Brain slices from people with Alzheimer’s disease, the most common cause of dementia.Credits: Anatomical Journey/Science Photo Library
A study that followed thousands of people for 25 years identified a protein that is associated with the development of dementia when protein levels become unbalanced in middle age.
The survey results are scientific translational medicine July 19th1may contribute to the development of new diagnostic tests and even treatments for the diseases that cause dementia.
Most of the proteins have functions unrelated to the brain.
“Decades before the onset of typical dementia, the involvement of peripheral biology became very common,” says study author Keenan Walker, a neuroscientist at the National Institute on Aging in Bethesda, Maryland.
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Walker and his colleagues questioned whether looking at a person’s proteome (the collection of all proteins expressed throughout the body) in blood samples from more than 10,000 participants could predict the onset of dementia years in advance. They looked for signs of dysregulation when protein levels were much higher or lower than normal.
Samples were collected as part of an ongoing study that began in 1987. Participants returned for testing six times over a 30-year period, during which approximately one in five participants developed dementia.
Researchers found that 32 proteins that are dysregulated in people aged 45 to 60 were strongly associated with an increased likelihood of developing dementia later in life. It’s unclear how exactly these proteins are involved in the disease, but the association “is very unlikely to be pure chance,” Walker said.
“Not all proteins showed changes in both plasma and brain tissue,” says biochemist and neurologist Nicholas Seyfried of Emory University in Atlanta, Georgia. For example, GDF15, one of the proteins found to be most strongly associated with dementia risk, was not detected in the brain, suggesting “mechanisms below the neck may also play a role,” he added.
Walker said that a person’s proteome alone cannot predict the risk of developing dementia, but it may increase the strength of existing predictors such as age and family history.
protein balance
As expected, some of the proteins the researchers identified have activity in the brain, but most have other roles in the body. A few were associated with proteostasis, a process that carefully balances protein levels within the proteome.
This regulation is important in preventing protein abnormalities and aggregation of the amyloid and tau proteins in the brains of Alzheimer’s disease patients, the most common cause of dementia.
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The study found altered levels of many proteins in both the brain tissue of people who died of Alzheimer’s disease and the blood of people still living with Alzheimer’s disease. These are associated with the presence of amyloid and tau proteins, suggesting that they are somehow involved in disease-specific processes.
Other proteins identified in the study are related to the immune system, and “there is growing evidence for the role of innate and adaptive immune function in dementia,” said Jintai Yu, a medical scientist specializing in dementia at Fudan University in Shanghai, China. Yu and his team have previously found that people with immune disorders are more likely to develop Alzheimer’s later in life.2.
We still have a long way to go in understanding exactly how these proteins fit into the physiology of dementia, and a deeper understanding of the underlying mechanisms is needed if people are to benefit. Insights like this “could open the door for early intervention,” Seyfried said. Walker’s future goal is to determine whether these proteins could be used as markers to help identify different dysregulated pathways in people with dementia and help provide more personalized treatments.
