{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T06:04:34Z","timestamp":1792389874277,"version":"4.4.0"},"reference-count":84,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer\u2019s disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer\u2019s disease (defined as having abnormal amyloid, n\u2009=\u2009425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n\u2009=\u2009127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer\u2019s disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood\u2013brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer\u2019s disease (all P\u2009&amp;gt;\u20090.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer\u2019s disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer\u2019s disease heterogeneity. Compared to controls, all non-demented Alzheimer\u2019s disease individuals had increased risk of showing clinical progression (all P\u2009&amp;lt;\u20090.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P\u2009=\u20090.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P\u2009=\u20090.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer\u2019s disease patients, and suggest that subtypes may require tailored therapy.<\/jats:p>","DOI":"10.1093\/brain\/awaa325","type":"journal-article","created":{"date-parts":[[2020,9,9]],"date-time":"2020-09-09T07:10:56Z","timestamp":1599635456000},"page":"3776-3792","source":"Crossref","is-referenced-by-count":175,"title":["Pathophysiological subtypes of Alzheimer\u2019s disease based on cerebrospinal fluid proteomics"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-1797","authenticated-orcid":false,"given":"Betty M","family":"Tijms","sequence":"first","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6193-6193","authenticated-orcid":false,"given":"Johan","family":"Gobom","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M\u00f6lndal, Sweden"},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianne","family":"Reus","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Jansen","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjun","family":"Hong","sequence":"additional","affiliation":[{"name":"L\u00fcbeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerija","family":"Dobricic","sequence":"additional","affiliation":[{"name":"L\u00fcbeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Kilpert","sequence":"additional","affiliation":[{"name":"L\u00fcbeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"ten Kate","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - location VUmc, Amsterdam, The Netherlands"},{"name":"Institutes of Neurology and Healthcare Engineering, UCL London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Tsolaki","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, AHEPA University Hospital, Makedonia, Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans R 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Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Lle\u00f3","sequence":"additional","affiliation":[{"name":"IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Lu\u00eds","family":"Molinuevo","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain"},{"name":"Alzheimer\u2019s Disease Unit and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan","family":"Engelborghs","sequence":"additional","affiliation":[{"name":"Institute Born-Bunge, Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Belgium"},{"name":"Department of Neurology, UZ Brussel and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Bertram","sequence":"additional","affiliation":[{"name":"L\u00fcbeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of L\u00fcbeck, L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Lovestone","sequence":"additional","affiliation":[{"name":"University of Oxford, Oxford, UK"},{"name":"Janssen R&D, Beerse, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Streffer","sequence":"additional","affiliation":[{"name":"Institute Born-Bunge, Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Belgium"},{"name":"UCB Biopharma SPRL, Brain-l'Alleud, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Vos","sequence":"additional","affiliation":[{"name":"Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Bos","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands"},{"name":"Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Clinical 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