Groundbreaking test can reveal Alzheimer’s risk years before diagnosis

Neurofibrillary tangles are one of the key hallmarks of Alzheimer’s disease. These tangles form when tau protein builds up into twisted fibrils, known as paired helical and straight filaments. Their presence is tied to the memory loss and confusion that define the illness.

Tau-related damage offers stronger insight into disease progression than amyloid plaques, another Alzheimer’s feature. For decades, scientists could only see tangles by staining brain tissue after death. Newer tools like tau PET scans have helped, but they still miss the earliest changes. Those subtle shifts happen long before fully formed tangles appear.

That challenge has driven researchers to look for ways to catch tau changes at the start. Cryo-electron microscopy has revealed striking images of tau filaments at atomic detail. Yet turning that knowledge into therapies has been far more difficult than expected.

What has become clear is that the smaller tau assemblies seen early in the disease are more harmful than the mature tangles. These soluble forms, called STAs, spark and spread damage throughout the brain. Detecting them could change how doctors diagnose and treat Alzheimer’s.

A major step forward has now emerged. A team at the University of Pittsburgh School of Medicine has uncovered a cerebrospinal fluid biomarker that tracks these early tau assemblies.

The study, published in Nature Medicine, shows that this marker predicts cognitive decline even when amyloid levels are considered. The discovery points to a new path for catching Alzheimer’s before irreversible brain injury occurs.

In the past, most biomarker work focused on amyloid. Yet its role in predicting dementia has been unreliable. Many people carry heavy loads of amyloid plaques but never develop memory problems.

Tau, however, is more directly tied to symptoms. Its build-up aligns closely with the start of cognitive decline. Measuring tau pathology offers a sharper and more reliable window into the course of Alzheimer’s disease.

“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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