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While direct and indirect protein interactions are suggested, the relationships between different protein aggregates remain poorly understood. Here, we aimed to characterize \u03b1-syn, amyloid beta (A\u03b2), and tau load distributions of AD patients. Protein deposits were automatically quantified with random forest pixel classifiers in immunohistochemical stains of up to 28 brain regions in 72 brains with advanced AD neuropathological change. \u03b1-syn-negative cases were distinguished from amygdala predominant, brainstem predominant, and cortical \u03b1-syn-positive cases. Relationships with age, sex, and ApoE genotype were examined. \u03b1-syn co-pathology was detected in 60% of AD cases, more frequently, although not significantly, in women. Half of these positive cases presented \u03b1-syn deposits in the cortex, around one-third predominantly in the amygdala, and the remaining cases primarily in the brainstem. A high \u03b1-syn load in the amygdala was associated with an increased cortical A\u03b2 load. The cortical tau load was increased in the amygdala-predominant \u03b1-syn group, but decreased in the brainstem-predominant and cortical \u03b1-syn cases in comparison with \u03b1-syn-negative cases. ApoE4 was associated with higher hippocampal \u03b1-syn and cortical A\u03b2 deposition. Younger age at death was associated with a focally higher A\u03b2 and tau load. AD cases with cortical \u03b1-syn deposition tended to have a younger age at death. Here, we show that next to age, sex, and ApoE genotype, the \u03b1-syn distribution in AD is related to different A\u03b2 and tau loads. This may have therapeutic relevance for identifying patients who respond to A\u03b2 immunotherapy related to tau burden and underpin the need to define \u03b1-syn pathology and distribution in early disease stages.<\/jats:p>","DOI":"10.1007\/s00401-025-02952-w","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T10:30:14Z","timestamp":1761820214000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Alpha-synuclein deposition patterns in Alzheimer\u2019s disease: association with cortical amyloid beta and variable tau load"],"prefix":"10.1007","volume":"150","author":[{"given":"Antonia","family":"Neubauer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Weissenbrunner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Pekrun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrun","family":"Roeber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Ruf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Feyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix L.","family":"Str\u00fcbing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Herms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"2952_CR1","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1093\/jnen\/nlz080","volume":"78","author":"CH Adler","year":"2019","unstructured":"Adler CH, Beach TG, Zhang N, Shill HA, Driver-Dunckley E, Caviness JN et al (2019) Unified staging system for Lewy body disorders: clinicopathologic correlations and comparison to Braak staging. 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