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We report a mother and daughter with neuropathologically confirmed definite Alzheimer disease (AD) and extensive cerebral amyloid angiopathy (CAA). Copy number analysis identified an increased number of <jats:italic>APP<\/jats:italic> copies and genome sequencing (GS) revealed the underlying complex genomic rearrangement (CGR) including a triplication of <jats:italic>APP<\/jats:italic> with two unique breakpoint junctions (BPJs). The mosaic state in the mother had likely occurred <jats:italic>de novo<\/jats:italic>. Digital droplet PCR (ddPCR) on 42 different tissues, including 17 different brain regions, showed the derivative chromosome at varying mosaic levels (20\u201396%) in the mother who had symptom onset at age 58 years. In contrast, the derivative chromosome was present in all analyzed cells in the daughter whose symptom onset was at 34 years. This study reveals the architecture of a <jats:italic>de novo<\/jats:italic> CGR causing <jats:italic>APP<\/jats:italic> triplication and ADAD with a striking difference in age at onset between the fully heterozygous daughter compared to the mosaic mother. The GS analysis identified the complexity of the CGR illustrating its usefulness in identifying structural variants (SVs) in neurodegenerative disorders.<\/jats:p>","DOI":"10.1038\/s41598-025-86645-0","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T06:05:27Z","timestamp":1737612327000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease"],"prefix":"10.1038","volume":"15","author":[{"given":"Emma","family":"Ehn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Eisfeldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Laffita-Mesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kan","family":"Thonberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Schoumans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Portaankorva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"Viitanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lindstrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger","family":"Nennesmo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Graff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"86645_CR1","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/alz.12694","volume":"19","author":"A Gustavsson","year":"2023","unstructured":"Gustavsson, A. et al. 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Laffita-Mesa was incorrectly affiliated with \u201cDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden\u201d.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2025","order":7,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":8,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":9,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41598-025-94140-9","URL":"https:\/\/doi.org\/10.1038\/s41598-025-94140-9","order":10,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was performed according to the Helsinki Declaration and was approved by the Swedish Ethical Review Authority. Informed and written consents for research and publication of case reports were obtained for both subjects via the participants themselves and\/or next-of-kin.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate and publish"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2912"}}