Hot TopicsPublished: 15 August 2026Angela To ORCID: orcid.org/0000-0002-4622-00391 &Matthew J. Girgenti ORCID: orcid.org/0000-0003-1647-326X1 Neuropsychopharmacology (2026) Cite this articleSave articleView saved researchEmerging evidence suggests that psychopathology is broadly associated with accelerated cognitive decline and risk for Alzheimer’s disease (AD) and related dementias. Epidemiological studies have demonstrated that individuals with varying psychiatric illness exhibit higher rates of later-life cognitive decline, suggesting these biological systems may contribute to age-related neurobiological vulnerability [1]. A growing body of human brain multi-omic literature suggests that stress and addiction may leave a lasting molecular imprint on the brain’s immune system, especially in microglia [2, 3]. Understanding the effects neuropsychiatric illness has on the genome could therefore reveal the mechanisms leading to later-life decline.A similar pattern is emerging among substance-use disorders. A large epigenomic study of the central amygdala identified altered microglial cis-regulatory elements encompassing CALN1, a predominantly neuronal calcium-regulatory gene, suggesting that chronic alcohol exposure induces persistent epigenomic remodeling of neuroimmune regulatory programs [3, 4]. Consistent with these findings, KANSL1 and PLCG2 are also dysregulated in AUD microglia, paralleling observations in PTSD. Together, these convergent transcriptomic and epigenomic changes across cortical and amygdala circuits support a model in which stress and alcohol exposure drive durable microglial reprogramming that increases vulnerability to Alzheimer’s disease (Fig. 1).This is a preview of subscription content, access via your institutionAccess options Access through your institutionSubscribe to this journalReceive 13 print issues and online access269,00 € per yearonly 20,69 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutFig. 1: Lifespan trajectories of stress and multi-omic convergence on microglial senescence.SubjectsPost-traumatic stress disorderChromatin remodellingReferencesBellou V, Belbasis L, Tzoulaki I, Middleton LT, Ioannidis JPA, Evangelou E. 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Nat Neurosci. 2024;27:1116–24. https://doi.org/10.1038/s41593-024-01620-8.Article CAS PubMed Google Scholar Download referencesFundingThe research reported here was supported by a Brain and Behavior Research Foundation Young Investigator Award and NIH grants R01AA031017 and DP1DA060811 to MJG. This work was funded in part by the State of Connecticut, Department of Mental Health and Addiction Services. The views expressed here are those of the authors and do not necessarily reflect the position or policy of the U.S. government or the views of the Department of Mental Health and Addiction Services or the State of Connecticut. In addition, this material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program for AT under Grant No. DGE-2139841. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.Author informationAuthors and AffiliationsDepartment of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT, 06520, USAAngela To & Matthew J. GirgentiAuthorsAngela ToView author publicationsSearch author on:PubMed Google ScholarMatthew J. GirgentiView author publicationsSearch author on:PubMed Google ScholarContributionsAT and MJG conceptualized and wrote the manuscript.Corresponding authorCorrespondence to Matthew J. Girgenti.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissionsReprints and permissionsAbout this article