Exercise: Just What the Doctor Ordered, But Why? Elucidating Mechanisms for Women's Increased High-Density Lipoprotein Benefit From Exercise and for the Health ABC Study.

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: ß = 0.09, p = .013; exercise on HDL in women: ß = 0.07, p = .015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors.

The neuroinflammatory marker sTNFR2 relates to worse cognition and tau in women across the Alzheimer's disease spectrum.

Introduction: Despite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging-mild cognitive impairment (MCI)-AD continuum and the mediating role of phosphorylated tau (p-tau) versus other AD biomarkers. Methods: Participants included 284 individuals from the Alzheimer's Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase-3-like protein 1. AD biomarkers were CSF p-tau181 and amyloid beta1-42 levels and magnetic resonance imaging measures of hippocampal and white matter hyperintensity volumes. Results: We found a sex-by-sTNFR2 interaction on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p-tau181 eliminated the female-specific relationships between neuroinflammation and cognition. Discussion: Women may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.