Jijing Wang, PhD, and Hyun-Sik Yang, MD, of the Department of Neurology at Mass General Brigham, are the lead and senior authors of a paper published in Molecular Neurodegeneration, " Plasma TDP-43 is a potential biomarker for advanced limbic-predominant age-related TDP-43 encephalopathy neuropathologic change ."
Q: How would you summarize your study for a lay audience?
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently recognized cause of dementia that often occurs alongside Alzheimer's disease. While a person can be diagnosed with LATE after death, there are currently no reliable tests to make this diagnosis while a person is still alive.
Our study focused on whether a protein called TDP-43, which builds up in the brains of people with LATE, can also be detected in blood. We found that this was indeed the case, and that individuals with advanced LATE-related brain changes had much higher levels of TDP-43 in their blood, especially when Alzheimer's changes were also present.
Q: What knowledge gap does your study help to fill?
While Alzheimer's disease can now be diagnosed during life using blood or spinal fluid tests, LATE – another important cause of memory loss – can only be confirmed through a brain autopsy. We aimed to address this major gap in dementia research by investigating whether the TDP-43 protein could represent a viable biomarker to reveal the presence of LATE in living individuals.
Q: What methods or approach did you use?
We analyzed plasma samples from 50 participants in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), a well-established research cohort based at Rush University Medical Center in Chicago. The samples were collected several years before these older adults passed away and donated their brains to research. Using an ultra-sensitive test, we measured the amount of total and phosphorylated, or chemically-modified, TDP-43 in their blood samples, then compared these blood levels with the extent of disease observed in their brains at autopsy.
Q: What did you find?
We found that people with advanced LATE disease had significantly higher amounts of TDP-43 in their blood, particularly if they also had brain changes from Alzheimer's disease. We also discovered that both forms of TDP-43 that we measured in blood closely reflected how much of this protein had built up in the brain at autopsy. Importantly, these relationships stayed strong even after we accounted for other brain changes linked to Alzheimer's disease, including amyloid and tau proteins.
Q: What are the implications?
These findings are exciting since they suggest that a simple blood test could eventually help identify LATE during life, particularly in those who also have Alzheimer's disease. Identifying a reliable blood biomarker like this would make it possible to distinguish between different causes of dementia, and would represent an important step toward better diagnosis and treatment.
Q: What are the next steps?
While our findings are promising, larger and more diverse studies are needed to confirm these results and test whether blood TDP-43 can also detect LATE in people who don't have Alzheimer's disease. It will also be important to determine whether changes in blood TDP-43 levels can track disease progression over time. Our long-term vision is to incorporate TDP-43 into a blood-based toolkit to improve early detection, refine clinical trial design and advance our understanding of dementia beyond Alzheimer's disease.
Authorship: In addition to Wang and Yang, Mass General Brigham authors include Tracy L. Young-Pearse.
Paper cited: Wang, J., et al. "Plasma TDP-43 is a potential biomarker for advanced limbic-predominant age-related TDP-43 encephalopathy neuropathologic change." Molecular Neurodegeneration. DOI: 10.1186/s13024-025-00910-4.
Funding: This work was supported by grants from the National Institutes of Health (NIH), including (P30AG072975), (P30AG010161), (R01AG017917), (R01AG055909), (R01AG067482), and (R01AG080667).
Disclosures: Co-author Julie Schneider serves as a consultant to Lantheus. No other disclosures were reported.
