Why some cases lead to rapid decline and death



An international team led by Case Western Reserve University School of Medicine has made a significant breakthrough in understanding why Alzheimer’s disease progresses so rapidly in some people that they die within three years.

Researchers found link between misshapen and rapidly replicating strains of tau protein and accelerated cognitive decline – a critical finding that sheds light on variations in Alzheimer’s disease and may help lead to more accurate diagnoses and therapies targeted.

Such work could lead to changes in the management of Alzheimer’s disease, potentially offering patients and families a more precise prognosis.

“For the first time, we have established the link between the behavior of the tau protein in the test tube and the clinical duration of the disease in patients,” said Jiri Safar, professor in the departments of pathology, neurology and Case neuroscience. Western Reserve School of Medicine. “What the research generally says is that Alzheimer’s disease is not a single disease. There is a spectrum and different cases have distinct biological drivers of progression – and they should be treated as diseases. distinct. “

Their findings appeared on January 5 in Science Translational Medicine.

“We have to understand the disease and then categorize it into the different subsets or categories,” Safar said, “and that is indeed where we are now with Alzheimer’s disease.”

Safar’s co-authors include CWRU colleagues Alan Lerner, professor of neurology, and Mark Cohen, professor of pathology and neurology; David Westaway, professor in the Department of Medicine at the University of Alberta and director of its Center for Prions and Protein Folding Diseases; and Rohan de Silva, professor of molecular neuroscience at the Queen Square Institute of Neurology at University College London.

Safar hopes the research will help dispel the public perception that people with Alzheimer’s disease are likely to decline slowly over eight to ten years; 10 to 30% have the rapidly progressive form of the disease.

“We’re talking about 600,000 to 1.8 million patients in the United States alone,” he said. “So now we can think of it the same way we clinically treat malignant tumors like breast cancer or lung cancer – that different cancers have very different prognoses and treatment strategies.”

The next step is to translate the tools used in the study into clinical practice and identify those at high risk for rapid disease progression, then tailor treatments to the diagnosis.

Alzheimer’s disease research follows Safar’s groundbreaking work on prion proteins. He and his colleagues have found that when prions are folded incorrectly, they can replicate and damage the brain. They used concepts and tools developed in the prion work to study the mechanisms of misfolded proteins and applied them to the tau protein and Alzheimer’s disease.

Prion research has helped create a new paradigm for understanding Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases.

They knew that genetic and environmental factors linked to the increased risk of developing Alzheimer’s disease explained about 30% of cases. In recent research, they have sought to understand the remaining 70%.

The study

Scientists looked at brain samples from 40 people who died of Alzheimer’s disease – about half had slowly lost cognitive functions over the years and the rest declined rapidly and died within three years.

The researchers found that in the rapidly evolving cases, the nuclei of the tau protein particles had a different shape, meaning they had different structural organizations. Additionally, using processes they developed previously, they found that these misfolded tau species – like prions – can replicate faster in test tubes. They also deepened their understanding of the impacts of different structures and characteristics of abnormal tau and determined the attributes that predicted the rate of replication.



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