Recently, a new study in Science-Translational Medicine has brought new insights into the diagnosis and treatment of Alzheimer's disease, finding that a class of malformed and rapidly replicating tau proteins is associated with accelerated cognitive decline.
In the past, it may be thought that Alzheimer's disease will progress slowly in 8-10 years, but according to Professor Jiri Safar of case Western Reserve University School of Medicine, about 10%-30% of patients will experience rapid disease development. "In the United States alone, this group of Alzheimer's patients is 600,000-1.8 million," Professor Safar said.
In his view, Alzheimer's patients should not be generalized, just as cancer treatment is moving towards individualized therapy, we need to provide different treatments for Alzheimer's patients with different conditions, but how can we distinguish between the patient's condition?
Professor Safar's research experience in prions gave him some insights into whether a similar mechanism exists in the tau protein when it is misfolded and can continue to replicate and cause damage to the brain.
To that end, the team managed to obtain hippocampal samples from 40 Alzheimer's patients who had different rates of disease progression before their deaths, some of whom had slow loss of cognitive function over many years, and some of whom had rapid decline and died within three years of diagnosis.
They analyzed tau protein aggregates using protein configuration techniques established while studying prions. Since impaired hippocampal function is clearly linked to cognitive degradation, the state of tau protein in it is a good reflection of what effects it has.
During the comparison process, the researchers found that those patients who had a rapid degree of disease progression did not have the same core conformation of the tau protein in their brains as other patients, and these tau proteins misfolded significantly more frequently.
In the tau protein subtype, 4R tau proteins with 4 microtubule binding replicates play a more important role, accounting for about 80% of all abnormal tau proteins. In addition, the link between disease duration and tau protein does not appear to depend on the number of tau protein aggregates, but more on conformational anomalies.
▲Hippocampal samples from patients with different rates of disease progression (Image source: Reference[2])
In vitro, the researchers tried to cultivate tau protein samples in different samples, and the results were obviously faster to replicate those with misfolding, which also showed that this type of tau protein may be the real culprit of brain damage. The paper notes that a higher misfolded 4R tau in the tau protein may indicate a faster cognitive decline.
"This is the first time that a link between tau protein type and disease duration and progression has been found," Professor Safar said, "and it is now clear to us that Alzheimer's disease is not a single disease, it is more like a category, different patients have different disease drivers." ”
Studies believe that abnormal tau protein conformation is one of the important factors, and patients may be able to divide them into different diseases according to this indicator for treatment.
The next step for the research team is to transform the analytical tools used in the study into clinically usable applications to discern which Alzheimer's patients are at risk of rapid progression.
Resources:
[1] Findings open the way to more precise diagnoses and treatments of Alzheimer's disease. Retrieved Jan 6th, 2021 from https://medicalxpress.com/news/2022-01-precise-treatments-alzheimer-disease.html
[2] Chae Kim et al, Distinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer's disease, Science Translational Medicine (2022). DOI: 10.1126/scitranslmed.abg0253