Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD

Objective: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. Methods: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. beta-Amyloid 42 (A beta(42)), A beta(40), total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and A beta(42)/A beta(40) and tau/A beta(42) ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRSxCRF term in the models, we examined whether these associations were modified by CRF. Results: A higher PRS was associated with lower A beta(42)/A beta(40) (p < 0.001), higher t-tau/A beta(42) (p = 0.012), and higher p-tau/A beta(42) (p = 0.040). Furthermore, we observed PRS 3 CRF interactions for A beta(42)/A beta(40) (p = 0.003), t-tau/A beta(42) (p = 0.003), and p-tau/A beta(42) (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. Conclusions: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.