Study reveals shared and unique molecular markers across multiple forms of dementia

Researchers have identified for the first time degeneration-associated ‘molecular markers’ – observable changes in cells and their gene regulatory networks – that are shared by different forms of dementia that affect different areas of the brain. Crucial is the UCLA-led research published in the journal Cellalso identified markers specific to different forms of dementia, and the combined findings represent a potential paradigm shift in the search for causes, treatments and cures.

“This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for the development of therapies,” said senior and corresponding author Daniel Geschwind, MD, PhD, professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine . at UCLA and director of the Institute for Precision Health at UCLA Health.

Previous studies have focused on a single disorder at a time. Citing case-control studies, they compared “diseased” cells with normal cells and often focused only on one brain region. But in this study, the scientists also looked at molecular changes in three different forms of dementia, which may involve ‘tau pathology’, the accumulation of abnormal tau protein in vulnerable areas that vary by condition.

They performed single-cell genomic analysis on more than 1 million cells to identify distinct and shared molecular markers in three related conditions: Alzheimer’s disease, frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). In addition to validating changes previously observed in AD, they identify dozens of cell types whose changes are shared by multiple forms of dementia and several cell types whose disease changes were specific to a single condition, many of which had not been previously identified .

“Different disorders have different patterns of degeneration. We reasoned that a comparison between cases of different disorders, in addition to the typical case-control comparison, would be useful to identify shared components of neurodegeneration and to understand cell type-specific changes underlying all these disorders.” conditions,” Geschwind said, adding that most studies profile only one brain region – usually the frontal lobe.

In dementia and neurodegenerative diseases in general, specific brain areas and cells are most vulnerable in each disease. This is what leads to the different symptoms and signs in disorders. Because regional vulnerability is a core feature of the disorders, we reasoned that studying more than one region would provide new insights, and it did. In addition to identifying shared and distinct molecular markers, we showed how genetic risk is linked to these disease-specific pathways that are altered in the brain.”

Daniel Geschwind, MD, PhD, professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine at UCLA and director of the Institute for Precision Health at UCLA Health

Using this study design, the researchers found four genes that marked vulnerable neurons in all three conditions, highlighting pathways that could be used to develop new therapeutic approaches.

First author Jessica Rexach, MD, PhD, assistant professor of neurology and neurobehavioral genetics at the David Geffen School of Medicine at UCLA, said this work “profoundly changed” her perspective on the mechanisms underlying disease susceptibility .

‘It is remarkable and humbling to have identified several distinct molecular differences that distinguish cells from individuals with one form of dementia from those with closely related diseases. Although these disease-specific differences were in the minority of changes observed in diseased brains, they were strongly linked to heredity. This surprising finding opens new avenues to understand why and how certain genes influence the risk of developing a brain disease versus another closely related condition.”

Combined, Alzheimer’s disease, FTD and PSP affect more than 28 million people worldwide. Although Alzheimer’s disease has been extensively studied, there is no cure and existing approved medications only slow disease progression. Few clinical trials are available for FTD and PSP.

“We have created a comprehensive data resource that paves the way for identifying and investigating novel therapeutic candidates for neurodegenerative dementias,” said Rexach. “We have identified specific molecules that can now be developed as potential new disease regulators in experimental systems – importantly, based on primary human disease data. In addition, we have uncovered unexpected conceptual phenomena that may explain why certain cells show greater resilience or vulnerability against diseases, and we are eager to explore these findings further.”

The researchers:

• Identified unique changes specific to Alzheimer’s disease and showed that several findings in Alzheimer’s disease were also observed in the other conditions, identifying targets for therapeutic development.
• Found that ‘cellular resilience programs’ – molecular mechanisms that support cells in response to injury – activated or failed differently when comparing the same cell types in different conditions.
• We were surprised to find that each of the three disorders had changes in cells of the primary visual cortex – the area of ​​the brain that processes visual information and was not thought to be affected by dementia. In PSP, this discovery revealed previously unknown changes in brain cells called astrocytes.
• Specific changes identified in the expression of certain tau-related genes and others in PSP. These appear to correlate with the unique pattern of brain cell degeneration seen in PSP.

The authors, who will then begin experiments to validate the causal nature of their findings, expect the study to inspire similar research across different conditions.

“These data demonstrate that known risk genes function in specific neuronal and glial states or cell types that differ across related conditions. Furthermore, causally associated disease states may be restricted to specific cell types and regions,” the researchers said. Cell article concludes. “This underlines the importance of examining multiple brain regions to understand causal disease pathways at the cellular level. We show that this provides a clearer picture of shared and disease-specific aspects of resilience and vulnerability to inform the therapeutic roadmap.”