Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics

Using CSF proteomics, Tijms et al. identify three Alzheimer's disease subtypes that show: 1) hyperplasticity and increased BACE1 levels; 2) innate immune activation; and 3) blood-brain barrier dysfunction with low BACE1 levels. Future therapeutics may need tailoring to individual disease subtyp...

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Detalhes bibliográficos
Autores: Tijms, Betty M.|||0000-0002-2612-1797, Gobom, Johan|||0000-0001-6193-6193, Reus, Lianne|||0000-0001-6936-242X, Jansen, Iris E.|||0000-0003-1901-8131, Hong, Shengjun, Dobricic, Valerija|||0000-0001-8559-1097, Kilpert, Fabian, ten Kate, Mara|||0000-0002-8290-8543, Barkhof, Frederik|||0000-0003-3543-3706, Tsolaki, Magda|||0000-0002-2072-8010, Verhey, Frans R. J., Popp, Julius|||0000-0002-0068-0312, Martinez-Lage, Pablo|||0000-0001-5404-9967, Vandenberghe, Rik|||0000-0001-6237-2502, Lleó, Alberto|||0000-0002-2568-5478, Molinuevo, José Luis|||0000-0003-0485-6001, Engelborghs, Sebastiaan|||0000-0003-0304-9785, Bertram, Lars|||0000-0002-0108-124X, Lovestone, Simon|||0000-0003-0473-4565, Streffer, Johannes Rolf|||0000-0002-9387-5951, Vos, Stephanie J.B.|||0000-0002-2045-9818, Bos, Isabelle|||0000-0001-9648-6428, Blennow, Kaj|||0000-0002-1890-4193, Scheltens, Philip|||0000-0002-1046-6408, Teunissen, Charlotte E.|||0000-0002-4061-0837, Zetterberg, Henrik|||0000-0003-3930-4354, Visser, Pieter Jelle|||0000-0001-8008-9727
Formato: artículo
Fecha de publicación:2020
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:235958
Acesso em linha:https://ddd.uab.cat/record/235958
https://dx.doi.org/urn:doi:10.1093/brain/awaa325
Access Level:acceso abierto
Palavra-chave:Alzheimer's disease
Cerebrospinal fluid
Proteomics
Subtypes
Descrição
Resumo:Using CSF proteomics, Tijms et al. identify three Alzheimer's disease subtypes that show: 1) hyperplasticity and increased BACE1 levels; 2) innate immune activation; and 3) blood-brain barrier dysfunction with low BACE1 levels. Future therapeutics may need tailoring to individual disease subtypes. Alzheimer's 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's 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's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain 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's disease (all P.

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