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Volume 26
Issue 19
10.3390/ijms26199816
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer’s Disease

by
Maria Francesca Astorino
1,†,
Giovanni Luca Cipriano
2,†,
Ivan Anchesi
2,
Maria Lui
2,
Ivana Raffaele
2,
Marco Calabrò
1,* and
Concetta Crisafulli
1
1
Department of Biomedical and Dental Sciences and Morpho-Functional Imaging—BIOMORF, University of Messina, 98125 Messina, Italy
2
IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(19), 9816; https://doi.org/10.3390/ijms26199816 (registering DOI)
Submission received: 12 August 2025 / Revised: 4 October 2025 / Accepted: 8 October 2025 / Published: 9 October 2025
(This article belongs to the Special Issue Molecular Insights into the Role of Exercise in Disease and Health, 2nd Edition)
Versions Notes

Abstract

Alzheimer’s disease (AD), the most prevalent form of dementia, poses a critical global health challenge as its incidence rises with aging populations. Despite extensive research into its genetic and molecular underpinnings, effective therapeutic strategies remain limited. Growing evidence suggests that physical exercise may offer neuroprotective benefits, potentially mitigating AD progression through multifactorial mechanisms. This review synthesizes current findings on the interplay between aerobic exercise and AD pathophysiology, with a focus on amyloid-β (Aβ) metabolism, gene expression, and neuroinflammation. We explore how exercise influences Aβ clearance, modulates amyloid precursor protein (APP) processing, and impacts the activity of key enzymes such as secretases and neprilysin. Further, we highlight the gene–exercise crosstalk identified through transcriptomic data, particularly in the entorhinal cortex—an early site of Aβ deposition. Our analysis also discusses how exercise-induced modulation of molecular pathways—including mitochondrial function, oxidative stress responses, and neuroinflammatory cascades—may confer cognitive resilience. By integrating molecular, genetic, and systems biology data, this review underscores the potential of structured physical activity as a non-pharmacological intervention to delay or attenuate AD pathology. These insights support a precision medicine approach, which combines lifestyle interventions with molecular profiling, to improve prevention strategies and therapeutic outcomes in AD.
Keywords: Alzheimer’s Disease; genetics; physical exercise; amyloid metabolism; amyloid clearance Alzheimer’s Disease; genetics; physical exercise; amyloid metabolism; amyloid clearance

Share and Cite

MDPI and ACS Style

Astorino, M.F.; Cipriano, G.L.; Anchesi, I.; Lui, M.; Raffaele, I.; Calabrò, M.; Crisafulli, C. Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer’s Disease. Int. J. Mol. Sci. 2025, 26, 9816. https://doi.org/10.3390/ijms26199816

AMA Style

Astorino MF, Cipriano GL, Anchesi I, Lui M, Raffaele I, Calabrò M, Crisafulli C. Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer’s Disease. International Journal of Molecular Sciences. 2025; 26(19):9816. https://doi.org/10.3390/ijms26199816

Chicago/Turabian Style

Astorino, Maria Francesca, Giovanni Luca Cipriano, Ivan Anchesi, Maria Lui, Ivana Raffaele, Marco Calabrò, and Concetta Crisafulli. 2025. "Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer’s Disease" International Journal of Molecular Sciences 26, no. 19: 9816. https://doi.org/10.3390/ijms26199816

APA Style

Astorino, M. F., Cipriano, G. L., Anchesi, I., Lui, M., Raffaele, I., Calabrò, M., & Crisafulli, C. (2025). Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer’s Disease. International Journal of Molecular Sciences, 26(19), 9816. https://doi.org/10.3390/ijms26199816

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