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In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-\u03b2 (A\u03b2)42:38, A\u03b242:40 and A\u03b238:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-\u03b2 processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-\u03b2 between genotypes: higher A\u03b242:38 in PSEN1 versus APP (P\u2009&amp;lt;\u20090.001) and non-carriers (P\u2009&amp;lt;\u20090.001); higher A\u03b238:40 in APP versus PSEN1 (P\u2009&amp;lt;\u20090.001) and non-carriers (P\u2009&amp;lt;\u20090.001); while A\u03b242:40 was higher in both mutation groups compared to non-carriers (both P\u2009&amp;lt;\u20090.001). Amyloid-\u03b2 profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between A\u03b242:38, A\u03b242:40 and A\u03b238:40 ratios and parental age at onset. In vivo differences in amyloid-\u03b2 processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.<\/jats:p>","DOI":"10.1093\/brain\/awab166","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T15:50:05Z","timestamp":1619106605000},"page":"2964-2970","source":"Crossref","is-referenced-by-count":36,"title":["Plasma amyloid-\u03b2 ratios in autosomal dominant Alzheimer\u2019s disease: the influence of genotype"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4467-128X","authenticated-orcid":false,"given":"Antoinette","family":"O'Connor","sequence":"first","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK"},{"name":"UK Dementia Research Institute at UCL, London, WC1E 6AU, 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Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Portelius","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, S-431 80 M\u00f6lndal, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imogen J","family":"Swift","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, WC1E 6AU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J","family":"Heslegrave","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, WC1E 6AU, 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UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie S","family":"Ryan","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK"},{"name":"UK Dementia Research Institute at UCL, London, WC1E 6AU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M","family":"Polke","sequence":"additional","affiliation":[{"name":"Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M","family":"Nicholas","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK"},{"name":"Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, 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Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Frost","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, S-431 80 M\u00f6lndal, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London, WC1E 6AU, UK"},{"name":"Department of Psychiatry and Neurochemistry, 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