New biomarker test can detect Alzheimer’s years before current methods

Neurofibrillary tangles (NFTs) are a hallmark of Alzheimer’s disease, formed by the accumulation of tau protein into fibrillar structures. These tangles, composed of paired helical filaments and straight filaments, contribute to cognitive decline.

Unlike amyloid-beta plaques, another characteristic of Alzheimer’s, tau pathology is a stronger predictor of disease progression. Traditionally, NFTs have been identified through post-mortem brain staining and, more recently, through tau PET imaging. However, these methods lack sensitivity in detecting early tau changes, which precede the formation of full-fledged tangles.

Researchers have sought ways to pinpoint early-stage tau aggregation to improve Alzheimer’s diagnostics and treatment. Advances in cryo-electron microscopy have provided a detailed view of tau filaments, but therapeutic targeting of these structures has proven difficult.

The mature tau filaments that form NFTs are less neurotoxic than smaller tau assemblies that emerge earlier in the disease process. These early-stage soluble tau assemblies (STAs) play a critical role in seeding and spreading tau pathology, making them a promising target for early detection and treatment.

A breakthrough study led by researchers at the University of Pittsburgh School of Medicine has identified a novel cerebrospinal fluid biomarker that can detect early tau aggregation.

Published in Nature Medicine, the study highlights how this biomarker correlates with cognitive decline, independently of amyloid-beta deposits. This finding opens new possibilities for diagnosing and intervening in Alzheimer’s before significant brain damage occurs.

Previous efforts to develop Alzheimer’s biomarkers have focused primarily on amyloid-beta. However, the progression from amyloid-beta accumulation to cognitive impairment remains unpredictable. Many individuals with amyloid plaques never develop dementia.

Tau aggregation, on the other hand, is closely tied to the onset of cognitive symptoms. As a result, measuring tau pathology provides a more precise indication of disease progression.

“Our test identifies very early stages of tau tangle formation—up to a decade before tau clumps appear on a brain scan,” said Thomas Karikari, Ph.D., an assistant professor of psychiatry at Pitt and senior author of the study. “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 significant tau deposits.”

This research builds on Karikari’s earlier work identifying blood-based markers of neurodegeneration, including BD-tau, which reliably detects Alzheimer’s-related brain damage. His previous studies also demonstrated that specific forms of phosphorylated tau (p-tau181, p-tau217, and p-tau212) can predict amyloid-beta presence without costly brain imaging. However, these biomarkers largely detect amyloid pathology, leaving the challenge of early tau detection unresolved.

In the latest study, researchers used biochemical and molecular biology techniques to identify a core sequence of tau protein, called tau258-368, which is crucial for NFT formation. Within this sequence, they discovered two key phosphorylation sites—p-tau262 and p-tau356. These modifications serve as early markers of tau aggregation, detectable before NFTs become visible in brain imaging.

Detecting these early tau forms could lead to a major shift in Alzheimer’s diagnostics and treatment. Current tau PET imaging can only detect NFTs once a large number have accumulated, meaning patients are often diagnosed too late for effective intervention. In contrast, identifying early tau clumps allows for preemptive treatment, potentially slowing or even preventing cognitive decline.

“Amyloid-beta is a kindling, and tau is a matchstick,” Karikari explained. “A large percentage of people with brain amyloid-beta deposits will never develop dementia. But once 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.”

The ability to detect tangle-prone tau in cerebrospinal fluid and blood could allow doctors to identify individuals most at risk for Alzheimer’s-related cognitive decline. These findings provide a foundation for developing therapies that intervene before tau pathology leads to irreversible brain damage.

The discovery of these early tau biomarkers holds significant implications for Alzheimer’s treatment. A recent phase 3 clinical trial of an anti-amyloid monoclonal antibody found that patients with lower tau pathology at the start of treatment experienced better cognitive outcomes than those with severe NFT accumulation. This suggests that addressing tau pathology in its early stages may enhance the effectiveness of new therapies.

Despite the promise of this approach, understanding the biochemical properties of early tau aggregates remains a challenge. Researchers continue to investigate which tau domains contribute to STA formation and which sequences drive aggregation. Furthermore, improvements in diagnostic tools, such as liquid chromatography–mass spectrometry, could enhance the detection of pathological tau in cerebrospinal fluid and blood.

“Our findings represent a crucial step toward a reliable, accessible test for early Alzheimer’s detection,” Karikari said. “By identifying tau abnormalities before they become visible on brain scans, we can open new doors for preventive treatments.”

As researchers refine tau biomarkers and therapeutic strategies, the future of Alzheimer’s diagnosis and treatment is poised for transformation. Early detection of tau pathology could enable targeted interventions, offering new hope for slowing or preventing the progression of this devastating disease.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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