West LA Times

Researchers have identified molecular markers associated with cell degeneration that are shared across several forms of dementia. The UCLA-led study, published in the journal Cell, also found markers specific to different types of dementia. These findings could shift the approach to understanding causes, treatments, and cures for these conditions.

“This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for development of therapeutics,” said Dr. Daniel Geschwind, senior and corresponding author. Geschwind is the Gordon and Virginia MacDonald Distinguished 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 typically focused on a single disorder by comparing diseased cells with normal ones in one brain region. This research examined molecular changes across three dementias involving tau pathology: Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy.

The researchers performed single-cell genomic analysis on over 1 million cells to identify distinct and shared molecular markers in these conditions. They validated previously observed changes in Alzheimer’s disease and identified dozens of cell types with changes shared across multiple dementias as well as cell types with disease-specific changes.

“Different conditions have different patterns of degeneration,” Geschwind said. “We reasoned that comparison across cases from different disorders would be useful to identify shared components of neurodegeneration and understand cell type-specific changes that underlie all these conditions.” He noted that most studies profile only one brain region.

“In dementia and neurodegenerative disease more generally, specific brain regions and cells are most vulnerable in each disease. This is what leads to the different symptoms and signs across disorders,” Geschwind explained. “Since regional vulnerability is a core feature of the disorders, we reasoned that studying more than one region would give new insights.” The study design allowed investigators to find four genes marking vulnerable neurons across all three disorders.

Dr. Jessica Rexach, first author and assistant professor in neurology and neurobehavioral genetics at the Geffen School of Medicine, said this work “profoundly shifted” her perspective on disease susceptibility mechanisms.

“It is remarkable and humbling to have identified several distinct molecular differences that set apart cells from individuals with one form of dementia from those with closely related diseases,” Rexach stated. She noted that although these differences were among the minority observed in diseased brains, they were strongly linked to heritability.

Combined, Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy affect over 28 million people worldwide. Despite extensive research on Alzheimer’s disease, there is no cure; existing medications only slow progression. Few clinical trials exist for frontotemporal dementia or progressive supranuclear palsy.

“We have created an extensive data resource that paves the way for identifying new therapeutic candidates for neurodegenerative dementias,” Rexach said. She emphasized pinpointing specific molecules as potential novel regulators grounded in primary human disease data.

The researchers:

- Identified unique changes specific to Alzheimer’s disease.

- Found cellular resilience programs activated or failed differently when comparing cell types across disorders.

- Discovered unexpected changes in cells within the primary visual cortex.

- Identified tau-related gene expression changes correlating with brain cell degeneration patterns in progressive supranuclear palsy.

The authors plan further experiments to validate their findings' causal nature and anticipate inspiring similar cross-disorder research efforts.

“These data show that known risk genes act in specific neuronal and glial states or cell types differing across related disorders," concludes the Cell article. "This underscores examining multiple brain regions to understand causal pathways at a cellular level.”

Read more on the UCLA Health website.