Research Driving Breakthroughs in Neurodegeneration and Brain Health
University Hospitals is advancing innovative research to better understand and address neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), prion diseases and related neurological disorders.
Across the Department of Pathology, UH researchers investigate the molecular, immune, genetic, and cellular mechanisms that drive neurodegeneration. Using advanced experimental models, patient‑derived tissues and cutting‑edge technologies, our teams seek to uncover why neurons malfunction and degenerate. We then translate these discoveries into new diagnostics, biomarkers, and targeted therapeutic strategies to improve brain health, patient care and quality of life.
Prion Biology, Surveillance and Neurodegenerative Disease Mechanisms
UH research includes a strong focus on prion diseases, a unique class of fatal neurodegenerative disorders caused by misfolded proteins. This work advances understanding of how abnormal protein conformations spread in the brain, drive neurodegeneration and threaten public health. Insights gained from prion research also inform broader principles of protein misfolding, neurotoxicity and disease propagation that are shared across many neurodegenerative conditions.
National Prion Disease Pathology Surveillance Center
The National Prion Disease Pathology Surveillance Center at University Hospitals and Case Western Reserve University is the only U.S. center dedicated to monitoring and diagnosing human prion diseases. Led by Center Director, Brian Appleby, MD, the Center serves as the national reference laboratory for prion disease, provides free MRI consultation, and maintains a tissue repository to support research and public health surveillance. By integrating neuropathology, advanced imaging, molecular analysis and tissue repositories, UH researchers contribute to disease monitoring, accurate diagnosis and long-term surveillance efforts.
Biomarker Discovery for Alzheimer’s Disease and Related Dementias
UH research is focused on developing innovative, minimally invasive biomarkers to improve the diagnosis and monitoring of Alzheimer’s disease and related dementias. One area of emphasis is the detection of disease‑associated misfolded proteins, such as tau, outside of the brain.
By applying highly sensitive protein amplification technologies to accessible tissues, UH researchers aim to identify biomarkers that enable earlier diagnosis, distinguish Alzheimer’s disease from related neurodegenerative disorders and track disease progression or therapeutic response. This research supports the long‑term goal of diagnosing neurodegenerative diseases during pre‑symptomatic or early stages, when interventions may be most effective.
Oxidative Stress and Neuroprotective Pathways in Alzheimer’s Disease
UH research is examining how age‑related declines in cellular stress response pathways contribute to neurodegeneration in Alzheimer’s disease. A major focus is understanding how impaired activation of protective transcriptional pathways increases oxidative damage, promotes tau pathology, drives neuroinflammation and accelerates cognitive decline.
Researchers study how regulatory proteins influence these stress response systems and determine whether neurons remain resilient or become vulnerable during disease progression. By defining the molecular tipping points that govern neuronal survival, UH research aims to identify therapeutic targets that restore protective signaling and slow or prevent neurodegeneration.
Targeting Protein Misfolding and Aggregation in TDP‑43–Related Neurodegenerative Diseases
UH researchers are advancing research on TDP‑43 proteinopathies, which play a central role in ALS, frontotemporal lobar degeneration and a large subset of Alzheimer’s disease cases. Abnormal localization and aggregation of TDP‑43 disrupt RNA processing, trigger cellular stress and impair neuronal function.
This research area focuses on understanding how cellular protein‑quality control systems regulate TDP‑43 stability, clearance and toxicity. By defining pathways that promote or prevent pathological protein accumulation, UH research aims to identify new therapeutic targets that reduce neurodegeneration and preserve neuronal health across multiple diseases.
Mitochondrial Dysfunction and Genetic Drivers of Neurodegeneration
UH research investigates how mutations in genes essential for mitochondrial function contribute to neurodegenerative disease. Disruption of mitochondrial health impairs cellular energy production, protein clearance and neuronal resilience, accelerating disease progression in disorders such as FTD and ALS.
By studying disease‑associated genetic mutations in experimental models and human tissues, UH researchers seek to identify the specific mitochondrial defects that lead to neuronal injury and determine whether restoring mitochondrial function can prevent or reverse neurodegeneration. This work supports the development of therapies that target cellular energy and quality‑control pathways.
Immune and Gut–Brain Interactions in Neurodegenerative Disease
UH researchers are exploring how immune system dysfunction and gut microbiome signals contribute to neuroinflammation and neurodegeneration. Growing evidence suggests that immune cells, particularly T cells, and microbial‑derived signals influence disease risk and progression in disorders such as FTD, ALS and Alzheimer’s disease.
Research in this area focuses on how genetic risk factors alter immune balance, how gut‑immune interactions shape inflammatory responses, and why some individuals with disease‑associated mutations remain protected while others develop neurodegeneration. By identifying immune biomarkers and modifiable pathways, UH research aims to inform preventive and therapeutic strategies that target immune and microbiome‑driven mechanisms of brain disease.