Years before neurofibrillary tangles (NFTs) of tau protein show up in brain scans of patients with Alzheimer’s disease (AD), a biomarker test developed at the University of Pittsburgh School of Medicine may be able to detect small amounts of the clumping-prone tau protein and its misfolded pathological forms that litter the brain, cerebrospinal fluid (CSF) and potentially blood.
The researchers say that the new CSF biomarker test correlates with the severity of cognitive decline, independent of other factors, including brain amyloid deposition, and could enable early-stage disease diagnosis and intervention.
“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 Thomas Karikari, PhD, assistant professor of psychiatry at the University of Pittsburgh. “Early detection is key to more successful therapies for AD 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.”
Karikari is senior author of the team’s published paper in Nature Medicine, titled “Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease,” in which they state that their collective study results “inform about the status of early-stage tau aggregation, reveal aggregation-relevant phosphorylation epitopes in tau and offer a diagnostic biomarker and targeted therapeutic opportunities for AD.”
NFTs of tau protein are a defining neuropathological feature of AD, the authors explained. Since amyloid-beta (Aβ) pathology often precedes tau abnormalities in AD, most biomarker efforts have focused on early detection of Aβ changes.
However, the clumping of tau protein into the NFT structures is a more defining event for AD as it is more strongly associated with the cognitive changes seen in affected people. The severity of tau pathology, the authors noted, “… is a stronger correlate and predictor of cognitive outcomes than Aβ plaques, another neuropathological hallmark of AD.” Moreover, they noted, “Patients with AD with little or no quantifiable insoluble brain tau NFT pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs.”
Since many elderly people who have Aβ plaques in their brains will never go on to develop cognitive symptoms of AD 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 Aβ pathology and neurodegeneration. In a quest for early and accessible biomarkers for AD, Karikari’s earlier work showed that a brain-specific form of tau (brain-derived tau; BD-tau), can be measured in blood and reliably indicate the presence of AD-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 Aβ without the need for costly and time-consuming brain imaging.
But existing tools largely detect amyloid pathology, so the issue of early detection of tau still loomed large. “Aβ is a kindling, and tau is a matchstick,” noted Karikari. “A large percentage of people who have brain Aβ 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.” And 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.
The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs), the team further explained. “However, biochemical understanding and biomarkers of STAs are lacking.” At present, tau-PET scans can pick up the signal from NFT 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 in human brain tissue, using the tools of biochemistry and molecular biology, Karikari and team identified a core region of the tau protein that is necessary for NFT 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. “… we identified a minimal core STA peptide (~aa 258–368), revealing p-tau262 and p-tau356 aggregation-relevant phosphorylation sites,” the investigators wrote. The team used the findings from their research to develop a CSF biomarker of tau pre-NFT pathology, and verified its clinical performance.
“The STA core peptide addresses a critical need in drug development, that is, the discovery of druggable therapeutic target(s) for early-stage tau aggregates in AD,” they pointed out, suggesting that the STA core provides what they described as an accessible CSF biomarker that can detect small nonfibrillar tau species. “Future development of biofluid-based biomarker assays for these p-tau sites should enable identification of living individuals with this profile for mechanistic studies and inclusion in therapeutic trials for preventing tau pathology in AD.”
Added 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.”
In summary, the authors wrote, “… we identified a core peptide of STAs in AD brains, revealed aggregation-relevant phosphorylation sites and translated these findings to develop an accessible CSF biomarker of AD-type tau pathology that will pave the way for the quantification of early-stage soluble (prefibrillar) tau assemblies in CSF and the development of therapies against these soluble pathological entities that may not be detectable using tau-PET.”