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It currently lacks effective treatments, placing a heavy burden on patients, families, health care systems, and society. This is mainly due to our limited comprehension of the pathophysiology of AD progression, as well as the lack of effective drug targets and intervention timing to address the underlying pathology. AD is a multifactorial condition, and emerging evidence suggests that abnormalities in the gut microbiota play a significant role as environmental and multifaceted contributors to AD, although the exact mechanisms are yet to be fully explored. Changes in the composition of microbiota influence host neuronal health through their metabolites. These metabolites regulate intestinal epithelia, blood-brain barrier permeability, and neuroinflammation by affecting mitochondrial function. The decline in the proportion of beneficial microbes and their essential metabolites during aging and AD is directly linked to poor mitochondrial function, although the specific mechanisms remain unclear. In this review, we discuss recent developments in understanding the impact of the microbiome and its metabolites on various cell types, their influence on the integrity of the gut and blood-brain barriers, systemic and brain inflammation, and cell-specific effects in AD pathology. This information is expected to pave the way for a new understanding of the interactions between microbiota and mitochondria in AD, providing a foundation for the development of novel treatments for AD.<\/jats:p>","DOI":"10.1093\/gerona\/glad226","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T16:56:19Z","timestamp":1695056179000},"page":"2187-2202","source":"Crossref","is-referenced-by-count":41,"title":["The Triple Alliance: Microbiome, Mitochondria, and Metabolites in the Context of Age-Related Cognitive Decline and Alzheimer\u2019s Disease"],"prefix":"10.1093","volume":"78","author":[{"given":"Santosh K","family":"Prajapati","sequence":"first","affiliation":[{"name":"USF Center for Microbiome Research, Microbiomes Institute, University of South Florida , Tampa, Florida , USA"},{"name":"Department of Neurosurgery and Brain Repair, University of South Florida , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ria","family":"Shah","sequence":"additional","affiliation":[{"name":"USF Center for Microbiome Research, Microbiomes Institute, University of South Florida , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Alford","sequence":"additional","affiliation":[{"name":"USF Center for Microbiome Research, Microbiomes Institute, University of South Florida , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidharth P","family":"Mishra","sequence":"additional","affiliation":[{"name":"USF Center for Microbiome Research, Microbiomes Institute, University of South Florida , Tampa, Florida , USA"},{"name":"Department of Neurosurgery and Brain Repair, University of South Florida , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Jain","sequence":"additional","affiliation":[{"name":"USF Center for Microbiome Research, Microbiomes Institute, University of South Florida , Tampa, Florida , USA"},{"name":"Department of Neurosurgery and Brain Repair, University of South Florida , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Department, University of South Florida , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Sanberg","sequence":"additional","affiliation":[{"name":"Center of Excellence for Aging and Brain Repair, University of South Florida , Tampa, Flordia , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J A","family":"Molina","sequence":"additional","affiliation":[{"name":"Division of Geriatrics and Gerontology, School of Medicine, University of California San Diego , La Jolla, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4504-1597","authenticated-orcid":false,"given":"Hariom","family":"Yadav","sequence":"additional","affiliation":[{"name":"USF Center for Microbiome Research, Microbiomes Institute, University of South Florida , Tampa, Florida , USA"},{"name":"Department of Neurosurgery and Brain Repair, University of South Florida , Tampa, Florida , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,9,21]]},"reference":[{"key":"2024092100012047900_CIT0001","first-page":"1966","article-title":"Population estimate of people with clinical Alzheimer\u2019s disease and mild cognitive impairment in the United States (2020\u20132060)","volume-title":"Alzheimers Dement","author":"Rajan","year":"2021"},{"key":"2024092100012047900_CIT0002","first-page":"335","article-title":"Effects of Alzheimer disease on patients and their family","volume-title":"J 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