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We investigated how mutation position relative to codon 200 (pre\u2010\/postcodon 200) influences these pathologic features and dementia at different stages.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Individuals from families with known <jats:italic>PSEN1<\/jats:italic> mutations (<jats:italic>n<\/jats:italic>\u00a0=\u00a0393) underwent neuroimaging and clinical assessments. We cross\u2010sectionally evaluated regional Pittsburgh compound B\u2010positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging\u2010based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating<jats:sup>\u00ae<\/jats:sup> scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Mutation position influences A\u03b2 burden, SVD, and dementia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>PSEN1<\/jats:italic> pre\u2010200 group had stronger associations between A\u03b2 burden and disease stage.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>PSEN1<\/jats:italic> post\u2010200 group had stronger associations between SVD markers and disease stage.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>PSEN1<\/jats:italic> post\u2010200 group had worse dementia score than pre\u2010200 in late disease stage.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Diffusion tensor imaging\u2010based SVD markers mediated mutation position effects on dementia in the late stage.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13729","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T08:25:41Z","timestamp":1708503941000},"page":"2680-2697","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Presenilin\u20101 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9735-5152","authenticated-orcid":false,"given":"Nelly","family":"Joseph\u2010Mathurin","sequence":"first","affiliation":[{"name":"Washington University School of Medicine in Saint Louis  St. Louis Missouri 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