Cardiorespiratory Fitness Modifies the Association Between Cerebral Pulsatility on Amyloid Burden and Core CSF Biomarkers of Alzheimer’s Disease

Abstract Background Increasing evidence supports the notion that vascular dysfunction contributes to the evolution of Alzheimer’s disease (AD). Cerebral pulsatility index (PI) is reportedly higher in AD and MCI compared to age matched controls and has been associated with greater beta‐amyloid (Aß) burden. Higher cardiorespiratory fitness (CRF) positively affects vascular function and is associated with lower PI in several large cerebral vessels. Our objective was to examine whether CRF modifies the relationship between PI, Aß burden, and core AD cerebrospinal fluid (CSF) biomarkers. Method Cognitively unimpaired adults (n=33, Mean AGE =64.0) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who met study criteria were included. Aß burden was measured as global cortical PiB‐PET. CSF biomarkers were measured with the NeuroTookKit, a panel of robust prototype assays (Roche Diagnostics International Ltd). PI from bilateral MCA vessels were measured using 4D flow MRI and averaged (PI‐MCA AVG ). CRF was indexed as VO 2peak during a graded exercise treadmill test. A single multivariate regression, (covariate‐adjusted for sex, age, and APOE 4) examined whether CRF modifies the impact of PI‐MCA AVG on Aß burden and core‐AD CSF biomarkers [phosphorylated Tau 217 (pTau‐217), total Tau (tTau), Aß 42 /Aß 40 , pTau/Aß 42 ]. When significant, the PI*CRF interaction term would indicate a differential effect of PI on Aß burden or CSF biomarker as a function of CRF. Result There was a significant interaction between PI and VO 2peak on PET Aß burden (ß = ‐0.05, p = 0.04), Aß42/ Aß40 (ß=0.006, p =0.03), pTau (ß= ‐3.4, p =0.03), tTau (ß ‐29.8, p=0.04) and pTau/Aß42 (ß= ‐0.006, p =0.02), indicating less Aß burden and more favorable profiles for all core CSF biomarkers with increasing VO 2peak despite elevated PI. Conclusion Our findings support the hypothesis that greater CRF modifies the effect of cerebral PI on PET Aß burden and core AD CSF biomarkers, indicating that improved VO 2 seems to be protective against cerebrovascular alterations known to contribute to AD‐related biomolecular changes.