Whole genome sequencing analysis of over 3500 individuals dementia-free over 85 years old.

BackgroundIdentifying genetic variants conferring resilience to Alzheimer's disease and related dementia (ADRD) may hold promise for developing therapeutics.ObjectiveTo determine genetic associations with being dementia-free at age 85 (DF85).MethodsWe 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 = 3657) against individuals who were not DF85 (n = 20,010). We verified associations using a stricter control set who developed dementia before age 85 (n = 5552).ResultsWe 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 aggregate of rare loss of function and disruptive missense variants in FBXW10 on chr 17 (p = 1.4 × 10-7) associated with DF85.ConclusionsThrough 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.