- Research implicates aggregates of two proteins, known as tau and beta-amyloid, in the development of Alzheimer’s disease.
- A new study has tracked the replication and spread of tau in the living human brain for the first time.
- It found that, contrary to the prevailing view, local replication of tau is more important for the overall progression of the disease than its spread from region to region.
- The research has important implications for the development of drugs to slow or halt the progression of Alzheimer’s.
Alzheimer’s disease is the most common form of dementia, accounting for 60–80% of all cases. It affects around 5.8 million people in the United States alone.
In people with Alzheimer’s, plaques of a misfolded protein called beta-amyloid, and fibrous tangles of another misfolded protein called tau, accumulate in the brain and kill nerve cells.
This gradual loss of nerve cells causes shrinkage of the brain and eventually interferes with a person’s ability to form new memories. Over time, it also disrupts a wide range of other cognitive skills, including language and the ability to navigate once familiar locations.
In the past, the search for an effective treatment for Alzheimer’s disease has mostly targeted the plaques, for example, with vaccines, but so far with limited success.
Meanwhile, there has been growing evidence that the buildup of tangles of tau protein correlates much better with the clinical progress of the disease and damage to the brain than the buildup of plaques.
“Tau isn’t the primary cause of Alzheimer’s, but it is thought to be the most closely correlated with the cascade of changes associated with the disease, including cognition,” Rebecca M. Edelmayer, Ph.D., senior director of scientific engagement at the Alzheimer’s Association, told Medical News Today.
Like cancer cells, aggregates or “seeds” of tau protein can replicate themselves and spread.
This has led to the idea that Alzheimer’s progresses when tau seeds spread to unaffected regions in the brain, like secondary tumors in cancer.
However, a new study suggests that the rate at which tau seeds replicate locally is a much more important measure of the disease’s progress than their spread to new regions.
This has important implications for the development of new treatments, as it suggests that they should target local replication of tau rather than the spread of seeds.
Scientists at the University of Cambridge in the United Kingdom led the study, which appears in Science Advances.
Living human participants
In the past, researchers have often relied on mouse models of the disease to chart its progress in the brain.
But for the first time, the new study used PET scans of the brains of living people, whose disease severity ranged from mild cognitive impairment to full-blown Alzheimer’s disease.
It also drew upon imaging data of postmortem brain samples from people with Alzheimer’s.
The researchers developed a mathematical model to simulate the progression of the disease and applied it to five different imaging datasets.
They discovered that in all five datasets, the total number of tau seeds in the brain doubled only every 5 years or so. This is much slower than the rate of spread predicted from earlier studies in mice.
This suggests that the most effective strategy to slow the progression of the disease would be to target the local replication of tau rather than its long-distance spread from region to region of the brain.
“Firstly, the method shows that the best strategy is [to] target replication of the tau aggregates rather than spreading, which is the main target at present,” senior author Professor Sir David Klenerman, Ph.D., from the U.K. Dementia Research Institute at the University of Cambridge, told MNT.
He said that future research could use the methodology he and his colleagues have developed to monitor how effective candidate drugs are at preventing tau replication.
“[W]e analyzed PET data from live patients to extract the replication rate so it would be possible to make the same measurements in the presence of drugs to see if the replication rate is reduced,” he said.
“We have not been able to measure the replication rate in humans before, so have not been able to see how it is altered by drugs,” he added.
Dr. Edelmayer told MNT that Alzheimer’s is just one of several brain diseases that involve abnormal tau, collectively known as “tauopathies.”
She said the Alzheimer’s Association is helping fund the Tau Pipeline Enabling Program, which aims to identify promising drug candidates for clinical trials.
Limitations of the new study
The authors of the new study note that one limitation of their research was that the imaging data did not provide insights into how tau might spread on very small scales, for example, between neighboring cells.
Dr. Edelmayer also pointed out that while tau is important, many factors contribute to Alzheimer’s disease.
She told MNT:
“Because of its contributions to the neurodegenerative process, tau is one of the major areas of focus for therapy development. But Alzheimer’s is a complicated disease, and we will likely need multiple treatments that target the various aspects of the disease. This includes amyloid, tau, and possibly others.”
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