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However, there is mounting evidence that A\u03b2 also plays a pathogenic role in other types of dementia and that specific post-translational A\u03b2 modifications contribute to its pathogenic profile. The objective of this study was to test the hypothesis that distinct types of dementia are characterized by specific patterns of post-translationally modified A\u03b2 variants. We conducted a comparative analysis and quantified A\u03b2 as well as A\u03b2 with pyroglutamate (pGlu3-A\u03b2 and pGlu11-A\u03b2), N-truncation (A\u03b2(4-X)), isoaspartate racemization (isoAsp7-A\u03b2 and isoAsp27-A\u03b2), phosphorylation (pSer8-A\u03b2 and pSer26-A\u03b2) or nitration (3NTyr10-A\u03b2) modification in <jats:italic>post mortem<\/jats:italic> human brain tissue from non-demented control subjects in comparison to tissue classified as pre-symptomatic\u00a0AD (Pre-AD), AD, dementia with Lewy bodies and vascular dementia. A\u03b2 modification-specific immunohistochemical labelings of brain sections from the posterior superior temporal gyrus were examined by machine learning-based segmentation protocols and immunoassay analyses in brain tissue after sequential A\u03b2 extraction were carried out. Our findings revealed that AD cases displayed the highest concentrations of all A\u03b2 variants followed by dementia with Lewy bodies, Pre-AD, vascular dementia and non-demented controls. With both analytical methods, we identified the isoAsp7-A\u03b2 variant as a highly abundant A\u03b2 form in all clinical conditions, followed by A\u03b2(4-X), pGlu3-A\u03b2, pGlu11-A\u03b2 and pSer8-A\u03b2. These A\u03b2 variants were detected in distinct plaque types of compact, coarse-grained, cored and diffuse morphologies and, with varying frequencies, in cerebral blood vessels. The 3NTyr10-A\u03b2, pSer26-A\u03b2 and isoAsp27-A\u03b2 variants were not found to be present in A\u03b2 plaques but were detected intraneuronally. There was a strong positive correlation between isoAsp7-A\u03b2 and Thal phase and a moderate negative correlation between isoAsp7-A\u03b2 and performance on the Mini Mental State Examination. Furthermore, the abundance of all A\u03b2 variants was highest in APOE 3\/4 carriers. In aggregation assays, the isoAsp7-A\u03b2, pGlu3-A\u03b2 and pGlu11-A\u03b2 variants showed instant fibril formation without lag phase, whereas A\u03b2(4-X), pSer26-A\u03b2 and isoAsp27-A\u03b2 did not form fibrils. We conclude that targeting A\u03b2 post-translational modifications, and in particular the highly abundant isoAsp7-A\u03b2 variant, might be considered for diagnostic and therapeutic approaches in different types of dementia. Hence, our findings might have implications for current antibody-based therapies of AD.<\/jats:p>","DOI":"10.1007\/s00401-024-02824-9","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T13:29:27Z","timestamp":1733232567000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Identification of isoAsp7-A\u03b2 as a major A\u03b2 variant in Alzheimer\u2019s disease, dementia with Lewy bodies and vascular dementia"],"prefix":"10.1007","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2436-2866","authenticated-orcid":false,"given":"Sarah","family":"Schrempel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2043-4062","authenticated-orcid":false,"given":"Anna Katharina","family":"Kottwitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Piechotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Gnoth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"B\u00fcschgens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Hartlage-R\u00fcbsamen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Morawski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Schenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kleinschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geidy E.","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agueda","family":"Rostagno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Ghiso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Heneka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Wirths","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Ro\u00dfner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"2824_CR1","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1038\/nn.2433","volume":"12","author":"E Abramov","year":"2009","unstructured":"Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I (2009) Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. 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