Researchers have, for the first time, discovered “molecular markers” linked to degeneration—observable changes in cells and their gene-regulating networks—common to different types of dementia that impact various brain regions. Furthermore, the UCLA-led study, featured in the journal Cell, also found markers unique to specific dementia types, potentially changing how we approach the search for causes, treatments, and cures.
For the first time, researchers have pinpointed degeneration-associated “molecular markers”—notable alterations in cells and their gene-regulating systems—that are common across various forms of dementia affecting different areas of the brain. Significantly, the research led by UCLA, published in Cell, also discovered unique markers for distinct dementia types. These findings could signify a significant shift in understanding the origins, treatments, and potential cures for these conditions.
Senior author Daniel Geschwind, MD, PhD, who is a professor of human genetics, neurology, and psychiatry at UCLA’s David Geffen School of Medicine and director of the Institute for Precision Health, stated, “This research sheds light on the mechanisms behind neurodegeneration and suggests new pathways for therapeutic development.”
Most previous research has concentrated on isolated disorders at a time, often employing case-control studies to compare “diseased” cells against healthy ones, usually focusing on one brain region. In contrast, this study examined molecular alterations across three dementia types associated with “tau pathology,” referring to the buildup of abnormal tau proteins in brain regions that vary across disorders.
Using single-cell genomic analysis on over one million cells, the team identified unique and shared molecular markers among three interconnected conditions: Alzheimer’s disease, frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). Alongside confirming previously noted changes in Alzheimer’s, they discovered numerous cell types showing changes that are common across multiple dementias, as well as some specific to single disorders—many of which were previously unidentified.
Geschwind explained, “Different diseases exhibit various degeneration patterns. We hypothesized that examining cases from different disorders, in addition to the traditional case-control comparisons, would help us pinpoint shared neurodegenerative components while clarifying cell type-specific changes common to these conditions.” He noted that many studies typically only analyze one brain region, often the frontal lobe.
“In dementia and other neurodegenerative diseases, particular brain regions and cells display varying vulnerability in each disease. This leads to different symptoms and signs across conditions,” added Geschwind. “Given that regional vulnerability is a fundamental characteristic of these disorders, we believed studying multiple areas would yield new insights, which proved true. We not only identified shared and distinct molecular markers but also illustrated how genetic risks relate to these disease-specific pathways affected in the brain.” Through their approach, researchers found four genes linked to vulnerable neurons in all three disorders, indicating pathways that could guide new therapeutic strategies.
Jessica Rexach, MD, PhD, the first author and assistant professor at UCLA in neurology and neurobehavioral genetics, expressed, “This work has profoundly changed my understanding of the mechanisms related to disease susceptibility.”
Rexach added, “It is both astonishing and humbling to identify several distinct molecular disparities distinguishing cells from individuals with one dementia type from those with related diseases. While these disease-specific differences were among the few changes noted in diseased brains, they correlated strongly with heritability. This unexpected finding opens new avenues for exploring how certain genes affect the risk of developing one brain disease over another similar condition.”
Alzheimer’s, FTD, and PSP collectively impact over 28 million people worldwide. Despite extensive research on Alzheimer’s, no cure exists, and currently approved medications only slow the disease’s progression. There are limited clinical trials for FTD and PSP.
“We have established a comprehensive data resource that sets the stage for identifying and examining new therapeutic candidates for neurodegenerative dementias,” Rexach stated. “We have identified specific molecules that can now be advanced as potential novel regulators of the disease within experimental systems, grounded in data from primary human diseases. In addition, we’ve revealed unexpected conceptual phenomena that may elucidate why certain cells display more resilience or vulnerability to disease, prompting us to pursue further investigation of these findings.”
The researchers:
- Pinpointed unique alterations specific to Alzheimer’s disease and demonstrated that many findings in Alzheimer’s were also observed in the other disorders, thus identifying targets for therapeutic development.
- Discovered that “cellular resilience programs”—molecular processes aiding cells in responding to injury—functioned differently when comparing the same cell types across disorders.
- Were surprised to find that all three disorders showed alterations in brain cells from the primary visual cortex—the area responsible for processing visual information, which was previously thought to be unaffected by dementia. In PSP, this finding unveiled unknown changes in brain cells known as astrocytes.
- Noted specific changes in the expression of certain tau-related genes in addition to findings in PSP, which appeared related to the unique pattern of brain cell degeneration seen in PSP.
The authors plan to start experiments to confirm their findings and hope this study encourages similar cross-disorder research.
The article in Cell concludes, “These data indicate that known risk genes operate within specific neuronal and glial states or cell types that vary across related disorders. Moreover, causally associated disease states may be restricted to certain cell types and regions. This highlights the need for examining various brain areas to comprehend causal disease pathways at the cellular level, ultimately providing a clearer picture of shared and disease-specific aspects of resilience and vulnerability, thus informing future therapeutic strategies.” The complete list of authors can be found in the Cell article.
This research received funding from Roche Pharmaceuticals (D.H.G., D.M.), BrightFocus (D.H.G., J.E.R), Rainwater Charitable Foundation (D.H.G. and W.W.S), NIH grants (K08 NS105916 (J.E.R), R01 AG075802 (J.E.R., L.T.G), 5UG3NS104095 (D.H.G)), and the John Douglas French Alzheimer’s Foundation (J.E.R.). The UCSF Neurodegenerative Disease Brain Bank is supported by NIH grants AG023501 and AG019724, the Rainwater Charitable Foundation, and the Bluefield Project to Cure bvFTD. The University of Pennsylvania Center for Neurodegenerative Disease Research receives support from NIH grant P01AG066597, P30AG072979, and U19AG062418.
