[ad_1]
Postmortem RNA sequencing has revealed three major molecular subtypes of Alzheimer’s disease, each of which appears differently in the brain and carries unique genetic risks.
This knowledge can help predict who is most susceptible to each subtype, how their disease might progress, and what treatments may work best for them, which can lead to better results.
Read more
It might also help explain why effective treatments for Alzheimer’s disease have been so hard to come by until now.
The researchers found that the mouse models used for pharmaceutical research matched a specific subset of Alzheimer’s disease, but not all subtypes simultaneously.
They say this may “partly explain why the vast majority of drugs that are successful in some mouse models are incompatible with widespread human trials on all Alzheimer’s disease subtypes.”
Therefore, the researchers concluded that the classification of patients with Alzheimer’s disease is a critical step towards precision medicine for this devastating disease.
Alzheimer’s disease is traditionally thought to be characterized by clusters of beta-amyloid (Aβ) plaques, as well as tau protein synapses (NFT) found in postmortem brain biopsies.
Each of these signs has become synonymous with disease, but in recent years our main assumptions about what it actually does with our brains have been called into question.
It is generally believed that accumulations of beta-amyloid and tau proteins lead to neuronal and synaptic loss, most commonly in the cerebral cortex and hippocampus. Further deterioration ensues, including inflammation and degeneration of the protective layer of nerve cells, which slows down signals in our brain.
Read more
Oddly, however, recent evidence shows that up to a third of patients with a clinical diagnosis do not have beta-amyloid plaques on postmortem biopsies. Additionally, many of those found with plaques upon death did not exhibit cognitive impairment in life.
Instead of being an early trigger for Alzheimer’s disease, leading to neurodegeneration, memory loss, and confusion, beta-amyloid (Aβ) plaques appear to be delayed in some people.
In contrast, recent evidence indicates the presence of tau proteins in the very early stages.
In light of all of this research, it is very likely that there are some subtypes of Alzheimer’s disease that scientists have yet to develop. The new research has made it possible to draw three main axes.
To do this, the researchers analyzed 1,543 copies of the genetic processes expressed in the cell across five regions of the brain, which were collected after the autopsy in two Alzheimer’s groups.
Using RNA sequencing to characterize these copies, the authors identified three major molecular subtypes of Alzheimer’s disease that correspond to different and unregulated pathways.
These pathways include: susceptibility to tau-mediated neurodegeneration, beta-amyloid neuritis, synaptic signaling, immune activation, mitochondrial regulation, and myelin formation.
All subtypes were independent of age and disease severity. Their molecular fingerprints were also present in all regions of the brain, but particularly in the hippocampus, which is widely associated with the formation of new memories.
Read more
In addition, beta-amyloid and tau proteins were not able to fully explain the different subtypes.
In fact, only about a third of Alzheimer’s cases exhibit these features of a “typical” Alzheimer’s presentation. The rest of the cases showed opposing forms of gene regulation within molecules, causing complex changes in multiple pathways and cell types in the brain.
“It is likely that the accumulation of beta-amyloid and tau is likely mediators or end-effects of neurodegeneration and inflammation, regardless of the hippocampal load,” the researchers wrote.
In other words, the mere presence of beta-amyloid and tau clusters might not be as important as how they interact with each other and with other cellular processes.
By comparing the results with mouse models, the authors found a serious mismatch. Most of the mouse models used in clinical research are based on “typical” presentations of Alzheimer’s disease, which will only cover a third of the cases in this study.
This means that treatments that have been tested in mice may not work for all patients. To develop a more personalized approach to treatment, scientists have tried to define it and verify molecular biomarkers like these.
The authors conclude: “As we have shown, Alzheimer’s subtypes have very different text signatures and are therefore likely to require specialized treatments. Since many major subtype organizations have opposing tendencies in certain Alzheimer’s subtypes, it is also possible that Drugs that reduce the symptoms of Alzheimer’s disease in one subtype may exacerbate the symptoms. in another subtype.
More research is needed to confirm this idea.
Source: ScienceAlert
[ad_2]
Source link
