Genetic risk for Alzheimer’s disease predicts hippocampal volume through the lifespan

INTRODUCTION It is unknown whether genetic risk for Alzheimer’s disease (AD) represents a stable influence on the brain from early in life, or whether effects are age-dependent. It is critical to characterize the effects of genetic risk factors on the primary neural substrate of AD, the hippocampus, throughout life. METHODS Relations of polygenic risk score (PGS) for AD, including variants in Apolipoprotein E (APOE) with hippocampal volume and its change were assessed in a healthy longitudinal lifespan sample (n = 1181, 4-95 years), followed for up to 11 years with a total of 2690 MRI scans. RESULTS AD-PGS showed a significant negative effect on hippocampal volume. Offset effects of AD-PGS and APOE ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed. DISCUSSION: Endophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in healthy persons. Highlights Genetic risk for AD affects the hippocampus throughout the lifespan APOE ε4 carriers have smaller hippocampi in development Different effects of genetic risk at different ages were not consistently observed Genetic factors increasing risk for AD impact healthy persons throughout life A broader population and age range are relevant targets for attempts to prevent AD

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