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

Abstract

To examine whether a polygenic risk score (PRS) derived from <i>APOE4, CLU,</i> and <i>ABCA7</i> 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. Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for <i>APOE4</i>, <i>CLU</i>, and <i>ABCA7</i>, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ₄₂), Aβ₄₀, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ₄₂/Aβ₄₀ and tau/Aβ₄₂ 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 PRS×CRF term in the models, we examined whether these associations were modified by CRF. A higher PRS was associated with lower Aβ₄₂/Aβ₄₀ (<i>p</i> < 0.001), higher t-tau/Aβ₄₂ (<i>p</i> = 0.012), and higher p-tau/Aβ₄₂ (<i>p</i> = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ₄₂/Aβ₄₀ (<i>p</i> = 0.003), t-tau/Aβ₄₂ (<i>p</i> = 0.003), and p-tau/Aβ₄₂ (<i>p</i> = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. 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.