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We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within <jats:italic>PSEN1. PSEN1<\/jats:italic> pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non\u2010carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated A\u03b2 compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre\u2010symptomatic and symptomatic phases of disease as compared to CY, using both cross\u2010sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by \u03b3\u2010secretase and the generation of toxic \u03b2\u2010amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.<\/jats:p>","DOI":"10.1111\/acel.13871","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T04:39:07Z","timestamp":1686285547000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Location of pathogenic variants in <i>PSEN1<\/i> impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal\u2010dominant Alzheimer's disease"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-4415","authenticated-orcid":false,"given":"Stephanie A.","family":"Schultz","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Shirzadi","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron P.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4604-4629","authenticated-orcid":false,"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital  Boston Massachusetts USA"},{"name":"Ann Romney Center for Neurologic Diseases  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen D.","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"McDade","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas R.","family":"Barthelemy","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Renton","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Joseph\u2010Mathurin","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Chen","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Goate","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Francisco","family":"Allegri","sequence":"additional","affiliation":[{"name":"INEBA  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie L. 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