Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles
Year: 2024
Type: article
Study design: Observational Study
Abstract: Alzheimer's disease (AD) is heterogenous at the molecular level. 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 = 419) compared to controls (n = 187). 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-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 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.
Source: Nature Aging
Authors: Betty M. Tijms, Ellen M. Vromen, Olav Mjaavatten, Henne Holstege, Lianne M. Reus, Sven van der Lee, Kirsten E. J. Wesenhagen, Luigi Lorenzini, Lisa Vermunt, Vikram Venkatraghavan, Niccoló Tesi, Jori Tomassen, Anouk den Braber, Julie Goossens, Eugeen Vanmechelen, Frederik Barkhof, Yolande A. L. Pijnenburg, Wiesje M. van der Flier, Charlotte E. Teunissen, Frode S. Berven, Pieter Jelle Visser
Institutions: Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, University of Bergen, University of California, Los Angeles, Delft University of Technology, ADx NeuroSciences, UCL Queen Square Institute of Neurology, University College London, Karolinska Institutet, Maastricht University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Funders: EU Joint Programme – Neurodegenerative Disease Research, European Federation of Pharmaceutical Industries and Associations, Health~Holland, International Progressive MS Alliance, National Institute for Health and Care Research, University College London, European Commission, ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Universitetet i Bergen, Norges Forskningsråd, Stichting Dioraphte, Alzheimer Nederland, Amsterdam Neuroscience, Bentham-Moxon Trust
Awards: G1090293845, G1568870981, G1613806636, G1798618210, G2074436950, G2075818824, G2428565418, G2501976640, European platform for neurodegenerative disorders, Identification of the Molecular Mechanisms of non-response to Treatments, Relapses and Remission in Autoimmune, Inflammatory, and Allergic Conditions, G434337789, G4409414385, European Prevention of Alzheimer’s Dementia Consortium, G5220050481, G5616778589, G574669212, G663896020, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, G696262100, G7417995046, G7461077622, G965995272, G975443604
OpenAlex ID: W4390706250