Abstract

INTRODUCTIONIt is unknown whether genetic risk for Alzheimers 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.\n\nMETHODSRelations 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.\n\nRESULTSAD-PGS showed a significant negative effect on hippocampal volume. Offset effects of AD-PGS and APOE {varepsilon}4 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.\n\nHighlightsO_LIGenetic risk for AD affects the hippocampus throughout the lifespan\nC_LIO_LIAPOE {varepsilon}4 carriers have smaller hippocampi in development\nC_LIO_LIDifferent effects of genetic risk at different ages were not consistently observed\nC_LIO_LIGenetic factors increasing risk for AD impact healthy persons throughout life\nC_LIO_LIA broader population and age range are relevant targets for attempts to prevent AD\nC_LI