Three major molecular subtypes of Alzheimer's disease (AD) each of which has a typical presentation in the brain with a unique genetic risk have been identified by researchers after performing an autopsy and then RNA sequencing .
It should be noted that the models currently used in mice for pharmaceutical research correspond to a particular subset of AD and not to all of its subtypes . And this is the reason why most of the drugs that are effective in mice have not been proven effective for all AD subtypes in widespread human trials.
The subtyping of patients with AD is therefore a critical step towards precision medicine for the understanding and treatment of this condition, because it makes it possible to predict which subtype is more vulnerable to which drug, and therefore to choose. the treatments in adequacy with each sub-type to hope for better results.
News on Alzheimer's disease
Traditionally, two markers found in postmortem brain biopsies characterize AD including amyloid-beta plaque clusters (Aβ), and tau protein entanglement (NFT).
The accumulation of these two markers is generally believed to be the cause of neuronal and synaptic loss in the cerebral cortex and the hippocampus. This leads to inflammation and degeneration of the protective coating of nerve cells, slowing brain signals.
However, it has recently been shown that in a third of cases, Aβ plaques do not exist in postmortem biopsies of patients with confirmed AD. While in those where they were found, a good part did not present cognitive impairment of their existence.
The Aβ plaques therefore appear to be retarders rather than early triggers of AD. Also, based on other evidence, tau proteins are present in the early stages of the disease.
What researchers tell us about these subtypes
Three major molecular subtypes of AD, corresponding to different deregulated pathways, were therefore identified after analysis by sequencing of the RNA of more than 1,500 transcriptomes – genetic processes expressed in the cell in five areas of the brain – collected post-mortem on of patients with AD.
These subtypes are thus defined from the weight of each of the following factors: susceptibility to neurodegeneration mediated by the tau protein, amyloid-β neuroinflammation, synaptic signaling, immune activity, organization of mitochondria and finally , myelination.
The researchers specify that the prevalence of these subtypes does not depend on the age or the severity of the disease. However, all areas of the brain can be affected, especially the hippocampus, where new memories are formed.