Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles
Open accessAbstract
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.
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Analyses using similarity network fusion have identified Alzheimer's disease subtypes characterized by immune activation, mitochondrial dysfunction, lipid dysregulation, and blood-brain barrier disruption.
“These analyses have identified subtypes characterized by immune activation, mitochondrial dysfunction, lipid dysregulation, and BBB disruption342,352,399,400.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [399]
Proteomic clustering has identified subgroups particularly responsive to drugs that modulate synaptic function and restore blood-brain barrier integrity.
“Proteomic clustering has identified subgroups particularly responsive to drugs that modulate synaptic function and restore BBB integrity342,345,347,350,352,399,400.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [399]
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- Authors
- Tijms, B. M., Vromen, E. M., Mjaavatten, O., Holstege, H., Reus, L. M., van der Lee, S., Wesenhagen, K. E., Lorenzini, L., Vermunt, L., Venkatraghavan, V., Tesi, N., Tomassen, J., den Braber, A., Goossens, J., Vanmechelen, E., Barkhof, F., Pijnenburg, Y. A., van der Flier, W. M., Teunissen, C. E., Berven, F., & Visser, P. J.
- Affiliations
- Amsterdam Neuroscience (NL)
- University of Bergen (NO)
- University of California, Los Angeles (US)
- Vrije Universiteit Amsterdam (NL)
- ADx NeuroSciences (BE)
- Karolinska Institutet (SE)
- Corresponding author
- Tijms, Betty M
- ORCID
- Venue
- medRxiv
- Publisher
- openRxiv
- Published
- 2023-05-11
- OpenAlex
- W4376129808
- Cited by
- 10
- References
- 25
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc
- Locations
- medRxiv (acceptedVersion, cc-by-nc)
- Funders
- ZonMw (733050512, 733051061, 09150171910068, #73305095007, 10510022110012, 733050824, 733051106)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- Alzheimer's disease, cerebrospinal fluid proteomics, molecular subtypes, disease heterogeneity, innate immune activation, blood-brain barrier dysfunction, brain atrophy, survival, genetic risk profiles, personalized medicine
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