Scientists Develop Blood Test That Diagnoses Alzheimer’s And Identifies What Stage It Has Reached

Alzheimer’s disease is the most common cause of dementia, a disorder that slowly destroys a person’s memory and cognitive skills, eventually resulting in an inability to carry out daily tasks. The disease is caused by the build-up of a protein, called amyloid, into plaques – extracellular deposits of misfolding proteins – followed by the development of tangles of tau proteins years later.

Tau proteins are microtubule-associated proteins that are principally found in neurons and are crucial for maintaining their structural integrity. However, in Alzheimer’s patients, these proteins have abnormal aggregations that form tangles that are the hallmark of the disease. In most patients, cognitive symptoms emerge around the time tau tangles become detectable and get worse as the tangles spread.

Traditionally, Alzheimer’s disease is detected through positron emission tomography (PET) brain scans, the Gold Standard test for the disease. These scans pick up the presence of amyloid plaques and tau tangles. Scans for the former can tell us about the presymptomatic and early symptomatic stages, while tau scans can offer an accurate insight into the later stages, but are expensive, time-consuming, and often unavailable outside of specialist research centers. As such, they are not widely used.

There are also some blood tests available for clinical diagnosis, including two based on technology licensed from Washington University. These tests can help identify the presence of the disease but do not indicate its clinical stage – the degree of impairment in thinking or memory.

As with many illnesses, it’s important to detect the disease earlier and current therapies are most effective at these stages. As such, having a way to quickly and reliably diagnose Alzheimer’s and track how far it has progressed could help doctors identify the best treatment options for their patients – such as which drugs would work best and to what extent – or even provide insight into whether the symptoms are caused by something other than Alzheimer’s. 

Now, however, researchers in Sweden have developed a new test blood that provides this information. The team found that levels of a protein called MTBR-tau243 in the blood can accurately reflect the amount of toxic accumulation of tau aggregates there are in the brain, which correlates with the severity of Alzheimer’s disease. While analyzing blood levels of MTBR-tau243 from a group of people with cognitive decline, the scientists were able to distinguish between people with early or later-stage Alzheimer’s and were able to separate these two groups of patients from others who had other diseases.

The study’s participants were volunteers at the Washington University Medicine’s Charles F. and Joanne Knight Alzheimer Disease Research Center and consisted of 108 people, along with a subset of 55 people from the Swedish BioFINDER-2 cohort.

“This blood test clearly identifies Alzheimer’s tau tangles, which is our best biomarker measure of Alzheimer’s symptoms and dementia,” Dr Randall J. Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University Medicine, explained in a statement.

“In clinical practice right now, we don’t have easy or accessible measures of Alzheimer’s tangles and dementia, and so a tangle blood test like this can provide a much better indication if the symptoms are due to Alzheimer’s and may also help doctors decide which treatments are best for their patients.”

In previous work, Bateman and colleagues showed that cerebrospinal fluid levels of MTBR-tau243 correlate closely with tau tangles in the brain. In this latest study, the team extended the analysis to blood, which is easier to collect samples of than tapping someone’s spine.

In order to assess whether their new method is generalizable, the team validated it in an independent dataset consisting of the remaining 739 people in the BioFINDER-2 cohort.  

The participants in the two cohorts were representative of all but the most severe ends of the spectrum of Alzheimer’s disease. They included the presymptomatic stage when brain amyloid levels were elevated but the patient’s cognition remained healthy, through to early-stage disease with mild symptoms and then patients with full-blown dementia. For comparison, the test also examined cognitively healthy people and others with diseases other than Alzheimer’s.

The analysis showed that blood MTBR-tau243 levels reflected the amount of tau tangles in the brain with 92 percent accuracy. MTBR-tau243 levels were also found to be normal in asymptomatic people regardless of amyloid status, meaning MTBR-tau243 levels don’t change between healthy people and those in the presymptomatic stages of Alzheimer’s disease with amyloid plaques.

People with mild cognitive impairment showed significantly elevated levels of MTBR-tau243, while those in the dementia phase showed levels that were up to 200 times higher. These differences translate to a clear separation of people with early and late-stage Alzheimer’s. The results also show that patients with other diseases can be ruled out as their MTBR-tau243 levels are the same as those with healthy cognition.

The technology for this blood test has been licensed by Washington University to C2N Diagnostics, a startup that developed the blood test for amyloid. These tests incorporate measures of another form of tau called p-tau217.

“I believe we will use blood-based p-tau217 to determine whether an individual has Alzheimer’s disease, but MTBR-tau243 will be a highly valuable complement in both clinical settings and research trials,” Dr Oskar Hansson, a professor of neurology at Lund University, added.

“When both of these biomarkers are positive, the likelihood that Alzheimer’s is the underlying cause of a person’s cognitive symptoms increases significantly, compared to when only p-tau217 is abnormal. This distinction is crucial for selecting the most appropriate treatment for each patient.”

“We’re about to enter the era of personalized medicine for Alzheimer’s disease,” Dr Kanta Horie, a research associate professor of neurology at Washington University Medicine, explained.

“For early stages with low tau tangles, anti-amyloid therapies could be more efficacious than in late stages. But after the onset of dementia with high tau tangles, anti-tau therapy or one of the many other experimental approaches may be more effective. Once we have a clinically available blood test for staging, plus treatments that work at different stages of the disease, doctors will be able to optimize their treatment plans for the specific needs of each patient.”

The paper is published in Nature Medicine.