Pleiotropic Associations with Alzheimer's Disease and Physical Activity: Sex Differences and the Effects of Environment.

Physical activity (PA) is a modifiable factor in mitigating/preventing Alzheimer's disease (AD). It is crucial to identify the conditions under which PA's effects on AD risk would be beneficial. This study aims to gain insights into pleiotropic predisposition to AD and PA within and across sexes and environmental effects. We performed a genome-wide association study (GWAS) of pleiotropic AD-PA associations in individuals (65 years and older) of European ancestry in a US sample (14,628 individuals), for men and women separately and combined, and contrasted them with the UK biobank (204,789 individuals) to elucidate the effects of the environment. Fisher's method and Wald's test were used for estimating the significance of pleiotropic associations and differences between the samples. We identified genetic markers in 60 loci with significant pleiotropic associations. Of them, 91.7% of loci exhibited antagonistic relationships characterized by a misalignment of the signs of the associations of the same alleles with AD and PA and a correlation between these phenotypes. Only 16.7% of associations were replicated in the UKB. Phosphorylation and the regulation of transcription were identified as more pronounced biological mechanisms of AD-PA pleiotropy in females and males, respectively. Our results demonstrate the intrinsic heterogeneity of AD-PA pleiotropy and suggest that PA should be used as an intervention against AD with caution, after identifying groups of individuals and combinations of gene-environment interactions with beneficial effects.