{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:19:28Z","timestamp":1791980368745,"version":"4.4.0"},"reference-count":278,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (A\u03b2) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. The failure of recent A\u03b2-targeted therapies to yield conclusive benefits necessitates further exploration of AD pathology. This review proposes the Mitochondrial\u2013Neurovascular\u2013Metabolic (MNM) hypothesis, which integrates mitochondrial dysfunction, impaired neurovascular regulation, and systemic metabolic disturbances as interrelated contributors to AD pathogenesis. Mitochondrial dysfunction, a hallmark of AD, leads to oxidative stress and bioenergetic failure. Concurrently, the breakdown of the blood\u2013brain barrier (BBB) and impaired cerebral blood flow, which characterize neurovascular dysregulation, accelerate neurodegeneration. Metabolic disturbances such as glucose hypometabolism and insulin resistance further impair neuronal function and survival. This hypothesis highlights the interconnectedness of these pathways and suggests that therapeutic strategies targeting mitochondrial health, neurovascular integrity, and metabolic regulation may offer more effective interventions. The MNM hypothesis addresses these multifaceted aspects of AD, providing a comprehensive framework for understanding disease progression and developing novel therapeutic approaches. This approach paves the way for developing innovative therapeutic strategies that could significantly improve outcomes for millions affected worldwide.<\/jats:p>","DOI":"10.3390\/ijms252111720","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T08:44:04Z","timestamp":1730364244000},"page":"11720","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["From Plaques to Pathways in Alzheimer\u2019s Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis"],"prefix":"10.3390","volume":"25","author":[{"given":"Sarah","family":"Kazemeini","sequence":"first","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Nadeem-Tariq","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Shih","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Rafanan","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabih","family":"Ghani","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4878-4233","authenticated-orcid":false,"given":"Thomas A.","family":"Vida","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine at UNLV, 625 Shadow Lane, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2023). 2023 Alzheimer\u2019s Disease Facts and Figures. 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