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Research from the University of Pittsburgh School of Medicine introduces a promising biomarker test capable of detecting early signs of tau protein clumping—an indicator of Alzheimer’s disease—before these changes are visible on standard brain imaging techniques. Published in Nature Medicine, the study highlights the potential for improved early diagnosis and intervention strategies in managing Alzheimer’s disease.
This novel cerebrospinal fluid biomarker test relates directly to cognitive decline severity, effectively operating independently of other factors such as amyloid-beta presence in the brain. This advancement suggests a significant step towards diagnosing Alzheimer’s in its early stages, thereby facilitating timely therapeutic interventions.
Traditionally, much of the diagnostic focus has been placed on amyloid-beta pathology, which occurs before tau abnormalities in the course of Alzheimer’s disease. Nonetheless, tau clumping, forming structures called neurofibrillary tangles, is a pivotal event in the disease’s progression and has a stronger correlation with the cognitive deficits that patients experience.
According to Dr. Thomas Karikari, the lead author of the study and an assistant professor of psychiatry at Pitt, “Our test is capable of identifying tau tangle formations in their earliest stages—potentially up to ten years prior to their detection on brain scans.” This early identification is crucial, as clinical trials have indicated that patients with minimal or no quantifiable tau tangles are more likely to respond favorably to new therapies compared to those with significant tau accumulation.
Many older adults exhibit amyloid-beta plaques without exhibiting cognitive symptoms, posing challenges in reliable Alzheimer’s diagnosis. The Alzheimer’s Association recommends assessing the concurrent presence of tau and amyloid-beta pathology alongside neurodegeneration for diagnosing the disease. Dr. Karikari’s previous work has also indicated that a specific form of tau, known as BD-tau, can be detected in blood samples, providing a reliable indicator of Alzheimer’s-related neurodegeneration. He has previously demonstrated that certain phosphorylated tau forms, including p-tau181, p-tau217, and p-tau212, can predict brain amyloid-beta presence without the need for extensive brain imaging techniques.
Despite these advancements, a pressing need remains to accurately detect tau at earlier stages. While tau-PET imaging is a highly effective tool for gauging tau burden, its use is limited by factors such as availability, resolution, and cost. These scans can only identify neurofibrillary tangles when they have reached significant levels in the brain, making late-stage cognitive decline likely irreversible.
The current study employed biochemical and molecular biology techniques to identify a specific segment of the tau protein essential for forming neurofibrillary tangles. This segment, designated tau258-368, encompasses 111 amino acids crucial for recognizing tau proteins prone to clumping, thereby aiding in early diagnostic processes and treatment options. Notably, two identified phosphorylation sites—p-tau-262 and p-tau-356—serve as reliable indicators of early-stage tau aggregation that could, with timely intervention, be reversible.
Dr. Karikari likens the relationship between amyloid-beta and tau to a fire, stating, “Amyloid-beta acts as kindling, while tau is the matchstick. Although many individuals with amyloid-beta deposits may never develop dementia, once tau tangles become visible, it may signify that it’s too late to reverse cognitive decline.” Thus, early detection of tau-prone individuals may lead to strategic interventions with contemporary therapeutic approaches.
Additional contributors to this research include Eric Abrahamson, Ph.D., Xuemei Zeng, Ph.D., Anuradha Sehrawat, Ph.D., and more, hailing from institutions such as the University of Gothenburg, University of Warwick, McGill University, and others.
This research received funding from several prominent organizations, including the National Institute on Aging and the Swedish Research Council, among others.
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