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Alzheimer’s Disease Polygenic Scores Predict Changes in Episodic Memory and Executive Function Across 12 Years in Late Middle Age

Published online by Cambridge University Press:  21 February 2022

Daniel E. Gustavson*
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA
Chandra A. Reynolds
Department of Psychology, University of California, Riverside, 900 University Ave., Riverside, CA, USA
Timothy J. Hohman
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA
Angela L. Jefferson
Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA
Jeremy A. Elman
Department of Psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA
Matthew S. Panizzon
Department of Psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA
Michael C. Neale
Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA
Mark W. Logue
National Center for PTSD, Behavioral Sciences Division, VA Boston Healthcare System, Boston, MA, USA Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Michael J. Lyons
Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA
Carol E. Franz
Department of Psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA
William S. Kremen
Department of Psychiatry and Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA
*Correspondence and reprint requests to: Daniel Gustavson, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Ave., Suite 700, Nashville, TN, 37203. E-mail:



Alzheimer’s disease (AD) is highly heritable, and AD polygenic risk scores (AD-PRSs) have been derived from genome-wide association studies. However, the nature of genetic influences very early in the disease process is still not well known. Here we tested the hypothesis that an AD-PRSs would be associated with changes in episodic memory and executive function across late midlife in men who were cognitively unimpaired at their baseline midlife assessment..


We examined 1168 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively normal (CN) at their first of up to three assessments across 12 years (mean ages 56, 62, and 68). Latent growth models of episodic memory and executive function were based on 6–7 tests/subtests. AD-PRSs were based on Kunkle et al. (Nature Genetics, 51, 414–430, 2019), p < 5×10−8 threshold.


AD-PRSs were correlated with linear slopes of change for both cognitive abilities. Men with higher AD-PRSs had steeper declines in both memory (r = −.19, 95% CI [−.35, −.03]) and executive functioning (r = −.27, 95% CI [−.49, −.05]). Associations appeared driven by a combination of APOE and non-APOE genetic influences.


Memory is most characteristically impaired in AD, but 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 early decline also relates to AD genetic influences, even in men CN at baseline.

Research Article
Copyright © INS. Published by Cambridge University Press, 2022

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