A key step in unravelling the mystery of Alzheimer’s disease and how to treat it.
A group of Dutch researchers appear to have discovered the existence of five molecular subtypes of Alzheimer’s disease (AD), each with distinct genetic profiles which may explain the varying effectiveness of AD treatments.
What they uncovered
The study analysed protein levels in cerebrospinal fluid (CSF) samples from 609 individuals, AD (n = 419) compared with controls (n = 187) and identified five AD molecular subtypes (3 individuals with normal cognition were excluded due to abnormal CSF t-tau levels): Neuronal hyperplasticity, innate immune activation, RNA dysregulation, choroid plexus dysfunction, and blood-brain barrier dysfunction. These subtypes were associated with specific protein expression, genetic risk variants, vascular damage, and clinical outcomes. The results suggest that the different underlying molecular processes and specific genetic risk profiles of each subtype may contribute to the variability in AD progression among patients. The findings provide a valuable insight into the heterogeneity of AD and its underlying molecular mechanisms.
Not so fast
Of course, there are caveats with a study like this, primarily the lack of treatment response data and any mechanistic information. The study results suggest that specific AD subtypes may require tailored treatments, while also acknowledging that while a treatment may benefit individuals of one subtype, it could also mean an increased risk of side effects associated with that therapy. This research emphasises the necessity for future studies to analyse proteomics in clinical trial samples to determine any subtype-specific effects of treatments.
Why does it matter?
Over the past two decades there has been an acknowledged lack of success developing therapeutics to treat Alzheimer’s disease. Only a few controversial successes exist, such as lecanemab, and one review reported at least 98 failed compounds between 2004 and 2021 that reached phase II and III trials. This study could help explain the failures of the past, leading to new druggable targets through re-evaluation of existing drugs that may impact specific subtypes of AD.
Take home messages
1. CSF proteomic samples show there are five subtypes of Alzheimer’s disease.
2. Identifying the underlying molecular processes for each subtype may help researchers understand what contributes to variability in patients
with AD.
3. The use of proteomics to study the subtype-specific effects of potential drugs may offer new insight into tailored treatments in AD.
Guest Author: Conor McQuaid, PhD
This article was written as part of a series of ‘journal club’ summaries for Scientific Writers Ltd., and is based on the following publication:
First Author: Betty M Tijms, et al.
Journal: Nature Aging
Date online: 9 January 2024
Other references: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198803/
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