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Objective: The objective of this study was to identify biomarkers of progressive cortical decline during early middle-age, a time when early intervention could target preclinical ad neurodegeneration. We hypothesized that genetic risk for ad would be associated with cortical thinning in areas of the brain that are the first to reflect ad pathology, including the medial temporal lobes and parietal cortex. In addition, we hypothesized that tau and Aβ would be associated with cortical thinning in ad -vulnerable brain regions. Method: Participants were 155 post-9/11 Veterans from the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort, an ongoing study at the VA Boston Healthcare System. Longitudinal change in cortical thickness was calculated as an annualized measure of the symmetrized percent change. Moderation models examined the interaction between ad PRS and plasma-based biomarker (t-tau or Aβ 42/40 ratio) on annual percent brain change. Results: Higher ad PRS was associated with cortical thinning in a right-hemisphere inferior parietal cortex cluster that included the supramarginal gyrus (peak voxel 59.73, −37.81, 22.74) and angular gyrus. Moderation analyses revealed a significant genetic by t-tau interaction (β = −0.266, p = 0.006). Conclusion: The current study revealed that genetic risk for ad and concentration of tau are associated with accelerated change in the parietal cortex, an area that has long been associated with early changes due to ad. The results underscore the importance of the parietal cortex in the identification of higher risk for neurodegeneration, decades prior to the onset of ad. [ABSTRACT FROM AUTHOR]