Detecting tangle-prone tau can catch Alzheimer's early

Researchers at the University of Pittsburgh have developed a biomarker test for Alzheimer’s disease, with the ability to detect small amounts of the clumping-prone tau protein and its misfolded pathological forms that litter the brain, the cerebrospinal fluid and potentially the blood — years before any tau tangles would show up in brain scans. Described in the journal Nature Medicine, the test correlates with the severity of cognitive decline, 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. But 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; indeed, 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.

While tau-PET imaging remains a reliable and accurate predictor of tau burden in the brain, 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. Assistant Professor Thomas Karikari, who has previously found forms of tau in the blood that indicate the presence of neurodegeneration and brain amyloid-beta, has now identified a core region of the tau protein that is necessary for neurofibrillary tangle formation.

“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,” Karikari said. “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.”

Detecting sites within that core region of 111 amino acids, a sequence dubbed tau_258–368, can apparently identify clumping-prone tau proteins and help initiate further diagnostics and early treatment. In particular, the two new phosphorylation sites, p-tau₂₆₂ and p-tau₃₅₆, 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,” Karikari said. “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. 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.”

Image credit: iStock.com/Ildar Abulkhanov