Aging and Disease · Oct 16, 2026

Exercise, Dynamic Functional Connectivity, and Sex in Alzheimer’s Disease: A Hypothesis-Generating Framework for the Sex-Dependent Dynamic Reconstitution Model

Alzheimer’s disease (AD) is increasingly viewed as a disorder of large-scale brain network dynamics. Whether exercise-related changes in dynamic functional connectivity (dFC) reflect neural reorganization, vascular effects, or both remains uncertain, and most studies have not tested sex as a moderator. We propose the Sex-Dependent Dynamic Reconstitution Model (SDDRM) as a hypothesis-generating framework. Exercise may influence temporal flexibility (a dynamic connectivity metric) through partially sex-dependent pathways. In females, estrogen-BDNF signaling may potentiate medial temporal lobe (MTL) flexibility gains from aerobic exercise, but this possibility is constrained by menopausal status, age, menopausal hormone therapy (MHT; also known as hormone replacement therapy, HRT) exposure, and limited direct evidence. In males, structured exercise may preferentially influence default mode-frontoparietal coupling through IGF-1-related mechanisms. Evidence for these pathways is predominantly indirect and preclinical, and male and female pathways may overlap substantially. We outline four candidate, sex-stratified predictions: (1) sex may moderate exercise-related MTL flexibility changes, with menopausal status as an exploratory moderator; (2) dynamic flexibility changes may partially mediate cognitive improvement, with indirect pathway magnitudes compared using moderated mediation; (3) exercise cessation may produce different flexibility decay trajectories by sex; and (4) exercise modality may interact with sex. We emphasize dFC methodological caveats—including scan duration, motion, test-retest reliability, and neurovascular coupling—and distinguish biomarker-confirmed AD from MCI and cognitively unimpaired populations. This framework is intended to guide hypothesis-driven, sex-stratified research, not clinical exercise prescriptions.

doi.org/10.14336/ad.2026.1096 Open access PubMed 42970313 Mechanisms