A Proteomic Model for Five Subtypes of Alzheimer's Disease
There has been some work in recent years aimed at distinguishing subtypes of Alzheimer's disease that may respond quite differently to therapies. How much of the poor results in clinical trials is a matter of aiming too broadly, at patients who cannot respond well to a specific therapy? Of late, this attempt at categorization has focused on proteomic analyses of patient samples. Here find a paper covering results that were discussed late last year, in which researchers propose that there are five important subtypes of Alzheimer's disease.
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.