Sex modifies the association between cardiorespiratory fitness and insulin resistance in adults at risk for Alzheimer’s disease

This study examines whether sex modifies the association between cardiorespiratory fitness (CRF) and insulin resistance in adults at risk for Alzheimer's disease (AD). This study included <i>n</i> = 1131 (791 females, 340 males; mean age 64.7 years) cognitively unimpaired, nondiabetic participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal observational cohort study enriched with persons with parental history of AD dementia. CRF was estimated using a validated equation, and the homeostatic model assessment for insulin resistance (HOMA-IR) quantified insulin resistance from blood samples. Cross-sectional linear regression models were assembled in a moderation framework to test the interaction between CRF and sex on HOMA-IR scores. Finally, sex-stratified analyses were performed to test within-group associations of CRF and HOMA-IR. CRF was negatively associated with HOMA-IR (β = -0.504, SE = 0.21, <i>p</i> = 0.018) and the interaction of CRF and sex was likewise significant (β = -0.849, SE = 0.18, <i>p</i> < 0.001). Stratified models showed that the magnitude of the association between CRF and HOMA-IR was over twice as strong among males than females (males: β = -0.837, SE = 0.26, <i>p</i> = 0.001; females: β = -0.400, SE = 0.19, <i>p</i> = 0.03). Among older adults at heightened risk for AD, CRF protects against insulin resistance; however, this association may be stronger in aging males than in females.