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Neurofibrillary tangles are a defining neuropathological feature of Alzheimer’s disease. Patients with Alzheimer’s disease with little or no quantifiable insoluble brain tau neurofibrillary tangle pathology demonstrate stronger clinical benefits of therapies than those with advanced neurofibrillary tangles. The formation of neurofibrillary tangles can be prevented by targeting the intermediate soluble tau assemblies, which form in the initial stages of the tau aggregation. Effective identification of early-stage tau tangle formation may serve as early diagnostic biomarkers and targets for effective anti-tau therapeutics. 

Investigators including Thomas Karikari, PhD (Assistant Professor of Psychiatry), Tharick Pascoal, MD, PhD (Associate Professor of Psychiatry and Neurology), Milos Ikonomovic, MD (Professor of Neurology and Psychiatry), and Eric Abrahamson, PhD (Research Assistant Professor of Neurology), used an integrative biochemical approach to identify a defining core sequence of soluble tau assemblies in postmortem human brain tissue with Alzheimer’s disease.

In a paper recently published in Nature Medicine, the investigators demonstrated that tau oligomers and related prefibrillar assemblies in the soluble fractions of Alzheimer’s disease brains are biochemically different from those in other tauopathy brains. They further identified p-tau262 and p-tau356 aggregation-relevant phosphorylation sites, findings that have potential biomarker and therapeutic values. Finally, the scientists developed a cerebrospinal fluid biomarker of tau pre- neurofibrillary tangles pathology and verified its clinical performance in a cohort with paired antemortem cerebrospinal fluid samples and in an antemortem cohort with positron emission tomography (PET) imaging.

“The biomarkers identified in this study will enable earlier detection and monitoring of tau tangle pathology in Alzheimer’s disease, which is critically needed to complement the now-improved detection of amyloid plaque pathology using blood tests including those previously developed by our group,” said Dr. Karikari, senior and corresponding author of the study. He further added that discovery of the core region of pre-fibrillar soluble will allow for the development of targeted therapies against the part of the protein that defines its early-stage aggregation capabilities. 

Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease
Islam T, Hill E, Abrahamson EE, Servaes S, Smirnov DS, Zeng X, Sehrawat A, Chen Y, Kac PR, Kvartsberg H, Olsson M, Sjons E, Gonzalez-Ortiz F, Therriault J, Tissot C, Del Popolo I, Rahmouni N, Richardson A, Mitchell V, Zetterberg H, Pascoal TA, Lashley T, Wall MJ, Galasko D, Rosa-Neto P, Ikonomovic MD, Blennow K, Karikari TK.
Nature Medicine (2025). https://doi.org/10.1038/s41591-024-03400-0