Researchers have for the first time identified degeneration-associated “molecular markers” —observable changes in cells and their gene-regulating networks—that are shared by several forms of dementia that affect different regions of the brain. The UCLA-led researchers carried out single-cell analysis of post mortem brain tissue, using techniques including single-nucleus sequencing of mRNA (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin (snATAC-seq), which in addition identified markers specific to different forms of dementia. 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 development of therapeutics,” said Daniel Geschwind, MD, PhD, a 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. Geschwind is senior and corresponding author of the researchers’ published paper in Cell, titled “Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics.” In their paper the team concluded “These data illustrate the heterogeneous spectrum of glial and neuronal composition and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.”
“Alzheimer’s disease (AD), the behavioral variant of frontotemporal dementia (bvFTD), and progressive supranuclear palsy (PSP) are syndromes that involve different forms of tau pathology,” the authors wrote. These three disorders collectively affect more than 28 million people worldwide. But as the authors continued, “Disease-altering therapeutic options are lacking, and there are few ongoing clinical trials in PSP and FTD.”
Previous studies have focused on a single disorder at a time, and case-control studies comparing “diseased” cells with normal cells often just focused on one brain region. The researchers further commented, “The genetic architectures of AD, PSP, and bvFTD are distinct, highlighting differential contributions of neurons and glia to disease risk.
And while single cell sequencing technologies have identified “candidate markers of selective vulnerability in AD,” the team continued, “Despite these advances, few studies have yet to formally compare across dementias, and much remains unknown, including the specificity of changes observed in AD compared with other disorders, their role in selective neuronal vulnerability, or glial diversity.”
For their newly reported study the researchers looked at molecular changes across the three different forms of dementia that can involve tau pathology, which is the accumulation of abnormal tau protein in vulnerable regions that differ across disorders. “All three disorders can involve tau pathology that begins in vulnerable regions that differ across disorders,” they stated. They analyzed cells from three brain cortical brain regions with different vulnerabilities to disease.
The researchers carried out single-cell genomic analysis on more than one million cells to identify distinct and shared molecular markers in the three related conditions, Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy. “Different conditions have different patterns of degeneration,” Geschwind said. “We reasoned that comparison across cases from 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 that underlie all these conditions.”
In addition to validating changes previously observed in AD, the study identified dozens of cell types whose changes are shared across multiple dementias, and several cell types whose changes in disease were specific to a single disorder, many of which had not been previously identified. “We identify 32 shared, disease-associated cell types and 14 that are disease specific,” they wrote. “We demonstrated that several findings in AD are observed across disorders, identifying targets for therapeutic development.”
“In dementia and neurodegenerative disease more generally, specific brain regions and cells are most vulnerable in each disease,” Geschwind noted. “This is what leads to the different symptoms and signs across disorders. Since regional vulnerability is a core feature of the disorders, we reasoned that studying more than one region would give new insights, and that was the case. In addition to identifying shared and distinct molecular markers, we showed how genetic risk relates to these disease-specific pathways that are altered in the brain.”
Among their results, the team found that “cellular resilience programs”—molecular mechanisms that support cells in response to injury—activated or failed differently, when comparing the same cell types across disorders. They were separately surprised to discover 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 which was thought to be unaffected by dementia. In PSP, this discovery revealed previously unknown changes in brain cells called astrocytes. The team in addition identified specific changes in the expression of certain tau-related genes and others in PSP. These appear to correlate with the unique pattern of brain cell degeneration that is observed in PSP.
Using their study design the investigators found four genes that marked vulnerable neurons across all three disorders, highlighting pathways that could be used to develop new therapeutic approaches. In their paper they stated, “Our design enables identification of new markers of neuronal vulnerability, varying glial states across disease, and disorder-specific cellular differences in the expression and regulation of known-risk genes.”
First author Jessica Rexach, MD, PhD, an assistant professor in neurology and neurobehavioral genetics at the David Geffen School of Medicine at UCLA, said this work “profoundly shifted” her perspective on the mechanisms underlying disease susceptibility. “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. Although these disease-specific differences were among the minority of the changes observed in diseased brains, they were strongly linked to heritability. This surprising finding opens new avenues for understanding why and how certain genes influence the risk of developing one brain disease over another closely related condition.”
Rexach further commented that the team had created an extensive data resource that “paves the way for identifying and exploring new therapeutic candidates for neurodegenerative dementias … We have pinpointed specific molecules that can now be advanced as potential novel regulators of disease in experimental systems—importantly, grounded in primary human disease data. Additionally, we’ve uncovered unexpected conceptual phenomena that may explain why certain cells exhibit more resilience or vulnerability to disease, and we’re eager to investigate these findings further.”
The authors aim to continue their work to validate the causal nature of their findings, and anticipate the study will inspire similar cross-disorder research. “These data show that known risk genes act in specific neuronal and glial states or cell types that differ across related disorders. Moreover, causally associated disease states may be limited to specific cell types and regions,” the authors concluded in their paper. “This underscores the importance of examining multiple brain regions to understand causal disease pathways at the cellular level, which we show provides a clearer picture of shared and disease-specific aspects of resilience and vulnerability to inform the therapeutic roadmap.”
