New blood test detects neurodegeneration in Alzheimer’s disease

A new blood test to assess brain-derived tau detected Alzheimer’s disease-related neurodegeneration and distinguished Alzheimer’s disease from other neurodegenerative diseases.

The test outperformed total tau and, unlike neurofilament light, showed specificity for Alzheimer’s-type neurodegeneration, said Dr. Thomas Karikari of the University of Gothenburg, Sweden and the University of Pittsburgh, Pennsylvania. brain.

“Thus, brain-derived tau demonstrates the potential to complete the AT(N) scheme in the blood, which will be useful in assessing Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.” writes Karikari and colleagues..

In the AT(N) framework, three components of Alzheimer’s disease pathology (amyloid plaques, tau tangles, and neurodegeneration) should be detected in imaging or cerebrospinal fluid (CSF) samples to diagnose Alzheimer’s disease. there is.

Blood-based biomarkers may make Alzheimer’s disease detection easier and more accessible. Blood tests have been developed to detect amyloid and tau, but reliable blood tests for neurodegeneration remain remains elusive. For example, neurofilament light, a marker of axonal damage, is elevated in Alzheimer’s disease, but also in other forms of dementia and other neurodegenerative diseases.

As a marker of neurodegeneration, “current plasma total tau (t-tau) assays do not show good diagnostic utility, in contrast to CSF ​​t-tau, which reliably reflects neurodegeneration in Alzheimer’s disease.” , but not in other neurodegenerative diseases such as Parkinson’s disease, Lewy bodies, dementia, and frontotemporal dementia,” the researchers observed.

To selectively detect brain-derived tau, Karikari and colleagues developed an antibody that binds to an expressed glutathione S-transferase binding protein construct. map Tau gene exons 4-5 and recombinant full-length tau 441 (rPeptide). The resulting TauJ.5H3 monoclonal antibody showed specific reactivity against the junction between MAPT exons 4 and 5, excluding peripherally derived tau species with exon 4a inserts.

Researchers validated the assay in five cohorts across 609 patient samples and found:

• Antibody-identified serum and CSF brain-derived tau were significantly correlated (rho=0.85, P.<0.0001), CSF total tau and blood-based tau measured with typical techniques did not (rho=0.23, P.=0.3364).
• Blood-based brain-derived tau showed comparable diagnostic performance to both CSF total tau and CSF brain-derived tau in distinguishing biomarker-positive Alzheimer’s disease participants from biomarker-negative controls.
• Blood-based brain-derived tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases with an area under the receiver operating curve (AUC) of 86.4%, whereas neurofilament light did not was (AUC 54.3%).

The researchers noted that performance was independent of the presence of concomitant medical conditions. Results were validated in two memory clinic cohorts where serum brain-derived tau distinguishes Alzheimer’s disease from other neurodegenerative diseases (including frontotemporal lobar degeneration and atypical Parkinson’s disease), with AUCs up to 99.6% .

“Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function,” write Karikari and co-authors. “In particular, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer’s disease and not in other neurodegenerative diseases.”

The researchers plan to conduct large-scale clinical validation of blood-brain-derived tau in a broad cohort, including cohorts with diverse racial and ethnic backgrounds. The study includes older people with various stages of the disease, as well as older people without biological evidence of Alzheimer’s disease.