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

Area of Science:

• Neuroscience
• Exercise Physiology
• Sex Differences in Disease

Background:

• The Dual-Pathway Neuroprotection Hypothesis differentiates voluntary and enforced exercise, linking them to distinct neural pathways.
• This hypothesis currently overlooks sex as a biological variable, despite Alzheimer's disease (AD) being sex-biased and exercise effects being sexually dimorphic.

Purpose of the Study:

• To propose a revision of the Dual-Pathway Neuroprotection Hypothesis that integrates sex as a critical biological moderator.
• To generate testable predictions regarding sex-specific neuroprotective effects of different exercise modalities in the context of AD.

Main Methods:

• Theoretical framework development based on existing literature and preliminary observations.
• Formulation of three testable predictions regarding sex-specific effects of voluntary and enforced exercise on neuroprotection in AD.
• Emphasis on integrating sex as a moderator rather than a confounder in exercise and AD research.

Main Results:

• Prediction 1: Voluntary exercise benefits may be potentiated in females via estrogen-BDNF signaling, potentially moderated by menopausal status.
• Prediction 2: Structured exercise may yield sex-divergent outcomes (e.g., Aβ clearance in females vs. neurotrophic upregulation in males).
• Prediction 3: Stress burden may attenuate the benefits of enforced exercise, requiring further investigation.

Conclusions:

• Sex should be considered a core biological moderator, not a confounder, in exercise-related neuroprotection research for AD.
• The proposed sex-aware framework can guide future research design but does not yet support clinical sex-stratified prescriptions.
• The hypothesis requires validation through rigorous, sex-stratified studies, acknowledging current reliance on preclinical and indirect evidence.