Sex as a Missing Moderator in the Dual-Pathway Neuroprotection Hypothesis

The Dual-Pathway Neuroprotection Hypothesis, recently proposed by Badea and colleagues, distinguishes voluntary from enforced exercise and links each to distinct neural pathways, moving beyond the unitary view of exercise as a homogeneous intervention. However, the hypothesis does not consider sex as a biological variable. Given that AD is a sex-biased disease affecting approximately 65-70% women, and that the neuroprotective effects of exercise are sexually dimorphic, we argue that sex may function as a critical moderator of this framework. We propose three testable predictions: (1) voluntary exercise's cortico-limbic effects may be potentiated in females through estrogen-BDNF signaling, but this effect may be constrained by menopausal status; (2) structured/supervised exercise may yield sex-divergent outcomes-with preliminary observations suggesting Aβ clearance in females versus neurotrophic upregulation in males-though evidence remains preliminary and derives from a limited number of heterogeneous studies; and (3) stress burden may reduce the net benefit of enforced exercise, but this will require direct testing. These predictions converge on a formal revision in which sex is not a confounder to be controlled for, but a core biological moderator that may moderate modality-specific neuroprotection. This extended model provides a hypothesis-generating framework for designing future sex-aware exercise studies in AD, but does not yet support sex-stratified clinical prescriptions. This framework is predominantly based on preclinical and indirect evidence from heterogeneous models, necessitating cautious interpretation and rigorous validation.