{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:43:05Z","timestamp":1792093385625,"version":"4.4.0"},"reference-count":84,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-\u03b2 plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood\u2013brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism\u2014the bidirectional interaction between immune activation and cellular metabolism\u2014in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD+, and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy.<\/jats:p>","DOI":"10.3390\/biom16050656","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:34:42Z","timestamp":1777458882000},"page":"656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Interplay Between Immunometabolism and Neuroinflammation in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"16","author":[{"given":"Tiziana","family":"Di Crescenzo","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-2935","authenticated-orcid":false,"given":"Giulio","family":"Papiri","sequence":"additional","affiliation":[{"name":"Neurology Unit, Ospedale Provinciale \u2018Madonna del Soccorso\u2019, 63074 San Benedetto del Tronto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Membrino","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonila","family":"Alia","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Cecati","sequence":"additional","affiliation":[{"name":"Department for the Promotion of Human Science and Quality of Life, San Raffaele Roma University, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2607-2734","authenticated-orcid":false,"given":"Roberto","family":"Campagna","sequence":"additional","affiliation":[{"name":"Department for the Promotion of Human Science and Quality of Life, San Raffaele Roma University, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3545-7388","authenticated-orcid":false,"given":"Mauro","family":"Silvestrini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"},{"name":"Neurological Unit, Azienda Ospedaliero Universitaria delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Luzzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"},{"name":"Neurological Unit, Azienda Ospedaliero Universitaria delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2496-7932","authenticated-orcid":false,"given":"Arianna","family":"Vignini","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.cell.2015.12.056","article-title":"The cellular phase of Alzheimer\u2019s disease","volume":"164","author":"Karran","year":"2016","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","author":"Kinney","year":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/s41586-024-07469-y","article-title":"A body\u2013brain circuit that regulates body inflammatory responses","volume":"630","author":"Jin","year":"2024","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1007\/s11064-011-0680-2","article-title":"Dysfunctional nucleus tractus solitarius: Its crucial role in promoting neuropathogenetic cascade of Alzheimer\u2019s dementia\u2014A novel hypothesis","volume":"37","author":"Daulatzai","year":"2012","journal-title":"Neurochem. 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