Sex differences in exercise-induced pro-inflammatory cytokine responses relevant to Alzheimer's disease: A systematic review and meta-analysis

Background Chronic inflammation contributes to the pathogenesis of Alzheimer's disease (AD), and physical exercise is a promising nonpharmacological strategy for modulating systemic inflammatory responses.However, evidence regarding sex-and exercise typespecific effects on AD-related pro-inflammatory cytokines remains fragmented.Objective To quantitatively synthesize evidence on sex differences in inflammatory cytokine responses relevant to AD according to exercise type, focusing on tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), and interleukin-1β (IL-1β).Methods A systematic search identified randomized controlled trials (RCTs) examining the effects of aerobic exercise (AE), resistance exercise (RE), and combined exercise (CE) on circulating cytokines in adult men and women.Percentage changes from pre-to postintervention were extracted and pooled using random-effects meta-analyses.Subgroup analyses were conducted by sex, exercise type, cytokine, and menopausal status. ResultsThirty-two RCTs involving approximately 1,200 participants were included.TNF-α showed the most consistent response, with significant reductions after AE and CE in both sexes, whereas RE reduced TNF-α primarily in women.IL-6 decreased across exercise typedependent modalities, with the largest reductions following AE and no consistent sex-specific differences.Effects on IL-1β were limited and largely nonsignificant across exercise types.Conclusions Exercise-induced modulation of inflammatory cytokines relevant to AD is cytokine-specific and exercise type-dependent, with additional influence from biological sex.TNF-α appears most responsive to exercise, supporting AE and CE as potential strategies to mitigate systemic inflammation associated with AD risk.Further trials are needed to clarify sex-specific mechanisms and the clinical relevance of exercise-induced inflammatory 3 modulation across the AD continuum.