@article{a8d7ad3d94ec4211a9b6994e49b8f9c6,
title = "Polygenic score modifies risk for Alzheimer's disease in APOE ε4 homozygotes at phenotypic extremes",
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.",
keywords = "Alzheimer's disease, Alzheimer's disease dementia, apolipoprotein E, dementia resilience, genetic modifiers, polygenic risk score",
author = "{Alzheimer's Disease Genetics Consortium} and Huq, {Aamira J.} and Brian Fulton-Howard and Moeen Riaz and Simon Laws and Robert Sebra and Joanne Ryan and Renton, {Alan E.} and Goate, {Alison M.} and Masters, {Colin L.} and Elsdon Storey and Shah, {Raj C.} and Anne Murray and John McNeil and Ingrid Winship and James, {Paul A.} and Paul Lacaze",
note = "Funding Information: ASPREE is supported by a Flagship cluster grant (including the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne); and grants (U01AG029824) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency. Paul Lacaze is supported by a National Heart Foundation Future Leader Fellowship. Dr. Raj Shah serves as a non-compensated member of the Board of Directors of the Alzheimer's Association–Illinois Chapter. Dr. Shah's institution, Rush University Medical Center, receives research support for his role as a Site Principal Investigator or Site Sub-Investigator for industry-initiated clinical trials and research studies of Alzheimer's disease sponsored by Amylyx Pharmaceuticals, Inc.; Eli Lilly & Co., Inc.; Genentech, Inc.; Lundbeck, Inc.; Merck & Co., Inc.; Navidea Biopharmaceuticals; Novartis Pharmaceuticals, Inc.; Roche Holdings AG; and Takeda Development Center Americas, Inc. The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. The NACC database is funded by NIA/NIH Grant U01 AG016976. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01). Dr. Aamira Huq is supported by the Commonwealth Research Training Program Scholarship, Australia (University of Melbourne reference number 96756) and the Yulgilbar Alzheimer Research Program. The authors would also like to acknowledge and thank all the participants in the various cohorts that took part in this study, and their families. Funding Information: ASPREE is supported by a Flagship cluster grant (including the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne); and grants (U01AG029824) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency. Paul Lacaze is supported by a National Heart Foundation Future Leader Fellowship. Dr. Raj Shah serves as a non‐compensated member of the Board of Directors of the Alzheimer's Association–Illinois Chapter. Dr. Shah's institution, Rush University Medical Center, receives research support for his role as a Site Principal Investigator or Site Sub‐Investigator for industry‐initiated clinical trials and research studies of Alzheimer's disease sponsored by Amylyx Pharmaceuticals, Inc.; Eli Lilly & Co., Inc.; Genentech, Inc.; Lundbeck, Inc.; Merck & Co., Inc.; Navidea Biopharmaceuticals; Novartis Pharmaceuticals, Inc.; Roche Holdings AG; and Takeda Development Center Americas, Inc. The National Institutes of Health, National Institute on Aging (NIH‐NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. The NACC database is funded by NIA/NIH Grant U01 AG016976. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24‐AG041689‐01). Dr. Aamira Huq is supported by the Commonwealth Research Training Program Scholarship, Australia (University of Melbourne reference number 96756) and the Yulgilbar Alzheimer Research Program. The authors would also like to acknowledge and thank all the participants in the various cohorts that took part in this study, and their families. Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association",
year = "2021",
doi = "10.1002/dad2.12226",
language = "English",
volume = "13",
journal = "Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring",
issn = "2352-8729",
publisher = "John Wiley & Sons Inc.",
number = "1",
}