{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T12:10:12Z","timestamp":1785327012063,"version":"3.55.0"},"reference-count":347,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI Grant-in-Aid","doi-asserted-by":"publisher","award":["26K12666"],"award-info":[{"award-number":["26K12666"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI Grant-in-Aid","doi-asserted-by":"publisher","award":["25K13155"],"award-info":[{"award-number":["25K13155"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI Grant-in-Aid","doi-asserted-by":"publisher","award":["23K21496"],"award-info":[{"award-number":["23K21496"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most common neurodegenerative disorder worldwide and remains a major unmet medical challenge in aging societies. Although amyloid-\u03b2 (A\u03b2) plaques and tau pathology are hallmark features of AD, the limited efficacy of many A\u03b2- and tau-targeted therapies suggests that AD arises from systemic and cerebral dysfunction. Aging-associated homeostatic failure\u2014including hepatic metabolic, vascular, neuroendocrine, inflammatory, oxidative, and mitochondrial dysfunctions\u2014promotes the accumulation of neurotoxic A\u03b2 and tau species, ultimately driving neurodegeneration and impairing endogenous neuroregeneration. Emerging evidence suggests that regular physical exercise induces metabolic, cardiovascular, and neuroendocrine adaptations, improving hepatic metabolic function, cerebral blood flow, oxygen delivery, mitochondrial activity, waste clearance pathways, and brain health. Exercise-induced musculoskeletal\u2013brain crosstalk further contributes to these benefits through the release of myokines and extracellular vesicles, which facilitate systemic intercellular communication to regulate neurovascular function, neuroplasticity, and neuroregeneration. Collectively, these adaptations reduce chronic inflammation and oxidative stress while enhancing resilience across interconnected peripheral and cerebral systems. Therefore, physical exercise may represent a multifaceted preventive and therapeutic strategy capable of restoring brain\u2013body homeostasis and mitigating AD progression. This comprehensive review discusses aging-associated systemic mechanisms underlying AD pathogenesis and summarizes recent advances in the understanding of exercise-mediated protection against AD progression.<\/jats:p>","DOI":"10.3390\/cells15151368","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:45:14Z","timestamp":1785325514000},"page":"1368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise as a Systemic Prevention and Management for Alzheimer\u2019s Disease: Restoring Brain\u2013Body Homeostasis Through Metabolic, Neurovascular, Anti-Inflammatory, and Regenerative Mechanisms"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3053-4930","authenticated-orcid":false,"given":"Li","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeshka Meihua","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan"},{"name":"India International School in Japan, 3-1-4 Sengoku, Koto-ku, Tokyo 136-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2071-8733","authenticated-orcid":false,"given":"Mai","family":"Mochizuki","sequence":"additional","affiliation":[{"name":"Department of Life Science Dentistry, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan"},{"name":"Department of Developmental and Regenerative Dentistry, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4637-1072","authenticated-orcid":false,"given":"Taka","family":"Nakahara","sequence":"additional","affiliation":[{"name":"Department of Developmental and Regenerative Dentistry, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, June 04). 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