BackgroundAge is the cardinal risk factor for Alzheimer’s disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD.MethodsOne hundred and seven cognitively unimpaired, late-middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF.ResultsAs expected, there was a significant association between age and WMH (p < .001). Importantly, there was a significant interaction between age and OUES on WMH (p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group (p < .001) but not in the High OUES group (p = .540), indicating that higher CRF attenuates the deleterious age association with WMH.ConclusionsHigher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD.

Introduction This study examined the relationship between cardiorespiratory fitness (CRF) and longitudinal cognitive functioning in a cohort enriched with risk factors for Alzheimer's disease (AD). Methods A total of 155 enrollees in the Wisconsin Registry for Alzheimer's Prevention completed repeat comprehensive neuropsychological evaluations that assessed six cognitive domains. Peak oxygen consumption (VO 2 peak) was the primary measure of CRF. Random effects regression was used to investigate the effect of CRF on cognitive trajectories. Results Higher CRF was associated with slower decline in the cognitive domains of verbal learning and memory ( P < .01) and visual learning and memory ( P < .042). Secondary analyses indicated that these effects were stronger among men than women, and for noncarriers of the apolipoprotein E ε4 allele. Discussion Higher CRF was associated with a slower rate of the decline in episodic memory that occurs as a natural consequence of aging in a cohort enriched with risk factors for AD.

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.