TMEM106B Variant Linked to TDP-43 Pathology in Alzheimer’s Disease
A Miller School study links a variant in TMEM106B to TDP-43 pathology, providing a potential clue to why cognitive decline differs among people with Alzheimer’s disease.
Key Takeaways
- A study of 2,604 individuals with neuropathologically confirmed Alzheimer’s disease identified a genetic association involving TMEM106B and TDP-43 pathology.
- TDP-43 pathology has been linked to faster cognitive decline, greater brain atrophy and poorer outcomes in Alzheimer’s disease.
- Researchers found that a TMEM106B variant was associated with increased odds of developing TDP-43 pathology, even after accounting for age, sex, disease severity and other factors.
- The findings may help explain why Alzheimer’s disease progresses differently among patients and could support future precision medicine research.
Researchers at the University of Miami Miller School of Medicine have identified a genetic variant that appears to increase the risk of a harmful brain pathology commonly found in Alzheimer’s disease. The discovery, published in Alzheimer’s & Dementia, may help explain why some patients experience more rapid cognitive decline than others and could eventually contribute to more personalized approaches to diagnosing and treating neurodegenerative disease.
The study, led by Leonard Petrucelli, Ph.D., founding director of the Miller School’s Neuroscience Institute, and Mercedes Prudencio, Ph.D., associate professor of neurology and biochemistry and molecular biology at the Miller School, focused on TMEM106B, a gene previously linked to several neurodegenerative disorders. Researchers found that a specific TMEM106B variant selectively increases the likelihood of developing TDP-43 pathology, a co-occurring brain abnormality associated with worse outcomes in Alzheimer’s disease.
Why This Research Matters
TDP-43 pathology is associated with faster cognitive decline, greater brain atrophy and poorer outcomes in Alzheimer’s disease. Researchers identified a genetic variant that specifically increases vulnerability to this harmful co-pathology.
The findings could support future precision medicine approaches that tailor treatments and clinical trials to an individual’s biological risk profile.
Looking Beyond Amyloid and Tau
Alzheimer’s disease is typically defined by the accumulation of amyloid plaques and tau tangles in the brain. Increasingly, scientists recognize that many patients also develop additional pathologies that influence disease progression. Among the most important are Lewy bodies, vascular lesions and aggregates of a protein called TDP-43.
TDP-43 pathology is present in a substantial proportion of Alzheimer’s patients and has been linked to increased hippocampal atrophy, lower cognitive performance and faster rates of decline. Previous research has even suggested that the absence of TDP-43 pathology may be one of the strongest predictors of cognitive resilience in older adults.
Despite growing recognition of its clinical significance, researchers have had limited understanding of why some individuals develop TDP-43 pathology while others do not. The new study sought to determine whether genetics might provide part of the answer.
Examining 2,600 Brains
To investigate, the research team analyzed postmortem brain tissue from 2,604 individuals with neuropathologically confirmed Alzheimer’s disease. Researchers evaluated the presence of Lewy body pathology, vascular lesions and TDP-43 pathology while performing detailed genetic analyses of TMEM106B and APOE, the best-known genetic risk factor for Alzheimer’s disease.
The study underscored the biological complexity of Alzheimer’s disease. TDP-43 pathology was found in 40% of cases, Lewy body pathology in 69%, and vascular lesions in 51%. Among patients who underwent complete characterization, more than 90% exhibited at least one pathology beyond the classic hallmarks of Alzheimer’s disease.
A Gene With a Specific Target
The researchers discovered that a TMEM106B variant known as rs3173615 was significantly more common in Alzheimer’s patients who had TDP-43 pathology. Carriers of the variant had increased odds of developing TDP-43 pathology even after accounting for age, sex, disease severity, APOE status and the presence of other co-pathologies.
Notably, TMEM106B did not increase the likelihood of developing Lewy body pathology or vascular lesions. This finding suggests the gene acts through a specific biological pathway rather than broadly increasing vulnerability to all forms of brain pathology.
The results stood in contrast to APOE ε4, which was associated with elevated risk for multiple co-pathologies, including TDP-43, Lewy body and vascular pathology. According to the researchers, APOE appears to create a more broadly permissive environment for disease processes, while TMEM106B exerts a much more selective influence.
A Link to a More Widespread Form of TDP-43 Pathology
The study also examined different forms of TDP-43 pathology. Researchers found that TMEM106B was strongly associated with TDP-43 subtype α, a form characterized by more widespread distribution of abnormal protein inclusions throughout the brain.
Patients carrying two copies of the risk variant were particularly likely to develop this subtype. The researchers observed similar results when examining a closely linked genetic element known as AluYb8, further strengthening evidence that the TMEM106B region plays a significant role in shaping TDP-43 pathology.
These findings suggest that TMEM106B may influence not only whether TDP-43 pathology develops but also how it spreads through the brain.
Frequently Asked Questions
What is TDP-43?
TDP-43 is a protein that can accumulate abnormally in nerve cells. In Alzheimer’s disease, its presence has been associated with greater cognitive impairment and faster decline.
What did researchers discover?
Researchers found that a variant in TMEM106B was associated with an increased likelihood of TDP-43 pathology in Alzheimer’s disease.
Does TMEM106B affect all Alzheimer’s-related pathologies?
No. The study found an association with TDP-43 pathology but not with Lewy body pathology or vascular lesions.
What Is Happening Inside Brain Cells?
Although the exact mechanism remains under investigation, the findings point toward disruptions in lysosomal pathways, the cellular systems responsible for processing and clearing proteins. Previous studies have shown that TMEM106B variants can promote the formation of TMEM106B fibrils and alter protein-clearance mechanisms. Researchers believe these changes may create conditions that facilitate TDP-43 aggregation.
The study also suggests that TMEM106B and TDP-43 may interact through overlapping pathways involved in protein homeostasis and cellular waste disposal. Understanding those interactions could reveal new therapeutic targets for Alzheimer’s disease and related neurodegenerative disorders.
Implications for Future Alzheimer’s Care
The findings do not immediately change patient care, but they contribute to a growing understanding that Alzheimer’s disease is biologically diverse. Rather than a single disorder defined solely by amyloid and tau, Alzheimer’s increasingly appears to be a collection of overlapping disease processes influenced by distinct genetic factors.
By identifying TMEM106B as a selective modifier of TDP-43 pathology, the study offers a potential path toward improved risk prediction, more targeted clinical trials and future therapies designed to address specific disease mechanisms.
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Tags: Aging Research, Alzheimer's disease, biochemistry and molecular biology, cognitive decline, Department of Biochemistry and Molecular Biology, Dr. Leonard Petrucelli, Dr. Mercedes Prudencio, Frontotemporal dementia, memory disorders, Neuroscience Institute