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In DS, lifelong overproduction of A\u03b2 due to triplication of the APP gene drives pathology, whereas in sporadic AD (sAD) impaired clearance and altered processing are considered to be major contributors to A\u03b2 pathology. Despite these shared hallmarks, it remains unclear whether the molecular composition of plaques, such as A\u03b2 isoform distribution and post-translational modifications, is truly comparable between the two conditions. Most published studies rely on bulk tissue or antibody-based methods, which average across plaques and overlook truncated or modified A\u03b2 isoforms, such as N-terminally or C-terminally truncated forms or pyroglutamate-modified species. Here, we applied a reflector-mode matrix-assisted laser desorption\/ionization mass spectrometry imaging (MALDI-MSI) approach, integrated with histology and immunoassay, to characterize A\u03b2 pathology in postmortem brain tissue from DS, sAD, and non-demented control patients at single-plaque resolution. We demonstrate that A\u03b2 plaques and neurofibrillary tangles are significantly larger in DS than in sAD, consistent with more aggressive disease progression. Molecular profiling revealed distinct peptide repertoires between the diseases. DS plaques contained nearly twice as many N-terminally truncated A\u03b2 peptides as sAD, with proportionally similar contributions from A\u03b2x-40 and A\u03b2x-42, and uniquely harbored A\u03b22-42, A\u03b2pE3-42, A\u03b23-40, A\u03b24-42, A\u03b28-42, and A\u03b2pE11-40\/42. In contrast, sAD plaques were dominated by truncated A\u03b240 while A\u03b242 remained largely full-length, and only sAD contained bi-terminally truncated isoforms such as A\u03b22-37, A\u03b22-39, and A\u03b29-38. Overall, inter-peptide correlations between the relative abundances of all A\u03b2 peptides as performed across individual plaques were significantly stronger in sAD than in DS, indicating that peptide levels co-vary more consistently within sAD plaques. Collectively, these findings indicate that A\u03b2 plaques in DS and sAD differ in their molecular composition and peptide profiles. Beyond providing mechanistic insight, these findings highlight the need to tailor A\u03b2-targeting therapies to disease-specific peptide signatures, particularly for individuals with DS, who are at exceptionally high risk of dementia and have been underrepresented in clinical research.<\/jats:p>","DOI":"10.1186\/s40478-026-02280-4","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T21:47:49Z","timestamp":1775166469000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MALDI mass spectrometry imaging (MSI) reveals molecular and structural heterogeneity of amyloid-\u03b2 in sporadic Alzheimer\u2019s disease and Down syndrome"],"prefix":"10.1186","volume":"14","author":[{"given":"Karolina","family":"Minta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"S\u00f6derberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Gkanatsiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malin","family":"Johannesson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christer","family":"M\u00f6ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"My","family":"Bj\u00f6rklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunilla","family":"Osswald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Lannfelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Fabre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Michno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"2280_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/S0140-6736(06)69113-7","volume":"368","author":"K Blennow","year":"2006","unstructured":"Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer\u2019s disease. 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