Researchers from UCLA have identified molecular markers—changes in cells and their gene-regulating networks—that are shared across Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). Published in Cell, the study also discovered markers unique to each condition, offering new directions for understanding neurodegeneration and possible treatment targets.
Examining Multiple Dementias
Previous studies have typically focused on a single disorder and brain region. In this study, however, researchers looked at molecular changes in cells from several brain regions affected by different forms of dementia. Using single-cell genomic analysis, they profiled over 1 million cells from individuals with AD, FTD, and PSP, revealing shared molecular markers across the diseases, as well as distinct changes specific to each condition.
“This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for development of therapeutics,” stated senior author Daniel Geschwind, a professor at the David Geffen School of Medicine at UCLA.
This comparative approach allowed the team to identify dozens of cell types with changes common across multiple dementias, along with several that displayed disease-specific alterations. These findings could lead to the development of more targeted therapeutic strategies.
Single-Cell Genomics and Tau Pathology
The team used single-cell genomic analysis to uncover molecular changes in brain cells, focusing on how tau pathology—the accumulation of abnormal tau protein—differs across brain regions vulnerable to degeneration. Their analysis revealed four genes that marked vulnerable neurons in all three diseases, highlighting potential targets for future treatments.
Geschwind explained the approach: “Different conditions have different patterns of degeneration. We reasoned that comparison across 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.”
New Discoveries in Dementia Pathways
First author Jessica Rexach noted that the findings offer a fresh perspective on the mechanisms of 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.
One surprising discovery was that changes in cells from the primary visual cortex—a region thought to be unaffected by dementia—were present across the disorders. In PSP, this included previously unknown changes in astrocytes, cells that support neurons. The team also found alterations in tau-related genes, which appear to drive unique patterns of brain cell degeneration in PSP.
“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 conclude in the original publication. “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.”
Original Publication
Rexach JE, Cheng Y, Chen L, et al. Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics. Cell. 2024 doi:10.1016/j.cell.2024.08.019
Examining Multiple Dementias
Previous studies have typically focused on a single disorder and brain region. In this study, however, researchers looked at molecular changes in cells from several brain regions affected by different forms of dementia. Using single-cell genomic analysis, they profiled over 1 million cells from individuals with AD, FTD, and PSP, revealing shared molecular markers across the diseases, as well as distinct changes specific to each condition.
“This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for development of therapeutics,” stated senior author Daniel Geschwind, a professor at the David Geffen School of Medicine at UCLA.
This comparative approach allowed the team to identify dozens of cell types with changes common across multiple dementias, along with several that displayed disease-specific alterations. These findings could lead to the development of more targeted therapeutic strategies.
Single-Cell Genomics and Tau Pathology
The team used single-cell genomic analysis to uncover molecular changes in brain cells, focusing on how tau pathology—the accumulation of abnormal tau protein—differs across brain regions vulnerable to degeneration. Their analysis revealed four genes that marked vulnerable neurons in all three diseases, highlighting potential targets for future treatments.
Geschwind explained the approach: “Different conditions have different patterns of degeneration. We reasoned that comparison across 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.”
New Discoveries in Dementia Pathways
First author Jessica Rexach noted that the findings offer a fresh perspective on the mechanisms of 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.
One surprising discovery was that changes in cells from the primary visual cortex—a region thought to be unaffected by dementia—were present across the disorders. In PSP, this included previously unknown changes in astrocytes, cells that support neurons. The team also found alterations in tau-related genes, which appear to drive unique patterns of brain cell degeneration in PSP.
“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 conclude in the original publication. “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.”
Original Publication
Rexach JE, Cheng Y, Chen L, et al. Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics. Cell. 2024 doi:10.1016/j.cell.2024.08.019