Menachem M. Kiwak Ph.D, LMHC

A groundbreaking study led by researchers at the University of California, Los Angeles (UCLA) has identified cellular mechanisms shared across three major forms of dementia—Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). This discovery marks a significant shift in the search for dementia treatments and potentially paves the way for new therapeutic targets. Published in Cell on September 11, 2024, the study reveals how molecular markers, linked to degeneration, affect cells and gene-regulating networks in these dementias. Furthermore, the team also discovered unique markers specific to each form of dementia, enhancing the understanding of how these diseases evolve and progress differently.

Dr. Daniel Geschwind, senior author and professor at UCLA’s David Geffen School of Medicine, highlighted that the study offers new insights into the underlying mechanisms of neurodegeneration. “We identified new candidate pathways for the development of therapeutics,” Geschwind said, emphasizing the potential of the findings to transform treatment approaches.

Expanding the Scope of Dementia Research

Traditionally, dementia research has relied on case-control studies, which focus on one disorder at a time, comparing diseased cells with healthy ones. However, this new research took a broader approach by analyzing molecular changes across three types of dementia that exhibit “tau pathology”—a process involving the abnormal accumulation of tau proteins in specific brain regions.

The research team conducted single-cell genomic analysis on over one million cells, identifying both distinct and shared molecular markers in AD, FTD, and PSP. The results validated changes previously associated with Alzheimer’s while revealing dozens of previously unknown changes in other dementias.

“Different conditions exhibit different degeneration patterns,” said Geschwind. “By comparing across disorders, we uncovered shared components of neurodegeneration, as well as cell type-specific changes.” The study stands out for its analysis of multiple brain regions, moving beyond the typical focus on a single region like the frontal lobe. This multi-regional approach provided insights into how genetic risk factors influence these diseases across various brain areas.

Key Findings and Implications for Treatment

One of the most significant findings was the identification of four genes marking vulnerable neurons in all three dementias, offering potential pathways for new therapeutic interventions. The study also found that “cellular resilience programs,” or mechanisms that allow cells to cope with injury, behaved differently depending on the disorder, revealing another potential avenue for therapy.

Another surprising discovery was the involvement of the primary visual cortex, which processes visual information and was previously thought to be unaffected by these dementias. This finding, particularly in PSP, pointed to unexpected changes in astrocytes—key support cells in the brain.

Dr. Jessica Rexach, the study’s first author and assistant professor at UCLA, noted that these findings significantly shifted her understanding of disease susceptibility. “It is remarkable and humbling to have identified distinct molecular differences between these closely related diseases,” Rexach said. The study showed that even though disease-specific differences were in the minority, they were closely linked to genetic heritability, shedding light on why certain genes predispose individuals to particular forms of dementia.

A New Frontier in Dementia Research

With over 28 million people affected by Alzheimer’s, FTD, and PSP globally, the potential impact of this research is enormous. Alzheimer’s disease alone has been extensively studied, yet no cure exists, and current treatments only slow disease progression. For FTD and PSP, therapeutic options are even more limited, with few clinical trials available.

The researchers have created a comprehensive data resource that can be used to identify and develop new therapeutic candidates. “We have pinpointed specific molecules that can now be tested as novel regulators of disease,” Rexach said. The study also uncovered cellular behaviors that could explain why some brain cells are more vulnerable or resilient to degeneration, a discovery the researchers plan to explore further.

This breakthrough study is poised to inspire similar cross-disorder research, expanding the understanding of how neurodegenerative diseases overlap at the cellular level. By examining multiple brain regions and disease states, the research presents a clearer picture of the mechanisms underlying resilience and vulnerability, which could ultimately lead to more effective treatments.

Funding and Future Directions

This research was funded by several organizations, including Roche Pharmaceuticals, BrightFocus, the Rainwater Charitable Foundation, and the National Institutes of Health (NIH). The team plans to begin further experiments to validate the causal nature of their findings, setting the stage for future advancements in the fight against dementia.

The full study is available in Cell, and its authors hope that this landmark research will guide the development of new therapies that address the shared and distinct pathways identified in Alzheimer’s, FTD, and PSP.

Source: University of California – Los Angeles Health Sciences. “Researchers uncover shared cellular mechanisms across three major dementias.” ScienceDaily, September 11, 2024.