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

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 = 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).

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 aggregate of rare loss of function and disruptive missense variants in FBXW10 on chr 17 (p = 1.4 × 10⁻⁷) associated with DF85.

Conclusions

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.