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Autosomal dominant Alzheimer disease (ADAD) with mutations in <jats:italic>PSEN1<\/jats:italic>, <jats:italic>PSEN2<\/jats:italic> and <jats:italic>APP<\/jats:italic> can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the A\u03b2-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma A\u03b2 concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>92 plasma samples were collected from at-risk individuals (<jats:italic>n<\/jats:italic>\u2009=\u200947) in a Swedish cohort of ADAD, including 18 mutation carriers (13 <jats:italic>APP<\/jats:italic>swe (p.KM670\/671NL) MC), 5 <jats:italic>PSEN1<\/jats:italic> (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of A\u03b21\u201338, A\u03b21\u201340 and A\u03b21\u201342 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS\/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma A\u03b2 peptides in <jats:italic>APP<\/jats:italic>swe MC, regardless of clinical status, compared to controls (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). <jats:italic>PSEN1<\/jats:italic> (p.H163Y) presymptomatic MC had a decrease of plasma A\u03b21\u201338 compared to controls (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). There was no difference in A\u03b21\u201342\/1\u201340 ratio between <jats:italic>APP<\/jats:italic>swe MC (PMC and SMC), <jats:italic>PSEN1<\/jats:italic> MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that <jats:italic>APP<\/jats:italic>swe MC have a stable A\u03b21\u201342\/1\u201340 ratio with increasing age, in contrast to the decrease seen with aging in both controls and <jats:italic>PSEN1<\/jats:italic> (p.H163Y) MC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>These data show very strong mutation-specific effects on A\u03b2 profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the A\u03b2 ratio might be a poor indicator of brain A\u03b2 pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13195-024-01574-w","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T16:36:18Z","timestamp":1727282178000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Gene-variant specific effects of plasma amyloid-\u03b2 levels in Swedish autosomal dominant Alzheimer disease"],"prefix":"10.1186","volume":"16","author":[{"given":"Charlotte","family":"Johansson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steinunn","family":"Thordardottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Laffita-Mesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Pannee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rodriguez-Vieitez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","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":[[2024,9,25]]},"reference":[{"issue":"6","key":"1574_CR1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe DJ, Hardy J. 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Written consent for inclusion was provided by all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"HZ has served at scientific advisory boards and\/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. CJ, ST, ERV, JLM, JP and CG declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"207"}}