Introduction Cardiorespiratory fitness (CRF) may mitigate Alzheimer's disease (AD) progression. This study examined the longitudinal associations of CRF with brain atrophy and cognitive decline in a late‐middle‐aged cohort of adults at risk for AD. Methods One hundred ten cognitively unimpaired adults (66% female, mean age at baseline 64.2 ± 5.7 years) completed a baseline graded treadmill exercise test, two brain magnetic resonance imaging scans (over 4.67 ± 1.17 years), and two to three cognitive assessments (over 3.26 ± 1.02 years). Linear mixed effects models examined the longitudinal associations adjusted for covariates. Results Participants with higher baseline CRF had slower annual decline in total gray matter volume ( P = .013) and cognitive function ( P = .048), but not hippocampal volume ( P = .426). Exploratory analyses suggested these effects may be stronger among apolipoprotein E ε4 carriers. Discussion CRF is a modifiable physiological attribute that may be targeted during the preclinical phase of AD in effort to delay disease progression, perhaps most effectively among those with genetic risk.

Introduction Individuals with Alzheimer's disease (AD) broadly exhibit lower cardiorespiratory fitness (CRF) compared to cognitively healthy older adults. Other factors, such as increasing age and female sex, are also known to track with lower CRF levels. However, it is unclear how these factors together with AD diagnosis and genetic risk (apolipoprotein e4 ; APOE4 ) collectively affect CRF. Methods Our primary objective was to characterize the collective relationship of age, sex, APOE4 carrier status , and cognitive status (nondemented or AD) with two commonly reported CRF outcomes, VO 2 max and oxygen uptake efficiency slope (OUES). To interrogate the unique and combined effect of age, sex, APOE4 , and cognitive status on CRF, we pooled multiple datasets and tested several statistical models allowing all possible interactions. Results AD diagnosis was consistently associated with lower maximal CRF, which declined with increasing age. APOE4 was also associated with lower maximal CRF (VO 2max ), but only in male subjects. Submaximal CRF (OUES) was lower in APOE4 carriers of both sexes, although this difference converged in male subjects with advancing age. Discussion This multi‐cohort analysis (n = 304) suggests that APOE4 carrier status and sex are important considerations for studies that evaluate maximal and submaximal CRF.

This study examined five-year changes in cardiorespiratory fitness, physical activity, and sedentary time in mid-to-late aged adults. Fifty-seven participants completed baseline and follow-up treadmill exercise tests and physical activity monitoring. We observed a 14% decline in fitness (p<.001), 12% decrease in physical activity (p= 0.010), and non-significant increase in sedentary time (p=.196). Age was negatively associated with five-year change in physical activity (r=-.31; p=.02) and this decline was strongest among APOE ε4 carriers (g=-0.75). Novelty: • Cardiorespiratory fitness and physical activity significantly declined from mid-to-late adulthood, these findings were most pronounced among older adults and those with genetic risk for Alzheimer’s disease.

Introduction Recent evidence has illustrated that gray matter (GM) atrophy, a diagnostic hallmark of Alzheimer’s disease (AD), may be influenced by psychosocial risk modifiers such as physical exercise and sleep. Cardiorespiratory fitness, a measure of oxygen delivery and utilization during exercise, is positively associated with both sleep quality and gray matter volume in brain areas associated with age-related cognitive decline, such as the hippocampus. In contrast, sleep apnea has been linked to global and regional gray matter atrophy, which is thought to be driven in-part by the incomplete modulation of cardiovascular and respiratory control during sleep. This study examines whether cardiorespiratory fitness modifies the deleterious relationship between sleep apnea and GM volume in a sample of non-demented older participants from the Wisconsin Sleep Cohort (WSC). Methods Using data from a subset of WSC participants (n=129, 51% female, mean [range] age at baseline=68 [49-85] years), cardiorespiratory fitness was estimated using a Non-Exercise CardioRespiratory Fitness Measure (NECRFM; based on age, sex, BMI, self-reported physical activity, and resting heart rate). Sleep apnea severity was measured by overnight polysomnography and characterized by the base 10 logarithm of the apnea-hypopnea index, log10(AHI+1). We assembled cross-sectional linear models of MRI-measured total GM volume using NECRFM and log10(AHI+1) as predictors while controlling for age, sex, BMI, education, and hypertension. Regional volumetric changes in the hippocampus and amygdala were assessed using analogous linear models, adjusting both outcome volumetrics for total intracranial volume. Results While the interaction between fitness and apnea severity was not significant (p=0.50), results stratified at the median NECRFM illustrated that among the less fit individuals, higher log10(AHI+1) was associated with a significant reduction in total GM volume (B(SE)=-0.06 (0.02); p=0.007); this relationship was not significant among those who were more fit (B(SE)=-0.03 (0.02); p=0.11). There were no significant effects in the hippocampus or amygdala. Conclusion These results indicate that cardiovascular fitness may attenuate the effect of severe sleep apnea on GM volume in older adults, supporting the protective role of cardiovascular fitness in aging brain health. Support (if any) This work was supported by United States National Institutes of Health grants R01AG058680, R01HL62252, 1R01AG036838, 1UL1RR025011, and R01AG062167.

Although previous studies have highlighted the association between physical activity and lower extremity function (LEF) in elderly individuals, the mechanisms underlying this relationship remain debated. Our recent work has recognized the utility of nonlinear trimodal regression analysis (NTRA) parameters in characterizing changes in soft tissue radiodensity as a quantitative construct for sarcopenia in the longitudinal, population-based cohort of the AGES-Reykjavík study. For the present work, we assembled a series of prospective multivariate regression models to interrogate whether NTRA parameters mediate the 5-year longitudinal relationship between physical activity and LEF in AGES-Reykjavík participants. Healthy elderly volunteers from the AGES-Reykjavík cohort underwent mid-thigh X-ray CT scans along with a four-part battery of LEF tasks: normal gait speed, fastest-comfortable gait speed, isometric leg strength, and timed up-and-go. These data were recorded at two study timepoints which were separated by approximately 5 years: AGES-I (n = 3157) and AGES-II (n = 3098). Participants in AGES-I were likewise administered a survey to approximate their weekly frequency of engaging in moderate-to-vigorous physical activity (PAAGES-I). Using a multivariate mediation analysis framework, linear regression models were assembled to test whether NTRA parameters mediated the longitudinal relationship between PAAGES-I and LEFAGES-II; all models were covariate-adjusted for age, sex, BMI, and baseline LEF, and results were corrected for multiple statistical comparisons. Our first series of models confirmed that all four LEF tasks were significantly related to PAAGES-I; next, modelling the relationship between PAAGES-I and NTRAAGES-II identified muscle amplitude (Nm) and location (μm) as potential mediators of LEF to test. Finally, adding these two parameters into our PAAGES-I → LEFAGES-II models attenuated the prior effect of PAAGES-I; bootstrapping confirmed Nm and μm as significant partial mediators of the PAAGES-I → LEFAGES-II relationship, with the strongest effect found in isometric leg strength. This work describes a novel approach toward clarifying the mechanisms that underly the relationship between physical activity and LEF in aging individuals. Identifying Nm and μm as significant partial mediators of this relationship provides strong evidence that physical activity protects aging mobility through the preservation of both lean tissue quantity and quality.