Years before tau fibrils become visible on brain scans of Alzheimer’s patients, 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 contaminate the brain, cerebrospinal fluid, and possibly blood. This is suggested by a new study published today in Nature Medicine.
The biomarker test in cerebrospinal fluid correlates with the severity of cognitive decline, independent of other factors, including amyloid deposition in the brain, thus opening doors for early-stage diagnosis and intervention of the disease.
Because Alzheimer’s disease often involves amyloid-beta pathology preceding tau abnormalities, most biomarker efforts have focused on early detection of amyloid-beta changes. However, the clumping of tau protein into well-ordered structures that pathologists call “neurofibrillary tangles” is a more concise event for Alzheimer’s disease, as it is more closely related to cognitive changes in affected individuals.
“Our test detects very early stages of tau fibril formation — up to a decade before tau clumps become visible 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, as studies show that patients with few to no quantifiable insoluble tau fibrils are more likely to benefit from new treatments than patients with a significant degree of tau deposition in the brain.”
Since many older people with amyloid-beta plaques in the brain do not develop cognitive symptoms of Alzheimer's disease over their lifetime, the Alzheimer's Association's widespread diagnostic framework establishes the three neuropathological pillars required to diagnose the disease: the combined presence of tau and amyloid-beta pathology, as well as neurodegeneration. In the search for early and easily accessible biomarkers for Alzheimer's disease, Karikari's previous work showed that a brain-specific form of tau called BD-tau can be measured in the blood and reliably indicates the presence of Alzheimer's-specific neurodegeneration. A few years earlier, Karikari had shown that certain forms of phosphorylated tau, p-tau181, p-tau217, and p-tau212, in the blood can predict the presence of amyloid-beta in the brain without the need for costly and time-consuming brain imaging.
However, since these tools primarily detect amyloid pathologies, the question of early tau detection remains a major issue. While tau PET continues to be a reliable and accurate indicator of tau burden in the brain, the test's utility is limited by availability, low resolution, high cost, labor intensity, and sensitivity. Currently, tau PET scans can only detect the signal from neurofibrillary tangles when a large number of them are present in the brain. At this point, the degree of brain pathology is pronounced and no longer easily reversible.
In this latest research, Karikari and his team used the tools of biochemistry and molecular biology to identify a core region of the tau protein that is necessary for the formation of neurofibrillary tangles. Detecting sites within this 111-amino acid core region, a sequence they call tau 258-368, can identify tau proteins prone to clumping and help initiate further diagnosis and early treatment. In particular, the two new phosphorylation sites p-tau-262 and p-tau-356 can accurately indicate the early-stage status of tau aggregation, which may be reversible with appropriate intervention.
"Amyloid-beta is a spark plug and tau is a match. A large percentage of people who have amyloid-beta deposits in the brain will never develop dementia. But when the tau tangles light up on a brain scan, it may be too late to put out the fire, and their cognitive health may rapidly decline," Karikari said. "Early detection of tau tangles that are prone to tangling could identify individuals who are likely to develop Alzheimer's-related cognitive decline and who could be helped with next-generation therapies."
https://www.nature.com/articles/s41591-024-03400-0
