Alzheimer’s disease polygenic scores predict changes in executive function across 12 years in late middle age

Abstract

Genome-wide association studies are instrumental in quantifying genetic influences underlying Alzheimer's disease (AD), and applications of polygenic scores derived from association studies have already shed light on early disease pathology. For example, AD polygenic scores (AD-PGS) are associated with amnestic mild cognitive impairment (MCI) diagnoses in midlife. What remains unclear is how AD-PGS relate to objectively measured cognitive changes across midlife. Moreover, executive function abilities have been somewhat neglected despite prominent executive impairments in MCI and AD. Here we tested the hypothesis that an AD-PGS would be associated with executive function and episodic memory changes across late midlife.We examined 1412 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively normal at their first assessment and had up to 3 cognitive assessments across 10-12 years (mean ages 56, 62, and 68). Latent growth models of executive function were based on 6 tasks spanning inhibition, shifting, and working memory subdomains and growth models of episodic memory were based on 7 subtests from the Logical Memory, Visual Reproductions, and California Verbal Learning tests. The AD-PRS (Lambert et al. 2013) significantly differentiated MCI and cognitively normal participants in earlier VETSA investigations.Latent growth models of executive function and memory indicated that, compared to baseline performance (i.e., intercept at mean age 56), 10-year variability in cognitive change was comparatively larger for executive function (e.g., slope variance/intercept variance ratio=39% for executive function, 22% for memory). Importantly, individuals with higher AD-PGS had sharper declines in executive functioning (r= -.24, 95% CI [-.41, -.08]) but not episodic memory (r= -.11, 95% CI [-.25, .04]). Baseline executive function (r=.00) and memory (r=-.02) were not associated with PD-PGS.AD genetic risk was associated with executive function changes, but not episodic memory changes, across midlife. These findings highlight the importance of considering executive function changes in midlife, especially for predicting disease progression and AD biology. Executive functions are one of the first cognitive abilities to decline in midlife in normal aging. This study is among the first to demonstrate that this decline also relates to AD genetic influences.