The study which followed thousands of people over the age of 25, identified proteins linked to the development of dementia if their levels are imbalanced in middle age. The findings published in Science Translational Medicine could contribute to the development of new diagnostic tests or even treatments for diseases that cause dementia.
Most proteins have functions unrelated to the brain
Keenan Walker, a neuroscientist at the US National Institute on Aging in Bethesda, Maryland says “We see so much involvement of peripheral biology decades before the typical onset of dementia”.
Armed with blood samples from more than 10,000 participants, Walker and his colleagues asked whether they could find predictors of dementia years before its onset by looking at a person’s proteome the collection of all the proteins expressed in the body. They looked for any signs of dysregulation when protein levels are much higher or lower than normal.
The samples were collected as part of an ongoing study that began in 1987. The participants returned for examination six times over three decades, during which time approximately 1 in 5 of them developed dementia.
The researchers found 32 proteins that, when dysregulated in people between the ages of 45 and 60, were strongly associated with an increased likelihood of developing dementia later in life. It’s not clear exactly how these proteins might be involved in the disease, but it’s “very unlikely that this association is due to chance alone,” Walker says.
He says “Not all proteins showed changes in both plasma and brain tissue,” says Nicholas Seyfried, a biochemist and neuroscientist at Emory University in Atlanta, Georgia. For example, one of the proteins found with the strongest link to dementia risk called GDF15 was not detected in the brain, suggesting that “mechanisms below the neck could also play a role”.
Walker says that while a person’s proteome alone cannot predict their risk of developing dementia, it could possibly enhance the power of existing predictors such as age and family history.
Protein balance
As expected, some of the proteins the researchers identified are active in the brain but most have other roles in the body. A handful have been linked to proteostasis the process of carefully balancing protein levels in the proteome.
This regulation is important to keep proteins from breaking down and clumping together, which happens to amyloid and tau protein in the brains of people with Alzheimer’s disease, the most common cause of dementia.
The study found altered levels of many proteins both in the brain tissues of those who died of Alzheimer’s disease and in the blood of those still living with it. These were 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 were linked to the immune system, adding to “growing evidence for the role of innate and adaptive immune function in dementia,” says Jin-Tai Yu, a physician and scientist who specializes in dementia at Fudan University in Shanghai, China. Yu and his team previously found that people with immune diseases are more susceptible to Alzheimer’s disease later in life.
There is still a long way to go to understand exactly how any of these proteins fit into the physiology of dementia, and a much better understanding of the underlying mechanisms is needed before humans will benefit. Such insights “can potentially open the door to early intervention,” says Seyfried. For Walker, the goal in the future is to see if these proteins could potentially be used as markers to identify different dysregulated pathways in people with dementia and help provide more personalized treatment.
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Reference: https://www.nature.com/articles/d41586-023-02374-2
