Breakthrough testing for Alzheimer's disease: selective neurodegenerative blood biomarkers

Neuroscientists have developed a groundbreaking test that can detect unique markers
of neurodegeneration in Alzheimer's disease in blood samples.

A team of neuroscientists has developed a test that can detect a new marker of neurodegenerative degeneration in Alzheimer's disease in blood samples
.
A researcher at the University of Pittsburgh School of Medicine studied their findings, which were published Dec.
27 in
the journal Brain.

This biomarker, known as "brain-derived tau," or BD-tau, is superior to the blood diagnostic tests
currently used to clinically detect neurodegenerative diseases associated with Alzheimer's disease.
It is endemic to Alzheimer's disease and has a good correlation
with Alzheimer's neurodegenerative biomarkers in cerebrospinal fluid (CSF).

"Currently, diagnosing Alzheimer's disease requires neuroimaging," said
senior author Dr.
Thomas Karikari, assistant professor of psychiatry at Pitt University.
"These tests are expensive and take a long time to schedule, and even in the U.
S.
, many patients don't have access to MRI and PET scanners
.
Accessibility is a major concern
.
”

Currently, to diagnose Alzheimer's disease, clinicians use guidelines
developed in 2011 by the National Institute on Aging and the Alzheimer's Association.
The guidelines, known as the AT(N) framework, call for imaging or analyzing cerebrospinal fluid samples to detect three different components of Alzheimer's pathology: the presence of amyloid plaques, tau tangles, and neurodegeneration
in the brain.

Unfortunately, both methods have economic and practical limitations, which dictate the need to develop convenient and reliable AT(N) biomarkers in blood samples, the collection of which is minimally invasive and requires fewer
resources.
Karikari said developing simple tools to detect signs of Alzheimer's disease in the blood without affecting blood quality is an important step
towards improving access.

"The most important use of blood biomarkers is to improve people's lives and improve clinical confidence and risk prognosis
for Alzheimer's disease diagnosis.
"

Current blood diagnostic methods can accurately detect abnormalities in plasma β amyloid and phosphorylated forms of tau, satisfying two of the three necessary examination markers to definitively diagnose Alzheimer's
.
But the biggest hurdle to applying the AT(N) framework to blood samples is that it is difficult to detect markers of neurodegeneration specific to the brain and is not affected by
potentially misleading contaminants produced elsewhere in the body.

For example, in people with Alzheimer's disease, Parkinson's and other dementias, blood levels of neurofilament light, a protein marker of nerve cell damage, are elevated, making it less useful
when trying to distinguish Alzheimer's disease from other neurodegenerative diseases.
On the other hand, measuring total tau protein in the blood proved inferior to monitoring tau levels
in the cerebrospinal fluid.

By applying their knowledge of the molecular biology and biochemistry of tau proteins in different tissues, such as the brain, Karikari and his team, including scientists at the University of Gothenburg in Sweden, developed a technique that selectively detects BD-tau while avoiding the free-floating "big tau" protein
produced by cells outside the brain.

To do this, they designed a special antibody that selectively binds to BD-tau, making it easily detectable
in the blood.
They validated their experiment in more than 600 patient samples from 5 separate cohorts, including those diagnosed with Alzheimer's disease after death, and those with memory deficits in early Alzheimer's disease
.

Tests have shown that BD-tau levels detected in blood samples from Alzheimer's patients using the new method match tau levels in CSF and reliably distinguish Alzheimer's disease from other neurodegenerative diseases
.
Anatomical analysis of the brain confirmed that BD-tau protein levels were also associated with
the severity of amyloid plaques and tau protein tangles in brain tissue.

The scientists hope that monitoring blood levels of BD-tau can improve clinical trial design and facilitate screening and enrollment of patients
from populations that have not historically been included in the study cohort.

Karikari said: "There is a great need for diversity in clinical research, not just in skin color, but also in socioeconomic background
.
To develop better drugs, trials need to recruit people from diverse backgrounds, not just those who live near academic medical centers
.
Blood testing is cheaper, safer, and easier to administer, and it can increase clinical confidence
in diagnosing Alzheimer's disease and selecting participants in clinical trials and disease surveillance.
”

Karikari and his team plan to conduct large-scale clinical validation of blood BD-tau in a wide range of research groups, including those recruiting participants from diverse racial and ethnic backgrounds, memory clinics, and communities
.
In addition, the studies will include older adults who do not have biological evidence of Alzheimer's disease as well as those
who are at different stages of the disease.
These projects are critical to ensuring that biomarker results are applicable to people of all backgrounds and will pave the way
for BD-tau commercialization for a wide range of clinical and prognostic purposes.

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