Over 200 Misfolded Proteins Linked to Alzheimer's Disease Identified

In a groundbreaking study published on July 14, 2025, researchers from Johns Hopkins University have identified over 200 types of misfolded proteins potentially linked to age-related cognitive decline, expanding the understanding of Alzheimer's disease beyond the traditional focus on amyloid-beta and tau proteins. The findings suggest that these misfolded proteins could play a significant role in the cognitive impairments associated with Alzheimer's and other forms of dementia, which currently afflict millions of individuals over the age of 65.

The research, led by Dr. Stephen Fried, an assistant professor of chemistry and a protein scientist at Johns Hopkins University, emphasizes that amyloid plaques, while significant, may represent only a fraction of the broader spectrum of protein misfolding contributing to cognitive decline. "Amyloids are the buildup of misshapen proteins. They're big and ugly and easy to see under the microscope, so it makes sense that they catch our attention. But we're seeing hundreds of proteins misfolding in ways that don't clump together in an amyloid and yet still seem to impact how the brain functions," Dr. Fried stated.

To conduct this research, Fried and his team studied a cohort of 17 two-year-old rats from the same colony, of which seven exhibited cognitive impairment as determined by memory and problem-solving tests. The study utilized advanced protein analysis techniques to measure over 2,500 protein types within the hippocampus, a brain region crucial for learning and memory. The findings revealed that more than 200 proteins were misfolded in cognitively impaired rats while maintaining their proper shapes in cognitively healthy ones, indicating a direct correlation between misfolded proteins and cognitive decline.

According to the study published in the journal *Science Advances*, these misfolded proteins are unable to perform their necessary cellular functions, which could disrupt neuronal health and overall cognitive performance. Previously, the scientific community had primarily attributed cognitive disruptions solely to the aggregation of amyloid-beta and tau proteins into plaques. However, this new research indicates that a significant number of proteins could evade the cellular surveillance system that normally identifies and eliminates misfolded proteins, thereby complicating the biological landscape of Alzheimer's disease.

Dr. Fried noted, "We think there are a lot of proteins that can be misfolded, not form amyloids, and still be problematic. And that suggests these misfolded proteins have ways of escaping this surveillance system in the cell." This revelation points to potential new therapeutic targets for drug development aimed at addressing the underlying mechanisms of cognitive decline.

The implications of this research extend beyond immediate therapeutic targets. Understanding how these proteins contribute to cognitive decline could pave the way for developing preventive measures against Alzheimer's disease. As Dr. Fried emphasized, "A lot of us have experienced a loved one or a relative who has become less capable of doing those everyday tasks that require cognitive abilities. Understanding what's physically going on in the brain could lead to better treatments and preventive measures."

The research team plans to employ high-resolution microscopy techniques in future studies to gain deeper insights into the structural deformities of these misfolded proteins. This approach aims to elucidate the exact nature of the misfolding and its implications for neuronal function and overall brain health.

The findings from this study represent a significant advancement in the quest to unravel the complexities of Alzheimer's disease. By broadening the scope of research to include a wider array of misfolded proteins, scientists may ultimately develop more effective treatments and enhance the quality of life for millions of individuals affected by cognitive decline.

### References - Tarbox HE, Branch A, Fried SD. Proteins with cognition-associated structural changes in a rat model of aging exhibit reduced refolding capacity. *Sci Adv*. 2025;11(28):eadt3778. doi: 10.1126/sciadv.adt3778. - Johns Hopkins University. (2025). New findings on misfolded proteins in Alzheimer's research. *Technology Networks*.