A brand new biomarker check can detect early-stage tau protein clumping as much as a decade earlier than it seems on mind scans, enhancing early Alzheimer’s analysis. In contrast to amyloid-beta, tau neurofibrillary tangles are instantly linked to cognitive decline.
Years earlier than tau tangles seem in mind scans of Alzheimer’s sufferers, a biomarker check developed by the College of Pittsburgh College of Drugs can detect small quantities of tau protein susceptible to clumping, together with its misfolded pathological varieties within the mind, cerebrospinal fluid, and probably blood, in line with new analysis printed in Nature Drugs.
This cerebrospinal fluid check correlates with cognitive decline severity, impartial of things reminiscent of mind amyloid deposition, providing a possible pathway for early analysis and intervention.
Since amyloid-beta abnormalities usually emerge earlier than tau pathology in Alzheimer’s illness, most biomarker analysis has prioritized detecting amyloid-beta modifications. Nonetheless, the clumping of tau protein into well-ordered buildings referred to by pathologists as “neurofibrillary tangles” is a extra defining occasion for Alzheimer’s illness as it’s extra strongly related to the cognitive modifications seen in affected individuals.
“Our check identifies very early levels of tau tangle formation – as much as a decade earlier than any tau clumps can present up on a mind scan,” mentioned senior creator Thomas Karikari, Ph.D., assistant professor of psychiatry at Pitt. “Early detection is essential to extra profitable therapies for Alzheimer’s illness since trials present that sufferers with little-to-no quantifiable insoluble tau tangles usually tend to profit from new therapies than these with a major diploma of tau mind deposits.”
The Want for a Extra Dependable Tau Biomarker
Since many aged individuals who have amyloid-beta plaques of their brains won’t ever go on to develop cognitive signs of Alzheimer’s illness throughout their lifetime, the broadly adopted diagnostics framework developed by the Alzheimer’s Affiliation specifies the three neuropathological pillars essential to diagnose the illness – mixed presence of tau and amyloid-beta pathology and neurodegeneration.
In a quest for early and accessible biomarkers for Alzheimer’s illness, Karikari’s earlier work confirmed {that a} brain-specific type of tau, referred to as BD-tau, may be measured in blood and reliably point out the presence of Alzheimer’s disease-specific neurodegeneration. A number of years prior, Karikari confirmed that particular types of phosphorylated tau, p-tau181, p-tau217, and p-tau212, within the blood can predict the presence of mind amyloid-beta with out the necessity for expensive and time-consuming mind imaging.
However these instruments largely detect amyloid pathology, so the difficulty of early detection of tau nonetheless looms massive. Whereas tau-PET stays a dependable and correct predictor of tau burden within the mind, the check’s utility is restricted by availability, low decision, excessive price, labor, and sensitivity. At current, tau-PET scans can choose up the sign from neurofibrillary tangles solely when a big quantity are current within the mind, at which level the diploma of mind pathology has turn into pronounced and isn’t simply reversible.
A Breakthrough in Early Tau Detection
On this newest analysis, utilizing the instruments of biochemistry and molecular biology, Karikari and staff recognized a core area of the tau protein that’s mandatory for neurofibrillary tangle formation. Detecting websites inside that core area of 111 amino acids, a sequence they name tau258-368, can establish clumping-prone tau proteins and assist provoke additional diagnostics and early remedy. Specifically, the 2 new phosphorylation websites, p-tau-262 and p-tau-356, can precisely inform the standing of early-stage tau aggregation that, with an applicable intervention, might probably be reversed.
“Amyloid-beta is a kindling, and tau is a matchstick. A big share of people that have mind amyloid-beta deposits won’t ever develop dementia. However as soon as the tau tangles gentle up on a mind scan, it could be too late to place out the fireplace and their cognitive well being can shortly deteriorate,” mentioned Karikari. “Early detection of tangle-prone tau might establish the people who’re more likely to develop Alzheimer’s-associated cognitive decline and may very well be helped with new technology therapies.”
Reference: “Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s illness” by Tohidul Islam, Emily Hill, Eric E. Abrahamson, Stijn Servaes, Denis S. Smirnov, Xuemei Zeng, Anuradha Sehrawat, Yijun Chen, Przemysław R. Kac, Hlin Kvartsberg, Maria Olsson, Emma Sjons, Fernando Gonzalez-Ortiz, Joseph Therriault, Cécile Tissot, Ivana Del Popolo, Nesrine Rahmouni, Abbie Richardson, Victoria Mitchell, Henrik Zetterberg, Tharick A. Pascoal, Tammaryn Lashley, Mark J. Wall, Douglas Galasko, Pedro Rosa-Neto, Milos D. Ikonomovic, Kaj Blennow and Thomas Okay. Karikari, 10 February 2025, Nature Drugs.
DOI: 10.1038/s41591-024-03400-0
This examine was supported by, amongst others, the Nationwide Institute on Getting older (grants R01AG083874, U24AG082930, P30AG066468, RF1AG052525-01A1, R01AG053952, R37AG023651, RF1AG025516, R01AG073267, R01AG075336, R01AG072641, P01AG14449, and P01AG025204, amongst others), the Swedish Analysis Council (grant 2021-03244), the Alzheimer’s Affiliation (grant AARF-21-850325), the Swedish Alzheimer Basis, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Basis, the Emil and Wera Cornells Basis and a professorial endowment fund from the Division of Psychiatry, College of Pittsburgh.