Cardiorespiratory fitness bolsters cerebrovascular health in adults at risk for Alzheimer’s disease

Abstract

Background: Cerebral blood flow (CBF) alterations and brain microvascular deficits contribute to progression of Alzheimer's disease (AD). The aim of this series of studies was to evaluate whether cardiorespiratory fitness (CRF) supports cerebrovascular health among individuals at risk for AD. Methods: Four studies were conducted among participants from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Both cohorts are enriched for AD risk due to parental history and/or the APOE e4 allele. Study 1 assessed resting cardiac workload via rate pressure product (RPP=systolic blood pressure*heart rate). Study 2 used 4D flow MRI to quantify pulsatility index [PI=(flow max -flow min )/flow mean ] in cerebral large vessels. Study 3 deployed 3D arterial spin labeling imaging to measure CBF. Study 4 assessed white matter hyperintensity (WMH) lesion volume using 3D MRI scans. In these studies, CRF was assessed via gold-standard graded maximal exercise test or estimated using a validated formula; physical activity (PA) was measured using accelerometry; amyloid and tau were measured from cerebrospinal fluid. Multiple linear regression was used to assess associations among the variables of interest in each study.Results: Study 1 established a positive association between RPP and p-tau and t-tau, but not Ab 42 . This effect was exacerbated in old age. Study 2 revealed that higher CRF was associated with lower PI in the internal carotid and basilar arteries and that traditional cardiovascular risk factors partly mediate those associations. Study 3 revealed that CRF, but not PA, was positively associated with CBF in brain regions vulnerable to hypoperfusion in aging and AD. This effect was stronger among females. Study 4 revealed that increasing age was associated with WMH lesion volume and that this relationship is attenuated by CRF. Conclusion:These studies support that deleterious cardio-and cerebrovascular characteristics associated with AD risk may be ameliorated by CRF, and that age and sex are important modifiers deserving of greater attention in future studies. Notably, CRF appears to exert a stronger effect than PA per se. In sum, CRF is a modifiable physiological characteristic that may reduce cerebrovascular risk in individuals with familial or genetic predisposition to AD.