002/dad2.12226PMC PMC8339682
Open this paper in CoChat — free accountOpen PDF

Abstract

Introduction: Diversity in cognition among apolipoprotein E ( APOE ) ε4 homozygotes can range from early‐onset Alzheimer's disease (AD) to a lifetime with no symptoms. Methods: We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy APOE ε4 homozygotes aged ≥75 years (n = 213) and early‐onset APOE ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results: The PRS for AD was significantly higher in APOE ε4 homozygote AD cases compared to older cognitively healthy APOE ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0–35.2; P = .003). The difference in the same PRS between APOE ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98–9.92; P = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case‐controls. Discussion: A PRS for AD contributes to modified cognitive expression of the APOE ε4/ε4 genotype at phenotypic extremes of risk.

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 · 10.1002/dad2.12226

Cites

14 of 14 references verified0 citation errors · 0 not checkable

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?

  • A cohort of people homozygous for APOEε4 who were still cognitively unimpaired at age >75 ('resilient') had a much lower polygenic risk score than an early-onset (<65 years) Alzheimer disease cohort.

    “This moderating effect has been elegantly shown by comparing the polygenic risk score (PRS) of a cohort of people homozygous for APOEε4 who either had early-onset (<65 years) AD or were still cognitively unimpaired at age >75 (‘resilient’); the resilient cohort had a much lower PRS than the early-onset cohort21.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [21]

    The Methods (Participants; page not available) describe APOE ε4 homozygotes with early-onset AD and older cognitively healthy controls, and the Abstract (Results; page not available) reports a significantly higher AD polygenic risk score in the cases. The age cutoffs differ slightly: the paper includes cases with onset at 65 (≤65) and controls aged 75 (≥75), whereas the claim specifies <65 and >75. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

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

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

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 33

  1. [3]Ridge PG, Hoyt KB, Boehme K, et al. Assessment of the genetic variance of late‐onset Alzheimer's disease. Neurobiol Aging. 2016; 41: 200 e13‐ e20. PMC4948179 27036079
  2. [8]Farrer LA, Cupples LA, Haines JL, et al. 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. 1997; 278: 1349‐ 1356. 9343467
  3. [9]Corder EH, Saunders AM, Strittmatter WJ, et al. 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
  4. [10]Wisdom NM, Callahan JL, Hawkins KA. The effects of apolipoprotein E on non‐impaired cognitive functioning: a meta‐analysis. Neurobiol Aging. 2011; 32: 63‐ 74. 19285755
  5. [11]Davies G, Armstrong N, Bis JC, et al. Genetic contributions to variation in general cognitive function: a meta‐analysis of genome‐wide association studies in the CHARGE consortium (N = 53949). Mol Psychiatry. 2015; 20: 183‐ 192. 25644384 PMC4356746
  6. [12]Marioni RE, Campbell A, Scotland G, Hayward C, Porteous DJ, Deary IJ. Differential effects of the APOE e4 allele on different domains of cognitive ability across the life‐course. Eur J Hum Genet. 2016; 24: 919‐ 923. 26395552 PMC4705436
  7. [13]Lyall DM, Ward J, Ritchie SJ, et al. Alzheimer disease genetic risk factor APOE e4 and cognitive abilities in 111,739 UK Biobank participants. Age Ageing. 2016; 45: 511‐ 517. 27103599
  8. [14]Mayeux R, Saunders AM, Shea S, et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease. N Engl J Med. 1998; 338: 506‐ 511. 9468467
  9. [15]Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011; 13: 597‐ 605. 21577118 PMC3326653
  10. [16]Lambert JC, Ibrahim‐Verbaas CA, Harold D, et al. Meta‐analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45: 1452‐ 1458. 24162737 PMC3896259
  11. [17]Jansen IE, Savage JE, Watanabe K, et al. Genome‐wide meta‐analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nat Genet. 2019; 51: 404‐ 413. 30617256 PMC6836675
  12. [18]Kunkle BW, Grenier‐Boley B, Sims R, et al. Genetic meta‐analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019; 51: 414‐ 430. 30820047 PMC6463297
  13. [19]Chouraki V, Reitz C, Maury F, et al. Evaluation of a genetic risk score to improve risk prediction for Alzheimer's disease. J Alzheimers Dis. 2016; 53: 921‐ 932. 27340842 PMC5036102
  14. [20]Escott‐Price V, Shoai M, Pither R, Williams J, Hardy J. Polygenic score prediction captures nearly all common genetic risk for Alzheimer's disease. Neurobiol Aging. 2017; 49: 214 e7‐ e11. 27595457
  15. [22]Mormino EC, Sperling RA, Holmes AJ, et al. Polygenic risk of Alzheimer disease is associated with early‐ and late‐life processes. Neurology. 2016; 87: 481‐ 488. 27385740 PMC4970660
  16. [23]Martiskainen H, Helisalmi S, Viswanathan J. Effects of Alzheimer's disease‐associated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach. J Alzheimers Dis. 2015; 43: 565‐ 573. 25096612
  17. [25]Ellis KA, Bush AI, Darby D, et al. The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease. Int Psychogeriatr. 2009; 21: 672‐ 687. 19470201
  18. [26]McNeil JJ, Woods RL, Nelson MR, et al. Baseline characteristics of participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci. 2017; 72: 1586‐ 1593. 28329340 PMC5861878
  19. [27]Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele?. Ann Hum Genet. 1999; 63: 301‐ 310. 10738542
  20. [29]Barnett IJ, Lee S, Lin X. Detecting rare variant effects using extreme phenotype sampling in sequencing association studies. Genet Epidemiol. 2013; 37: 142‐ 151. 23184518 PMC3601902
  21. [30]Lambert SA, Abraham G, Inouye M. Towards clinical utility of polygenic risk scores. Hum Mol Genet. 2019; 28: R133‐ R42. 31363735
  22. [31]Choi SW, O'Reilly PF. PRSice‐2: polygenic Risk Score software for biobank‐scale data. Gigascience. 2019; 8: giz082. 31307061 PMC6629542
  23. [32]Euesden J, Lewis CM, PRSice O'ReillyPF. Polygenic Risk Score software. Bioinformatics. 2015; 31: 1466‐ 1468. 25550326 PMC4410663
  24. [33]Xu W, Tan L, Wang HF, et al. Meta‐analysis of modifiable risk factors for Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2015; 86: 1299‐ 1306. 26294005
  25. [34]Larsson SC, Traylor M, Malik R, et al. Modifiable pathways in Alzheimer's disease: mendelian randomisation analysis. BMJ. 2017; 359: j5375. 29212772 PMC5717765
  26. [36]Chan BKC. Data analysis using R programming. Adv Exp Med Biol. 2018; 1082: 47‐ 122. 30357717
  27. [37]Huq AJ, Fransquet P, Laws SM, et al. Genetic resilience to Alzheimer's disease in APOE epsilon4 homozygotes: a systematic review. Alzheimers Dement. 2019; 15: 1612‐ 1623. 31506248
  28. [38]Khera AV, Chaffin M, Aragam KG, et al. Genome‐wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018; 50: 1219‐ 1224. 30104762 PMC6128408
  29. [39]Andrews SJ, Fulton‐Howard B, Goate A. Interpretation of risk loci from genome‐wide association studies of Alzheimer's disease. Lancet Neurol. 2020; 19: 326‐ 335. 31986256 PMC8176461
  30. [40]Barnes DR, Rookus MA, McGuffog L, et al. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genet Med. 2020; 22(10): 1653‐ 1666. 32665703 PMC7521995
  31. [43]DeKosky ST, Aston CE, Kamboh MI. Polygenic determinants of Alzheimer's disease: modulation of the risk by alpha‐1‐antichymotrypsin. Annals of the New York Academy of Sciences. 1996; 802: 27‐ 34. 8993481
  32. [45]Andrews SJ, Fulton‐Howard B, O'Reilly P, Marcora E, Goate AM. collaborators of the Alzheimer's Disease Genetics C. Causal associations between modifiable risk factors and the Alzheimer's phenome. Ann Neurol. 2020. PMC8088901 32996171
  33. [48]Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017; 390: 2673‐ 2734. 28735855

