Ultrasensitive Test Detects TDP-43 Biomarkers for Frontotemporal Lobar Degeneration

An ultrasensitive test developed by Mass General Brigham investigators detects abnormal clumps of TDP-43 protein in cerebrospinal fluid, enabling diagnosis of the frontotemporal lobar degeneration subtype FTLD-TDP, a pathology for which no biomarkers previously existed. The test, described in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, could improve diagnostic accuracy, research, and drug development. Dementia affects over 57 million people worldwide, a number expected to nearly double in the next 20 years.

The digital seed amplification assay (dSAA) separates a patient's cerebrospinal fluid into tiny, nano-liter-sized compartments and digitally counts the number of TDP-43 protein seeds they contain under a microscope. In an analysis of 30 CSF samples from individuals with FTLD-TDP and 10 from healthy controls, those with FTLD-TDP had higher concentrations of TDP-43 seeds, and seed levels correlated with disease severity — the more severe the patient's symptoms, the more seeds the test detected. Current diagnostic tools for FTLD, such as imaging tests, can determine if the brain is degenerating but do not differentiate the molecular pathology. The study is limited by its small number of participants, lack of autopsy-confirmed diagnoses, and lack of comparison to groups with other types of dementia; larger studies incorporating diverse neurodegenerative pathologies and long-term follow-up are needed to validate the test's specificity.

Separate research suggests at-home testing could identify dementia risk remotely. A study published in Nature Communications examined data from 174 participants in the UK-based PROTECT study who were given at-home finger prick blood tests detecting p-tau217 and glial fibrillary acidic protein (GFAP). Capillary p-tau217 was significantly higher in people with dementia than in those without and was significantly associated with cognitive performance and function. While both p-tau217 and GFAP identified individuals with cognitive impairment, p-tau217 showed a stronger link to Alzheimer's disease risk, and the presence of both proteins allowed participants to be categorized as low, medium, or high risk. The authors said the work raises the potential for a remote triage method for identifying individuals likely to be biomarker positive for Alzheimer's disease, noting that currently only one in 1,000 people with early cognitive impairment receives a specialist evaluation.

Clinical uptake of blood-based biomarkers remains limited. Less than 1 in 4 primary care clinicians report using newer blood-based Alzheimer's disease tests, according to research presented at the American Geriatrics Society 2026 Annual Scientific Meeting. An analysis of 1,992 community clinicians found that 16.7% of primary care clinicians sometimes or routinely ordered plasma biomarker tests for suspected cognitive impairment, far lower than neuropsychological testing (71.1%) or CT imaging (77.4%) and similar to PET scans (18.4%). Among primary care clinicians, 21.7% reported low confidence in diagnosing dementia in adults aged 65 or older, and 41.2% reported low confidence in diagnosing Alzheimer's disease. Lower confidence was associated with increased referrals to neurologists, while higher confidence was somewhat more likely to lead to biomarker test use (r = 0.20-0.24, P < .001). Most clinicians (72%) rated plasma biomarkers a low priority for ongoing care, and 18% were unsure; researchers say the tests are not yet ready for population-based screening because of a lack of effective treatment at early disease stages. The FDA approved the first blood test to detect plasma biomarkers for Alzheimer's disease in 2025.

At the Alzheimer's Association International Conference 2026, University of Miami Miller School of Medicine researchers presented 16 studies, including encouraging results for neflamapimod, an oral kinase inhibitor under investigation as a treatment for dementia with Lewy bodies (DLB), the second most common neurodegenerative dementia after Alzheimer's disease. Participants who achieved therapeutic drug concentrations experienced a slower rate of clinical worsening and reduced markers of neurodegeneration, providing evidence that neflamapimod may have disease-modifying potential in DLB patients without concurrent Alzheimer's pathology. The center also presented MethylCog, a DNA methylation-based index that estimates general cognitive ability from a blood sample and may offer a scalable method for identifying individuals at risk for cognitive decline when traditional testing is not readily available.

Experts emphasize the need for standardization before blood biomarkers are widely used in clinical care. "For blood biomarkers to be implemented in clinical care across Europe, we need to establish harmonized and standardized methods, such as test cutoffs, that effectively work across different clinical settings," said a professor of molecular medicine at the University of Gothenburg at the MindShift event in Rome. He said there is no single application model for blood biomarkers in clinical care, that use cases need to be defined at both primary and secondary care levels, and that "we shouldn't rush until science has provided all the evidence we need to actually define the right use case."