Age-related polygenic effects of Alzheimer's disease on brain structures and cognition in middle aged and elderly adults from UK Biobank

Abstract The aetiology of Alzheimer’s disease (AD) involves multiple genes and their interactions, and the polygenetic risk score for AD (AD-PRS) offers a genome-wide assessment of an individual's risk for developing AD. Despite previous suggestions of the polygenic influences on brain structures in cognitively intact ageing populations, the dynamic effects of the AD-PRS on brain structures and cognition throughout the ageing process have not been sufficiently quantified. Here, we analysed data from 29,645 cognitively intact UK Biobank participants. Using a model-free sliding window approach, we revealed that individuals with high AD-PRS exhibited smaller brain structures compared to those with low AD-PRS, with these differences increasing with age in specific brain regions (|ρ| > 0.8, pFDR<0.001). Notable age-related differences were observed in the volumes of the thalamus and hippocampus, as well as the microstructural integrity of the fornix and cingulum. These differences were observed to emerge around the age of 60 and reach approximately 5% difference after the age of 75. Furthermore, the associations between AD-PRS and cognitive performances were mediated by brain structures, with these mediating effects becoming more pronounced with ageing. Additionally, complex interactions between AD-PRS and age on brain structures were observed for specific apolipoprotein E (APOE) genotypes. Our findings underscore the involvement of the hippocampal-thalamic regions in the age-related associations between the AD-PRS and cognitive functions among cognitively normal ageing individuals. This study provides insights into the early screening and intervention strategies leveraging AD-PRS.