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Previously, we observed an atypical A\u03b2 deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque\u2019s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (\u00d8\u2009\u2248\u200980\u00a0\u00b5m) deposit, characterized as having multiple cores and A\u03b2-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of A\u03b2-positive cases (<jats:italic>n<\/jats:italic>\u2009=\u200974), including non-demented cases (<jats:italic>n<\/jats:italic>\u2009=\u200915), early-onset (EO)AD (<jats:italic>n<\/jats:italic>\u2009=\u200938), and late-onset (LO)AD cases (<jats:italic>n<\/jats:italic>\u2009=\u200921). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous <jats:italic>APOE<\/jats:italic> \u03b54 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque\u2019s neuritic component (pTau, APP, PrP<jats:sup>C<\/jats:sup>), A\u03b2 isoform composition (A\u03b2<jats:sub>40<\/jats:sub>, A\u03b2<jats:sub>42<\/jats:sub>, A\u03b2<jats:sub>N3pE<\/jats:sub>, pSer8A\u03b2), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of A\u03b2<jats:sub>40<\/jats:sub>. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular A\u03b2<jats:sub>40<\/jats:sub> shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent A\u03b2 plaque-type associated with EOAD. Differences in A\u03b2 processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other A\u03b2 deposits. Disentangling specific A\u03b2 deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.<\/jats:p>","DOI":"10.1007\/s00401-020-02198-8","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T13:03:10Z","timestamp":1600088590000},"page":"811-830","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["The coarse-grained plaque: a divergent A\u03b2 plaque-type in early-onset Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4922-3286","authenticated-orcid":false,"given":"Baayla D. 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