Genetically linked brain imaging markers of memory decline in aging and Alzheimer's disease

INTRODUCTION: Memory is a strong endophenotype for Alzheimer's disease (AD) but is typically detectable only after substantial brain change. Genetically linking late-life memory with mid-life brain traits may identify early markers of AD-related cognitive decline. METHODS: We leveraged GeNetic cOVariance Analyzer (GNOVA) to estimate genetic covariance between genome-wide association studies (GWASs) of memory performance (MEM) and decline (memslopes) and 3935 UK Biobank (UKB) imaging-derived phenotypes (IDPs) across diffusion, structural, and functional modalities, stratifying by cognitive status and apolipoprotein E (APOE) inclusion. Memory GWASs included 24,216 non-Hispanic White older adults (mean = 74.46 years); IDP GWASs included 33,224 European-ancestry mid-life participants (45.1 to 81.8 years, mean = 64.28). RESULTS: Diffusion and structural IDPs in medial temporal and frontal regions showed the strongest genetic covariance with memory, with additional shared genetic architecture in default mode network functional connectivity. DISCUSSION: Mid-life brain traits genetically linked to late-life memory map to AD-vulnerable regions, suggesting biologically relevant risk pathways and potential drug targets for cognitive decline.