Long-term Study Links Unbalanced Proteins in Middle Age to Dementia

A long-term study has shed light on a potential link between unbalanced proteins during middle age and the development of dementia later in life.

The study, published in Science Translational Medicine on 19 July, followed thousands of individuals for an impressive 25-year period, unraveling vital insights that could pave the way for new diagnostic tests and even treatments for dementia-causing diseases.

Identifying Dementia Predictors

A Nature report tells us that the research led by neuroscientist Keenan Walker from the US National Institute on Aging in Bethesda, Maryland delved into the proteome - the collection of all expressed proteins in the body - of more than 10,000 participants.

The aim was to identify predictors of dementia years before its onset by analyzing the dysregulation of proteins, where their levels deviate significantly from the norm.

Astonishingly, the study found 32 proteins that, if dysregulated between the ages of 45 to 60, were strongly associated with an elevated risk of developing dementia later in life.

Surprisingly, most of these identified proteins play roles unrelated to the brain, indicating a significant involvement of peripheral biology decades before dementia's typical onset.

More Findings

Nicholas Seyfried, a biochemist and neurologist at Emory University in Atlanta, Georgia, pointed out that not all the proteins detected changes in both plasma and brain tissues.

One striking example is the protein GDF15, which showed the strongest association with dementia risk but was not detected in the brain. This suggests that mechanisms beyond the brain may also play a crucial role in dementia development.

Notably, some identified proteins are involved in proteostasis, a vital process that carefully balances protein levels in the proteome. This regulation is essential for preventing protein clumping, a hallmark of Alzheimer's disease, the most common cause of dementia.

The researchers further corroborated their findings by studying cerebrospinal fluid, the fluid surrounding the brain and spinal cord. They discovered that 12 of the 32 dementia-associated proteins were linked to biomarkers of Alzheimer's disease, neurodegeneration, or neuroinflammation - indicators of brain damage or inflammation.

Employing advanced analysis methods, the researchers identified a protein signature that predicted dementia risk in midlife, nearly two decades before the manifestation of dementia symptoms.

This signature highlighted issues with specific immune and protein balance pathways, along with problems related to coagulation and complement signaling, about ten years before the onset of dementia.

To support the study's credibility, the researchers cross-validated their results using genetic data, confirming that nine candidate proteins were indeed markers of Alzheimer's disease in midlife. Additionally, they identified the SERPINA3 protein as a potential player in the development of Alzheimer's disease.

Despite these groundbreaking findings, the researchers emphasized the need for a deeper understanding of how these proteins are integrated into the physiology of dementia. Such insights could potentially open doors for early interventions and more personalized treatments for this debilitating condition.

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