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Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009419) compared to controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood\u2013brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with\n                    <jats:italic>TREM2<\/jats:italic>\n                    R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.\n                  <\/jats:p>","DOI":"10.1038\/s43587-023-00550-7","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T06:03:05Z","timestamp":1704780185000},"page":"33-47","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":217,"title":["Cerebrospinal fluid proteomics in patients with Alzheimer\u2019s disease reveals five molecular subtypes with distinct genetic risk profiles"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-1797","authenticated-orcid":false,"given":"Betty M.","family":"Tijms","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M.","family":"Vromen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olav","family":"Mjaavatten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7688-3087","authenticated-orcid":false,"given":"Henne","family":"Holstege","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianne M.","family":"Reus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1606-8643","authenticated-orcid":false,"given":"Sven","family":"van der Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten E. 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US2022196683A1, owner VUmc Foundation). E.V. is cofounder of ADx NeuroSciences, while J.G. is an employee of ADx NeuroSciences. F.B. is on the steering committee or data safety monitoring board for Biogen, Merck, ATRI\/ACTC and Prothena. He is a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen and Combinostics. He has research agreements with Merck, Biogen, GE Healthcare and Roche, and he is cofounder and shareholder of Queen Square Analytics LTD. L.V. received consulting fees from Roche and Olink, all paid to Amsterdam UMC. C.E.T. performed contract research for ADx NeuroSciences, AC-Immune, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Siemens, Toyama and Vivoryon. She is editor of <i>Alzheimer Research and Therapy<\/i>, and serves on the editorial boards of <i>Medidact Neurologie\/Springer<\/i> and <i>Neurology: Neuroimmunology & Neuroinflammation<\/i>. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}