Cited by

Sorted by citations

Authors
Huq, A. J., Fulton‐Howard, B., Riaz, M., Laws, S., Sebra, R., Ryan, J., Alzheimer's Disease Genetics Consortium, Renton, A. E., Goate, A. M., Masters, C. L., Storey, E., Shah, R. C., Murray, A., McNeil, J., Winship, I., James, P. A., & Lacaze, P.
Affiliations
  • The Royal Melbourne Hospital (AU)
  • Icahn School of Medicine at Mount Sinai (US)
  • Monash University (AU)
  • Edith Cowan University (AU)
  • The University of Melbourne (AU)
  • Rush University Medical Center (US)
  • University of Minnesota (US)
Corresponding author
Huq, Aamira J.
ORCID
Venue
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Publisher
Wiley
Published
2021-01
Volume
13
Issue
1
Pages
e12226-e12226
ISSN
2352-8729 (ISSN-L)
DOI
10.1002/dad2.12226
PMC
PMC8339682
OpenAlex
W3189143631
Cited by
17
References
14
Citations by year
2026: 5 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 3
FWCI
1.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Australasian Journal of Paramedicine (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
Funders
  • Alzheimer's Association
  • Victorian Cancer Agency
  • Rush University
  • Commonwealth Scientific and Industrial Research Organisation (U01 AG029824)
  • Monash University
  • Menzies Institute for Medical Research
  • National Institutes of Health (1127060, 1s10od026880-01, 334047)
  • Medical Research Council
  • National Health and Medical Research Council (1127060, 334047 and 1127060, 334047)
  • National Institute on Aging (U01AG058635, 1127060, U01AG016976, U01AG029824, 334047, U01AG032984, RC2AG036528, U01AG052411, U24AG041689, U24AG021886)
  • National Cancer Institute (1127060, 334047)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, polygenic risk score, early-onset Alzheimer's disease, genetic risk, educational attainment, cognitive aging

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