A Proteomic Model for Five Subtypes of Alzheimer’s Disease
Recent work has focused on categorizing subtypes of Alzheimer’s disease to better understand how patients may respond to different therapies. A paper discussing results from proteomic analyses proposes the existence of five important subtypes of Alzheimer’s disease, each associated with distinct molecular processes and clinical outcomes. This molecular heterogeneity highlights the need for personalized medicine and may be useful in selecting individuals for specific therapeutic treatments.
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 (CSF), 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. CSF-based subtyping may be useful to select individuals for a specific therapeutic treatment, either for a priori subject stratification or for responder and side effect analysis in clinical trials.
Link: https://doi.org/10.1038/s43587-023-00550-7
