Years before tau tangles show up in brain scans of patients with Alzheimer's disease, a biomarker test developed at the University of Pittsburgh School of Medicine can detect small amounts of the clumping-prone tau protein and its misfolded pathological forms that litter the brain, cerebrospinal fluid and potentially blood, new research published today in Nature Medicine suggests.
The cerebrospinal fluid biomarker test correlates with the severity of cognitive decline, independent of other factors, including brain amyloid deposition, thereby opening doors for early-stage disease diagnosis and intervention.
Since amyloid-beta pathology often precedes tau abnormalities in Alzheimer's disease, most biomarker efforts have focused on early detection of amyloid-beta changes. However, the clumping of tau protein into well-ordered structures referred to by pathologists as "neurofibrillary tangles" is a more defining event for Alzheimer's disease as it is more strongly associated with the cognitive changes seen in affected people.
"Our test identifies very early stages of tau tangle formation – up to a decade before any tau clumps can show up on a brain scan," said senior author Thomas Karikari, Ph.D., assistant professor of psychiatry at Pitt. "Early detection is key to more successful therapies for Alzheimer's disease since trials show that patients with little-to-no quantifiable insoluble tau tangles are more likely to benefit from new treatments than those with a significant degree of tau brain deposits."
Since many elderly people who have amyloid-beta plaques in their brains will never go on to develop cognitive symptoms of Alzheimer's disease during their lifetime, the widely adopted diagnostics framework developed by the Alzheimer's Association specifies the three neuropathological pillars necessary to diagnose the disease – combined presence of tau and amyloid-beta pathology and neurodegeneration. In a quest for early and accessible biomarkers for Alzheimer's disease, Karikari's earlier work showed that a brain-specific form of tau, called BD-tau, can be measured in blood and reliably indicate the presence of Alzheimer's disease-specific neurodegeneration. Several years prior, Karikari showed that specific forms of phosphorylated tau, p-tau181 , p-tau217 and p-tau212 , in the blood can predict the presence of brain amyloid-beta without the need for costly and time-consuming brain imaging.
But these tools largely detect amyloid pathology, so the issue of early detection of tau still looms large. While tau-PET remains a reliable and accurate predictor of tau burden in the brain, the test's utility is limited by availability, low resolution, high cost, labor and sensitivity. At present, tau-PET scans can pick up the signal from neurofibrillary tangles only when a large number are present in the brain, at which point the degree of brain pathology has become pronounced and is not easily reversible.
In this latest research, using the tools of biochemistry and molecular biology, Karikari and team identified a core region of the tau protein that is necessary for neurofibrillary tangle formation. Detecting sites within that core region of 111 amino acids, a sequence they call tau258-368, can identify clumping-prone tau proteins and help initiate further diagnostics and early treatment. In particular, the two new phosphorylation sites, p-tau-262 and p-tau-356, can accurately inform the status of early-stage tau aggregation that, with an appropriate intervention, could potentially be reversed.
"Amyloid-beta is a kindling, and tau is a matchstick. A large percentage of people who have brain amyloid-beta deposits will never develop dementia. But once the tau tangles light up on a brain scan, it may be too late to put out the fire and their cognitive health can quickly deteriorate," said Karikari. "Early detection of tangle-prone tau could identify the individuals who are likely to develop Alzheimer's-associated cognitive decline and could be helped with new generation therapies."
Other authors of this research are Eric Abrahamson, Ph.D., Xuemei Zeng, Ph.D., Anuradha Sehrawat, Ph.D., Yijun Chen, M.S., Tharick Pascoal, M.D., Ph.D., and Milos Ikonomovic, M.D., all of Pitt; Tohidul Islam, Ph.D., Przemysław Kac, M.S., Hlin Kvartsberg, Ph.D., Maria Olsson, B.S., Emma Sjons, B.S., Fernando Gonzalez-Ortiz, M.D., M.S., Henrik Zetterberg, M.D., Ph.D., and Kaj Blennow, M.D., Ph.D., all of University of Gothenburg, Sweden; Emily Hill, Ph.D., Ivana Del Popolo, M.S., Abbie Richardson, M.S., Victoria Mitchell, M.S., and Mark Wall, Ph.D., all of the University of Warwick, UK; Stijn Servaes, Ph.D., Joseph Therriault, Ph.D., Cécile Tissot, Ph.D., Nesrine Rahmouni, M.S., and Pedro Rosa-Neto, M.D., Ph.D., all of McGill University, Canada; Denis Smirnov, Ph.D., and Douglas Galasko, M.D., both of University of California, San Diego; Tammaryn Lashley, Ph.D., of University College London, UK.
This study was supported by, among others, the National Institute on Aging (grants R01AG083874, U24AG082930, P30AG066468, RF1AG052525-01A1, R01AG053952, R37AG023651, RF1AG025516, R01AG073267, R01AG075336, R01AG072641, P01AG14449, and P01AG025204, among others), the Swedish Research Council (grant 2021-03244), the Alzheimer's Association (grant AARF-21-850325), the Swedish Alzheimer Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Emil and Wera Cornells Foundation and a professorial endowment fund from the Department of Psychiatry, University of Pittsburgh.
