medRxiv · Mar 5, 2025

Physical activity and APOE neuropathology score modify the association of age and [¹¹C]-PiB-PET amyloid burden in a cohort enriched with risk for Alzheimer's disease

By Blum EG, Edmunds KJ, Breidenbach B et al.

BACKGROUND: Physical activity (PA) is a protective factor against amyloid-β (Aβ) accumulation in adults at risk for Alzheimer's disease (AD). This association, however, may differ by apolipoprotein E (APOE) genotype. This work examines interactions between age, PA, and neuropathology-based genetic risk for AD (APOE np ) on Aβ burden in cortical regions sensitive to its accumulation. MATERIALS AND METHODS: Included were 388 cognitively unimpaired, older (mean age ± SD = 68.10 ± 7.09; 66% female) participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study. The cohort was enriched with both family history of AD at enrollment and a higher overall prevalence of APOE ε4 allele carriage than typically observed in the general population. PA was assessed using a self-reported questionnaire. Aβ burden was measured using Pittsburg Compound B (¹¹C-PiB) PET imaging, which allowed us to derive volume corrected distribution volume ratio (DVR) maps from nine bilateral regions of interest (ROIs) and a global cortical composite score. Linear regression models examined the interactions between age, PA, and APOE np on Aβ burden. Finally, APOE np scores were aggregated according to estimated risk to illustrate the differential effects between active (weekly moderate PA ≥ 150 minutes) and inactive individuals. RESULTS: Three-way interactions (Age × PA × APOE np ) were significant (all P's ≤ 0.05) for the global cortical composite and six of the examined ROIs (the PPC, ACC, mOFC, SMG, MTG, and STG). Models stratified by APOE np and PA showed greater levels of age-related Aβ accumulation in each of these ROIs, with the greatest effects in inactive participants with high APOE np scores. CONCLUSION: Individuals with high APOE np scores who concomitantly engage in suboptimal weekly moderate-intensity PA have greater Aβ burden. These findings underscore how both PA and APOE haplotype play intersect in modifying age-related Aβ burden in brain regions susceptible to its deposition in cognitively unimpaired, older adults at risk for AD.

doi.org/10.1101/2025.03.01.25323157Open accessPubMed 40093261Populations