Alzheimer's disease pathology manifests in peripheral nerves months before cognitive symptoms appear, characterized by proteome remodeling centered on mitochondrial dysfunction. Both exercise and donepezil treatment initiated before symptom onset attenuate these peripheral changes and preserve neuromuscular function in a mouse model of early-stage disease.
Key Points
- Sciatic nerve proteome remodeling begins at 4 months, precedes neuromuscular dysfunction
- Mitochondrial pathways, calcium handling, inflammation drive peripheral nerve degeneration
- Exercise and donepezil equally delay peripheral phenotypes when started early
Longevity Analysis
The peripheral manifestation of Alzheimer's pathology years before cognitive decline creates a critical window for intervention. Mitochondrial dysfunction in peripheral nerves may serve as an earlier biomarker for disease trajectory than cognitive testing alone. The convergence of exercise and pharmaceutical approaches on mitochondrial-centric mechanisms suggests that optimizing energy production and cellular regeneration in peripheral tissues could modify disease progression at a stage when intervention is most likely to yield meaningful outcomes.
Original published by Wiley Aging Cell, by Matthew H. Brisendine, Dijanira Q. Nieves‐Esparcia, Orion S. Willoughby, Brieann Brown, John R. Brown, Daniel S. Braxton, Shelby N. Henry, Colin S. McCoin, John P. Thyfault, Jill K. Morris, Steven Poelzing, Robert W. Grange, Timothy J. Jarome, Charles P. Najt, Joshua C. Drake .