Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics
Tijms, Betty M. (Vrije Universiteit Amsterdam)
Gobom, Johan (Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg)
Reus, Lianne (Vrije Universiteit Amsterdam)
Jansen, Iris E (Vrije Universiteit Amsterdam)
Hong, Shengjun (Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck)
Dobricic, Valerija (Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck)
Kilpert, Fabian (Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck)
ten Kate, Mara (Vrije Universiteit Amsterdam)
Barkhof, Frederik (Institutes of Neurology and Healthcare Engineering, UCL London)
Tsolaki, Magda (AHEPA University Hospital (Grècia))
Verhey, Frans R. J. (Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University)
Popp, Julius (Geneva University Hospitals (Suïssa))
Martinez-Lage, Pablo (Fundación CITA-Alzhéimer Fundazioa)
Vandenberghe, Rik (Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Molinuevo, José Luis (Hospital Clínic i Provincial de Barcelona)
Engelborghs, Sebastiaan (Department of Neurology, UZ Brussel and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB))
Bertram, Lars (Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck)
Lovestone, Simon (Janssen R&D)
Streffer, Johannes (UCB Biopharma SPRL)
Vos, Stephanie (Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University)
Bos, Isabelle (Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University)
Blennow, Kaj (Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg)
Scheltens, Philip (Vrije Universiteit Amsterdam)
Teunissen, Charlotte E. (Neurochemistry laboratory, Department of Clinical Chemistry, Amsterdam UMC - location VUmc, Amsterdam Neuroscience)
Zetterberg, Henrik (UCL Institute of Neurology (Regne Unit). UK Dementia Research Institute)
Visser, Pieter Jelle (Karolinska Institutet (Estocolm, Suècia). Department of Neurobiology, Care Sciences and Society)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	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 > 0. 01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0. 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 = 0. 01), and subtype 3 at trend level (hazard ratio = 2. 1; 95% confidence interval = 1. 0, 4. 4; P = 0. 06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Alzheimer's disease ; Cerebrospinal fluid ; Proteomics ; Subtypes
Publicado en:	Brain, Vol. 143 (november 2020) , p. 3776-3792, ISSN 1460-2156

DOI: 10.1093/brain/awaa325
PMID: 33439986

17 p, 1.3 MB

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