Tau Biomarker Shows Promise for Use in Blood Test for Early AD

Learn about a potential blood test to diagnose AD and monitor its progression and response to treatments.

What: A potential blood test to diagnose AD and monitor its progression and response to treatments.

Where: O’Conner et al, Plasma Phospho-tau181 in Pre-symptomatic and Symptomatic Familial Alzheimer’s Disease: A Longitudinal Cohort Study, Molecular Psychiatry, 2020; and also Moscoso et al, Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain with Neurodegeneration in Alzheimer Disease, JAMA Neurology, 2021.

BrightFocus Connection: Thomas K. Karikari, PhD, a co-author on both publications, has a postdoctoral fellowship grant from the Alzheimer’s Disease Research program. He is a researcher in the Department of Psychiatry and Neurochemistry at the University of Gothenburg (Sweden).

Why It Is Important: Until fairly recently, a conclusive diagnosis of Alzheimer’s disease (AD) traditionally came after death, when a biopsy of brain tissue showed amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated tau protein. In recent decades, PET imaging scans and spinal taps to obtain cerebrospinal fluid for analysis have become the gold standard; however, while these techniques are able to provide evidence of amyloid plaques and tau tangles, they are time consuming and expensive to perform, and can be uncomfortable for patients. Thomas K. Karikari and colleagues at the University of Gothenburg have found a biomarker in the blood that positively correlates with neurodegeneration and cognitive impairment before symptoms begin. Hopefully, it can serve as an accessible marker for AD pathology and be used as an early and simpler diagnostic tool.

This is one of several promising efforts to develop blood tests that can provide earlier, more convenient, screening and diagnosis of AD. Over decades, the BrightFocus ADR program provided support for the first AD blood test to reach the market in the United States and European Union countries and for other early blood test research conducted by other scientists. (see our recent Research in Brief, “A Blood Sample Speeds Alzheimer’s Diagnosis”).

The tangles of tau proteins seen in the brains of AD patients contain a form of tau that is highly phosphorylated, meaning it has a lot of phosphoryl groups – an atom of phosphorus plus three atoms of oxygen – attached to it. Normal brains have phosphorylated tau as well, but there are certain spots on the tau protein that are much more likely to be phosphorylated in people with Alzheimer’s. One of these spots is at tau’s 181st amino acid. Tau protein with a phosphoryl group at this site is called p-tau181.

After discovering that p-tau181 might be a reasonable marker for AD in blood, the researchers looked to see if they could correlate p-tau181 blood levels with neurodegeneration and cognitive impairment in people with AD over time. They began with a group of seventy people in a study of familial AD, some of whom carry genetic mutations that cause early-onset AD. Concentration of p-tau181 was significantly higher in both symptomatic and pre-symptomatic people who carried the mutations than in noncarriers. It was also higher in people with symptoms than in those who were asymptomatic. These results were published in Molecular Psychiatry last year.

Familial AD is a rare form of the disease, however, accounting for less than 5 percent of people who have AD. To see if these findings held true for sporadic (ie, non-familial) AD, Dr. Karikari and colleagues examined a larger group of people: 1113 people from the Alzheimer’s Disease Neuroimaging Initiative. In this group, elevated levels of p-tau181 in the blood were also positively correlated with cognitive decline, and p-tau181 levels similarly increased along with cognitive decline – even in the pre-symptomatic stages of AD prior to cognitive impairment. In this follow up study the researchers also showed that p-tau181 in the blood was linked to neurodegeneration in brain regions often affected in AD, as assessed by neuroimaging. A blood test for p-tau181 might thus provide a noninvasive way to track neurodegeneration in real time and might be used to monitor AD progression and possibly, responsiveness to AD treatments. These results were published recently in JAMA Neurology.