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While research has long focused on amyloid beta (A\u03b2) and tau pathology, recent controversies and limited clinical success of A\u03b2\u2010targeting therapies have challenged their centrality in AD. Emerging evidence highlights neuroinflammation as an earlier and potentially more critical driver of disease, particularly in response to environmental and lifestyle factors. High saturated fat diets (HFD) are strongly associated with increased AD risk in both clinical and preclinical studies. This review examines how HFD promotes AD vulnerability via neuroinflammatory mechanisms, including toll\u2010like receptor 4 activation and complement system overactivation, which contribute to synaptic loss and cognitive decline\u2014often independent of A\u03b2 burden and metabolic dysfunction. Short\u2010term HFD exposure can rapidly induce neuroinflammation and impair memory, underscoring the direct impact of diet on brain health. These insights support a shift toward targeting immune pathways and synaptic preservation in AD prevention and treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>High saturated fat diets (HFDs) increases Alzheimer's disease risk independently of obesity or insulin resistance.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Neuroinflammation is a key driver of HFD\u2010induced cognitive decline.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Toll\u2010like receptor 4 (TLR4) activation links saturated fats to synaptic loss and memory deficits.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>HFDs promote complement\u2010mediated microglial synaptic engulfment.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Short\u2010term HFD exposure rapidly impairs memory and increases brain inflammation.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70911","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:04:30Z","timestamp":1763532270000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Neuroinflammatory mechanisms linking high\u2010fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis"],"prefix":"10.1002","volume":"21","author":[{"given":"Sabrina E.","family":"Mackey\u2010Alfonso","sequence":"first","affiliation":[{"name":"Medical Scientist Training Program The Ohio State University  Columbus Ohio USA"},{"name":"Neuroscience Graduate Program The Ohio State University  Columbus Ohio USA"},{"name":"Institute of Brain, Behavior, and Immunology The Ohio State University Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth M.","family":"Barrientos","sequence":"additional","affiliation":[{"name":"Institute of Brain, Behavior, and Immunology The Ohio State University Columbus Ohio USA"},{"name":"Department of Psychiatry and Behavioral Health The Ohio State University Columbus Ohio USA"},{"name":"Department of Neuroscience The Ohio State University  Columbus Ohio USA"},{"name":"Chronic Brain Injury Program The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1596\/33067"},{"key":"e_1_2_11_3_1","volume-title":"Ageing and health","author":"World Health Organization","year":"2025"},{"key":"e_1_2_11_4_1","volume-title":"Dementia","author":"World Health Organization","year":"2025"},{"key":"e_1_2_11_5_1","unstructured":"The top 10 causes of death.https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/the\u2010top\u201010\u2010causes\u2010of\u2010death"},{"key":"e_1_2_11_6_1","volume-title":"What is Alzheimer's Disease?","year":"2023"},{"key":"e_1_2_11_7_1","unstructured":"2023 Alzheimer's disease facts and 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