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Aging is a major risk factor for AD, and various studies have identified alterations in microglial molecular signatures and morphological patterns that overlap with microglial states during aging. However, the mechanisms underlying the divergence of aging trajectories toward disease remain unclear. Thus, understanding the molecular changes in microglia during aging and AD pathology is crucial to elucidating the mechanisms that drive disease progression. In this review, we examine current advances in understanding the phenotypic alterations in human microglia, highlighting gene signatures and morphological changes that may aid in defining microglia\u2019s molecular and functional programs in healthy aging and over the course of AD. We further explore the roles of oxidative stress and cellular senescence in driving the development of a chronic reactive state in microglia during aging, which may also contribute to the complex process underlying the onset and progression of AD pathology. This review highlights the advancements in therapeutic strategies focused on targeting pertinent pathological microglial changes during aging and in disease to mitigate the AD neurodegenerative process.<\/jats:p>","DOI":"10.3390\/cells15131159","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:49:23Z","timestamp":1782434963000},"page":"1159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human Microglial Molecular Alterations in Aging and Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7854-7004","authenticated-orcid":false,"given":"Karol Ann T.","family":"Baldo","sequence":"first","affiliation":[{"name":"School of Medical Sciences, Faculty of Health, University of Victoria, Victoria, BC V8P 5C2, Canada"},{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila 1004, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4641-1780","authenticated-orcid":false,"given":"Elisa","family":"Gozlan","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, George S. 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Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2863-9626","authenticated-orcid":false,"given":"Marie-\u00c8ve","family":"Tremblay","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Health, University of Victoria, Victoria, BC V8P 5C2, Canada"},{"name":"Institute on Aging and Lifelong Health (IALH), University of Victoria, Victoria, BC V8P 5C2, Canada"},{"name":"Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC V8P 5C2, Canada"},{"name":"Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1038\/s43587-024-00702-3","article-title":"Implausibility of Radical Life Extension in Humans in the Twenty-First Century","volume":"4","author":"Olshansky","year":"2024","journal-title":"Nat. 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