Work could lead to the discovery of new therapeutic targets.
For the first time, researchers have identified “molecular markers” linked to degeneration—detectable changes in cells and their gene-regulating networks—that are common across several types of dementia affecting different brain regions. Significantly, the UCLA-led study, published in the journal Cell, also discovered markers unique to specific forms of dementia. These combined findings could represent a major shift in the search for causes, treatments, and cures for these conditions.
“This work provides new insight into the mechanisms of neurodegeneration and identifies new candidate pathways for the development of therapeutics,” said senior and corresponding author 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.
Research Approach: Going Beyond Traditional Case-Control Studies
Previous studies have focused on a single disorder at a time. Called case-control studies, they compared “diseased” cells with normal ones and often just focused on one brain region. But in this research, the scientists also looked at molecular changes across three different forms of dementia that can involve “tau pathology,” the accumulation of abnormal tau protein in vulnerable regions that differ across disorders.
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 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.
The Role of Brain Regions and Cells in Neurodegeneration
“Different conditions have different patterns of degeneration. 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,” Geschwind said, adding that most studies profile only one brain region – typically the frontal lobe.
“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 said. “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.” Using this 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.
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.”
Combined, Alzheimer’s, FTD, and PSP affect more than 28 million people worldwide. Although Alzheimer’s has been studied extensively, there is no cure, and existing, approved medications only slow disease progression. There are few clinical trials available for FTD and PSP.
New Avenues for Therapeutic Development
“We have created an extensive data resource that paves the way for identifying and exploring new therapeutic candidates for neurodegenerative dementias,” Rexach said. “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 researchers:
- Identified unique changes specific to Alzheimer’s disease and demonstrated that several findings in Alzheimer’s were also observed across the other disorders, 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 across disorders.
- Were 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.
- 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.
The authors, who will next begin experiments to validate the causal nature of their findings, 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 Cell article concludes. “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.”
Reference: “Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics” by Jessica E. Rexach, Yuyan Cheng, Lawrence Chen, Damon Polioudakis, Li-Chun Lin, Vivianne Mitri, Andrew Elkins, Xia Han, Mai Yamakawa, Anna Yin, Daniela Calini, Riki Kawaguchi, Jing Ou, Jerry Huang, Christopher Williams, John Robinson, Stephanie E. Gaus, Salvatore Spina, Edward B. Lee, Lea T. Grinberg, Harry Vinters, John Q. Trojanowski, William W. Seeley, Dheeraj Malhotra and Daniel H. Geschwind, 11 September 2024, Cell.
DOI: 10.1016/j.cell.2024.08.019
Funding for this work was provided by 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 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 is supported by NIH grant P01AG066597, P30AG072979 and U19AG062418.
Disclosures: Geschwind has received research funding from Hoffman-LaRoche for this project.
(D.H.G. has received research funding from Hoffman-LaRoche for this project. D.C. is a full-time employee of F. Hoffmann-La Roche, Basel, Switzerland. During the study period, D.M. was a full-time employee of F. Hoffmann-La Roche, Basel, Switzerland, and is currently a full-time employee of Biogen, Cambridge, MA, USA.)
News
First U.S. H5N1 Death Sparks Urgency: Scientists Warn Bird Flu Is Mutating Faster Than Expected
A human strain of H5N1 bird flu isolated in Texas shows mutations enabling better replication in human cells and causing more severe disease in mice compared to a bovine strain. While the virus isn’t [...]
AI Breakthrough in Nanotechnology Shatters Limits of Precision
At TU Graz, a pioneering research group is leveraging artificial intelligence to drastically enhance the way nanostructures are constructed. They aim to develop a self-learning AI system that can autonomously position molecules with unprecedented precision, potentially [...]
How Missing Sleep Lets Bad Memories Haunt Your Mind
Research reveals that a lack of sleep can hinder the brain’s ability to suppress unwanted memories and intrusive thoughts, emphasizing the importance of restful sleep for mental health. Sleep deprivation has been found to [...]
WHO issues new warning over ‘mystery virus’ and calls for return of COVID restrictions
The World Health Organization (WHO) has called for the reinstatement of restrictions implemented during the COVID-19 pandemic as cases of human metapneumovirus (HMPV) continue to surge. While hospitals in China are overwhelmed with positive [...]
A Breath Away From a Cure: How Xenon Gas Could Transform Alzheimer’s Treatment
A breakthrough study highlights Xenon gas as a potential game-changer in treating Alzheimer’s disease, demonstrating its ability to mitigate brain damage and improve cognitive functions in mouse models. A forthcoming clinical trial aims to test its [...]
False Memories Under Fire: Surprising Science Behind What We Really Recall
New research challenges the ease of implanting false memories, highlighting flaws in the influential “Lost in the Mall” study. By reexamining the data from a previous study, researchers found that many supposed false memories [...]
Born Different? Cambridge Scientists Uncover Innate Sex Differences in Brains
Cambridge researchers found that sex differences in brain structure exist from birth, with males having more white matter and females more grey matter, highlighting early neurodiversity. Research from the Autism Research Centre at the University [...]
New study shows risk factors for dementia – virus causes deposits in the brain
Research into the causes of Alzheimer's is not yet complete. Now a new study shows that head trauma can activate herpes viruses and promote the disease. Frankfurt am Main – As a neurodegenerative disease, [...]
Are Machines Truly Thinking? Modern AI Systems Have Finally Achieved Turing’s Vision
Modern AI systems have fulfilled Turing’s vision of machines that learn and converse like humans, but challenges remain. A new paper highlights concerns about energy consumption and societal inequality while calling for more robust [...]
The Surprising Link Between Smell, Sound, and Emotions
New research reveals how smell and hearing interact in the brain to drive social behavior, using mouse maternal instincts as a model. Imagine you’re at a dinner party, but you can’t smell the food [...]
Brain cells age at different rates
As our body ages, not only joints, bones and muscles wear out, but also our nervous system. Nerve cells die, are no longer fully replaced, and the brain shrinks. "Aging is the most important risk factor [...]
Long COVID Breakthrough: Spike Proteins Persist in Brain for Years
Researchers have discovered that the SARS-CoV-2 spike protein persists in the brain and skull bone marrow for years after infection, potentially leading to chronic inflammation and neurodegenerative diseases. Researchers from Helmholtz Munich and Ludwig-Maximilians-Universität (LMU) have [...]
Water-Resistant Paper Could Revolutionize Packaging and Replace Plastic
A groundbreaking study showcases the creation of sustainable hydrophobic paper, enhanced by cellulose nanofibres and peptides, presenting a biodegradable alternative to petroleum-based materials, with potential uses in packaging and biomedical devices. Researchers aimed to [...]
NIH Scientists Discover Game-Changing Antibodies Against Malaria
Novel antibodies have the potential to pave the way for the next generation of malaria interventions. Researchers at the National Institutes of Health (NIH) have identified a novel class of antibodies that target a previously unexplored region [...]
Surprising Discovery: What If Some Cancer Genes Are Actually Protecting You?
A surprising discovery reveals that a gene previously thought to accelerate esophageal cancer actually helps protect against it initially. This pivotal study could lead to better prediction and prevention strategies tailored to individual genetic [...]
The Cancer Test That Exposes What Conventional Scans Miss
Researchers at UCLA have unveiled startling findings using PSMA-PET imaging that reveal nearly half of patients diagnosed with high-risk prostate cancer might actually have metastases missed by traditional imaging methods. This revelation could profoundly affect future [...]