Moving Toward a Tau Plasma Biomarker for Alzheimer’s Disease

Image: Neurofibrillary tangles (dark neurons) in an AD brain, from which tau fragments may derive

Progress in creating and evaluating a tau biomarker test at Brigham and Women’s Hospital is spurring rapid movement toward a blood-based screen to diagnose or predict risk for Alzheimer’s disease (AD) perhaps without the need for spinal fluid or imaging.

An initial report earlier this year, published by a Brigham-led team in Alzheimer’s & Dementia, showed the ability to measure tau fragments in cerebrospinal fluid and plasma. Since then, the work has extended into a larger testing phase, made possible by deep expertise of the hospital’s Alzheimer’s Center where laboratory research is led by Dennis J. Selkoe, MD, and clinical trials are led by Reisa Sperling, MD, who directs the Center for Alzheimer Research and Treatment (CART).

“This was the first evidence of the ability to detect fragments of the tau protein in the blood in a way that could discriminate people with AD from control subjects—essentially the achievement of a plasma biomarker for Alzheimer’s, which has been a major goal,” said Dr. Selkoe, also co-director of the Ann Romney Center for Neurologic Diseases. An expert in the biology of AD and the beta-amyloid and tau proteins, whose work initially formulated the relationship between the two, Dr. Selkoe was among the study authors. “We think we’re on the verge of a well-characterized blood test for Alzheimer’s disease.”

Creating and Evaluating an NT-1 Blood Test

While the tau protein has long been implicated in AD, tau occurs as a family of related molecules that have subtly different properties. Taking advantage of this complexity of tau, the research team developed and tested several assays capable of detecting different populations of tau fragments in cerebrospinal fluid (csf) and blood.

They initially applied these biomarker tests to csf and plasma from a total of 65 participants in the Harvard Aging Brain Study (HABS) and from the Institute of Neurology in London. Results were validated in a second group of 86 patients from the Shiley-Marcos Alzheimer’s Disease Research Center at the University of California, San Diego. The work was reported in March 2019.

The researchers found that the assay known as N terminal one (NT1) showed sufficient sensitivity and specificity to be further investigated as a potential screening tool for AD. Authors of that international study concluded that levels of certain fragments are increased in AD and that “measurement of plasma NT1 tau should be aggressively pursued as a potential blood-based screening test” for AD and Mild Cognitive Impairment.

“We’ve never been able just to send a sample of blood off to see the likelihood of whether you have Alzheimer’s and whether you will decline cognitively,” said Dr. Selkoe. “But the NT1 fragment seems to allow that.”

Blood samples and neuroimaging work from HABS are making it possible to accelerate that research. HABS, co-led by Dr. Sperling of Brigham and Women’s in collaboration with Massachusetts General Hospital, is an observational study of older adults aimed at defining neurobiological and clinical changes in early AD, primarily through imaging amyloid plaques and tau tangles.

Using a larger, 230-subject HABS cohort, longitudinal testing of the NT1 assay is underway. This research is expected to increase understanding of the potential diagnostic and predictive value of an NT-1 test.

Several Blood Tests May be Needed to Solve Riddles of AD

To speed overall plasma test research, Brigham researchers are describing their assays and data widely, so that other researchers can validate the findings of the NT1 test across different populations. Brigham researchers also are analyzing blood from other cohorts. And, blood from the HABS cohort is being shared with other research teams that are developing different blood tests for beta-amyloid and tau.

A successful blood test is also expected to enable more streamlined research into potential AD treatments.

“We’ve been really interested in what modulates cognitive decline. What factors put you at greater risk? What can protect you?” said Dr. Sperling. “I feel confident now that amyloid build-up is associated with greater decline, but there’s heterogeneity. For example, some people can show evidence of amyloid for a decade and be fine for many years. Other people, within two years, will develop cognitive impairment. We are trying to understand how to achieve better prediction on an individual level. That’s what this blood test will help us do.”

Dr. Sperling noted that it is important for multiple tests to be investigated to determine which correlate best with changes in individuals over time: “We need to understand which of these blood tests—and probably it will be a combination of blood tests—will be most predictive of cognitive change over time.”

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