Language

English

Publication Date

6-1-2026

Journal

Journal of Alzheimer's Disease

DOI

10.1177/13872877261444302

PMID

42024100

PMCID

PMC13162269

PubMedCentral® Posted Date

5-13-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

BACKGROUND:

Identifying genetic variants conferring resilience to Alzheimer’s disease and related dementia (ADRD) may hold promise for developing therapeutics.

OBJECTIVE:

To determine genetic associations with being dementia-free at age 85 (DF85).

METHODS:

We examined genetic associations, using whole genome sequencing data, with DF85 in three Trans-Omics for Precision Medicine cohorts and the Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium. We tested common variants individually and aggregation of rare (MAF≤1%) coding and non-coding variants in DF85 participants (n=3,657) against individuals who were not DF85 (n=20,010). We verified associations using a stricter control set who developed dementia before age 85 (n=5,552).

RESULTS:

We observed an association at APOE (rs429358, MAF=0.21, odds ratio [OR]=0.49, 95% confidence interval [CI]=0.46–0.53, p=1.0×10−92) as well as for two common variants (rs16892237-A near MAL2, MAF=0.08, OR=1.34, 95% CI=1.21–1.48, p=1.1×10−8 and rs8004018-G near GCH1, MAF=0.16, OR=1.24, 95% CI=1.15–1.34, p=1.7×10−9) and an aggregated rare loss of function and disruptive missense variants in FBXW10 on chr 17 (p=1.4×10−7) associated with DF85.

CONCLUSION:

Through a genome-wide assessment of a resilience-focused outcome, we identified common and rare genetic variants contributing to DF85 status. Genes associated with DF85 may delay onset of ADRD and provide translational impact.

Keywords

Humans, Whole Genome Sequencing, Female, Male, Aged, 80 and over, Dementia, Alzheimer Disease, Genome-Wide Association Study, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Variation, Cohort Studies, Alzheimer’s Disease, association study, common variants, dementia-free, genetic association, protective variants, rare variants

Published Open-Access

yes

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