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

Abstract

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.

Cardiorespiratory fitness mitigates brain atrophy and cognitive decline in adults at risk for Alzheimer's disease

“…The greatest known genetic risk for AD is the presence of APOE ε4, where carriers have a three‐fold increased risk. 18 Recent research suggests that APOE ε4 carriers have lower CRF than non‐carriers 17 raising the possibility that decreased CRF may be a contributing factor to the increased prevalence of AD observed in this genotype. Exploratory analyses suggest higher CRF at baseline was associated with a slower decline in total gray matter volume and cognitive function among carriers of APOE ε4, but not within non‐carriers.…”

“…We hypothesized that greater baseline CRF would be associated with a reduced rate of brain atrophy and cognitive decline. Lastly, based on data describing the presence of the apolipoprotein E ε4 allele ( APOE ε4) influencing CRF 17 and future risk of AD, 18 we explored the potential effect of APOE ε4 carrier status within our sample.…”

“…Lastly, based on data describing the presence of the apolipoprotein E ε4 allele (APOE ε4) influencing CRF 17 and future risk of AD, 18 we explored the potential effect of APOE ε4 carrier status within our sample.…”

Cardiorespiratory fitness and cognition in persons at risk for Alzheimer's disease

“…These findings suggest that there may be potentially different effects of CRF on longitudinal cognition between the sexes and based on carriage of the APOE ε4 allele. 16,37 That said, it should be noted that the APOE ε4group was about twice the size of the APOE ε4+ group, which may have played a role in the differential APOE ε4 effect. Further studies are necessary for more fully understanding these preliminary findings.…”

“…There is strong evidence that CRF differs between sexes, with males showing higher CRF on average. 15 , 16 Additionally, sex‐dependent differences have been observed when investigating the linkage between CRF and cognition. 8 , 17 Although carriage of the apolipoprotein E ( APOE ) ε4 allele is associated with increased risk of cognitive impairment and decline, 18 this impact of APOE ε4 carriage has been shown to potentially be altered by behavioral choices.…”