Leveraging the comprehensive resources of the UK Biobank, we aimed to: (1) investigate the associations of trajectories of plasma AD-related biomarkers (Aβ42/40 ratio, GFAP, NfL, and p-tau181) with longitudinal changes in cognitive function and brain structures; and (2) examine whether cognitive reserve moderates the associations of plasma AD-related biomarkers with cognitive decline in dementia-free middle-aged and older adults. This evidence concerns the gene GFAP and Mental deterioration.