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Here, we aimed to characterize the prevalence, morphology, regional patterns, and clinical relevance of co-pathologies in a well-characterized MSA autopsy cohort. Regional load (%area) and morphological characterization of \u03b1-syn (KM51), A\u03b2 (6F\/3D), p-tau (AT8), and pTDP-43 (pSer409) pathology were assessed in limbic regions of MSA (<jats:italic>n<\/jats:italic>\u2009=\u200970) donors from the Netherlands Brain Bank. APOE-\u03b54 genotyping and clinical parameters of the cohort were collected. Associations with clinical features were analyzed using ANCOVA and mixed linear models, adjusted for age and sex. A\u03b2, p-tau, and pTDP-43 pathology were detected in 31%, 91%, and 11% of all MSA cases, respectively, with the highest burdens in the entorhinal cortex and amygdala. Mixed MSA\u2009+\u2009AD cases had a higher age at death (75\u2009\u00b1\u20097 vs. 64\u2009\u00b1\u20097, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), and more frequently APOE-\u03b54 alleles (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) than pure MSA. Cognitive impairment (CDR scores) was associated with diffuse and compact A\u03b2 plaques across all regions (r\u2009\u2265\u20090.24, <jats:italic>p<\/jats:italic>\u2009\u2264\u20090.015), p-tau pathology in CA1 and CA3\u2009+\u20094 (r\u2009\u2265\u20090.32, <jats:italic>p<\/jats:italic>\u2009\u2264\u20090.020), and neuronal \u03b1-syn inclusions in the amygdala (r\u2009=\u20090.54, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). No robust correlations were found between total \u03b1-syn burden and A\u03b2 or p-tau. Misdiagnoses increased with co-pathology burden (A\u03b2: <jats:italic>p<\/jats:italic>\u2009=\u20090.040; p-tau: <jats:italic>p<\/jats:italic>\u2009=\u20090.020) and age at onset (80% in those with onset\u2009&gt;\u200975\u00a0years). Our results demonstrate that limbic A\u03b2, p-tau, and neuronal \u03b1-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset. By providing a systematic quantitative and morphological assessment of co-pathologies in limbic regions of MSA, our study advances beyond prior prevalence reports and highlights their direct clinical relevance. These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.<\/jats:p>","DOI":"10.1007\/s00401-025-02940-0","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T16:38:20Z","timestamp":1758213500000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Limbic Alzheimer\u2019s co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy"],"prefix":"10.1007","volume":"150","author":[{"given":"Janna","family":"van Wetering","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasja A. 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WvdB was financially supported by grants from Dutch Research council (ZonMW 70-73305-98-106; 70-73305-98-102; 40-46000-98-101), Alzheimer association (AARF-18-566459), MJ Fox foundation (17253), Parkinson Association (2020-G01), Health Holland and Stichting Woelse Waard. WvdB performed contract research for Roche Tissue Diagnostics, Discoveric Bio and Genentech, and received research consumables from Hoffmann-La Roche and Prothena.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}},{"value":"All donors signed informed consent for brain donation and the use of material and clinical information for research purposes. The procedures for brain tissue collection of NBB have been approved by the Medical Ethical Committee of Amsterdam UMC, Vrije Universiteit Amsterdam.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"Approved by all authors.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"30"}}