Collective effects of age, sex, genotype, and cognitive status on fitness outcomes

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, VO2 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 (VO2max), 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.