Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles
Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles
Abstract Alzheimer’s disease (AD) is heterogenous on the molecular level. Understanding this heterogeneity is critical for AD drug development. We aimed to define AD molecular subtypes by mass spectrometry proteomics in cerebrospinal fluid (CSF). Of the 3863 proteins detected in CSF, 1058 proteins had different levels in individuals with AD (n=419) compared with controls (n=187). Cluster analyses of AD individuals on these 1058 proteins revealed five subtypes: subtype 1 was characterized by 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 dysfunction. Distinct genetic profiles were associated with subtypes, e.g., subtype 1 was enriched with TREM2 R47H. Subtypes also differed in brain atrophy and clinical outcomes. For example, survival was shorter in subtype 3 compared to subtype 1 (5.6 versus 8.9 years). These novel insights into AD molecular heterogeneity highlight the need for personalized medicine.
Mjaavatten Olav、Vermunt Lisa、Venkatraghavan Vikram、Tesi Niccol¨?、Goossens Julie、Vanmechelen Eugeen、Barkhof Frederik、Pijnenburg Yolande AL、Holstege Henne、Reus Lianne M、Lorenzini Luigi、Tijms Betty M、den Braber Anouk、Teunissen Charlotte E、Tomassen Jori、Berven Frode、van der Lee Sven、Visser Pieter Jelle、van der Flier Wiesje M、Vromen Ellen M、Wesenhagen Kirsten EJ
PROBE, department of biomedicine, University of BergenAmsterdam Neuroscience||Neurochemistry Laboratory, Department of Clinical Chemistry Vrije Universiteit AmsterdamAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam NeuroscienceGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam||Delft Bioinformatics Lab, Delft University of TechnologyADx NeuroSciencesADx NeuroSciencesCenter for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles||Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam||Institutes of Neurology and Healthcare Engineering, University College LondonAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam NeuroscienceAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam Neuroscience||Amsterdam NeuroscienceAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam Neuroscience||Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los AngelesDepartment of Radiology and Nuclear Medicine Vrije Universiteit Amsterdam||Amsterdam NeuroscienceAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam NeuroscienceAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam NeuroscienceAmsterdam Neuroscience||Neurochemistry Laboratory, Department of Clinical Chemistry Vrije Universiteit AmsterdamAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam NeurosciencePROBE, department of biomedicine, University of BergenAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam Neuroscience||Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit AmsterdamAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam Neuroscience||Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University||Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska InstitutetAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam NeuroscienceAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam NeuroscienceAlzheimer Center Amsterdam Vrije Universiteit Amsterdam||Amsterdam Neuroscience
神经病学、精神病学基础医学分子生物学
Alzheimer’s diseasecerebrospinal fluidproteomicsdisease heterogeneity
Mjaavatten Olav,Vermunt Lisa,Venkatraghavan Vikram,Tesi Niccol¨?,Goossens Julie,Vanmechelen Eugeen,Barkhof Frederik,Pijnenburg Yolande AL,Holstege Henne,Reus Lianne M,Lorenzini Luigi,Tijms Betty M,den Braber Anouk,Teunissen Charlotte E,Tomassen Jori,Berven Frode,van der Lee Sven,Visser Pieter Jelle,van der Flier Wiesje M,Vromen Ellen M,Wesenhagen Kirsten EJ.Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles[EB/OL].(2025-03-28)[2025-04-27].https://www.medrxiv.org/content/10.1101/2023.05.10.23289793.点此复制
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