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Genetic modifiers of APOE-ε4-associated cognitive decline

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Producción científica: Article › revisión exhaustiva

Resumen

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4–associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Idioma originalEnglish
Número de artículo2982
PublicaciónNature Communications
Volumen17
N.º1
DOI
EstadoPublished - dic 2026

Nota bibliográfica

Publisher Copyright:
© The Author(s) 2026.

Financiación

The ADSP Phenotype Harmonization Consortium (ADSP-PHC) is funded by NIA (U24 AG074855, U01 AG068057, and R01 AG059716). The ADSP-PHC cohorts include: Adult Changes in Thought (ACT, U01 AG006781, U19 AG066567), the Alzheimer’s Disease Neuroimaging Initiative (ADNI), funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904), and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The Memory and Aging Project at the Knight-ADRC (Knight-ADRC), supported by NIH grants R01AG064614, R01AG044546, RF1AG053303, RF1AG058501, U01AG058922, and R01AG064877 to Carlos Cruchaga. The recruitment and clinical characterization of research participants at Washington University was supported by NIH grants P30AG066444, P01AG03991, and P01AG026276. Data collection and sharing for this project was supported by NIH grants RF1AG054080, P30 AG066462, R01AG064614, and U01AG052410. Additional funding includes K01-073584. The Minority Aging Research Study (MARS, R01 AG22018, R01 AG42210). The National Alzheimer’s Coordinating Center (NACC, U01 AG016976) database, funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P30 AG086403 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD); the Religious Orders Study (P30 AG10161, P30 AG72975, R01 AG15819, R01 AG17917, U01 AG46152, and U01 AG61356), the RUSH Memory and Aging Project (MAP, R01 AG017917, R01 AG42210), and the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania funded by NIA. ROSMAP resources can be requested at https://www.radc.rush.edu and www.synpase.org . The BLSA study is supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. The BIOCARD study is supported by U19–AG033655 from the National Institute on Aging. WRAP was supported by R01 AG027161 and RF1AG054047. A.G.C. was supported by T32 AG058524-07. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf . T.J.H., PhD, is a member of the scientific advisory board for Circular Genomics, serves as the deputy editor of Alzheimer’s & Dementia: Translational Research and Clinical Intervention, and serves as Section Editor for Alzheimer’s & Dementia. P.M.T., PhD, received partial grant support from Biogen, Inc., for research unrelated to this work. S.J. has served on advisory boards for AlzPath and Enigma Biomedical in the past 3 years. The remaining authors declare no competing interests.

FinanciadoresNúmero del financiador
Northern California Institute for Research and Education
DoD Alzheimer's Disease Neuroimaging Initiative
University of Southern California
National Institute of Biomedical Imaging and Bioengineering
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis
Biogen, Inc., Cytokinetics, Inc.
National Institutes of Health (NIH)U01AG058922, RF1AG058501, R01AG064877, R01AG064614, R01AG044546, RF1AG053303, P01AG026276, P01AG03991, P30 AG066462, K01-073584, R01 AG42210, P30AG066444, U01 AG024904, U01AG052410, RF1AG054080, R01 AG22018
ADSP-PHCU19 AG066567, U01 AG006781
Rush UniversityR01 AG42210, R01 AG017917
National Alzheimer's Coordinating CenterP30 AG062677, P30 AG086403, P30 AG066514, P30 AG066515, P30 AG72975, P30 AG066518, P30 AG062715, P30 AG066519, P20 AG068053, P30 AG072975, P30 AG072931, P30 AG072976, P20 AG068077, P30 AG072977, P30 AG072972, P30 AG066468, P30 AG072973, U01 AG46152, P30 AG072978, P30 AG072979, P30 AG072958, P30 AG072959, R01 AG15819, P30 AG079280, U01 AG016976, P30 AG062421, P30 AG062422, P30 AG066546, R01 AG17917, U01 AG61356, P30 AG066506, P30 AG066507, P30 AG10161, P30 AG066508, P30 AG062429, P30 AG066509, P30 AG066530, P30 AG066511, P30 AG066512, U24 AG072122, P20 AG068024, P30 AG072946, P30 AG072947
National Institute on AgingR01 AG059716, U24 AG074855, U01 AG068057
The Pennsylvania State UniversityR01 AG027161, U19–AG033655, RF1AG054047, T32 AG058524-07
U.S. Department of DefenseW81XWH-12-2-0012
National Institute on Aging Genetics of Alzheimer’s Disease Data Storage SiteU24AG041689

    ASJC Scopus subject areas

    • General Chemistry
    • General Biochemistry, Genetics and Molecular Biology
    • General
    • General Physics and Astronomy

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