Two primary biomarkers are produced in the brains of those with Alzheimer’s disease (AD). They are misfolded versions of proteins called amyloid-β (Aβ) and tau. Despite having known this for quite some time, there has long been a lack of effective and cost-efficient testing to determine the presence of these proteins for a definitive AD diagnosis. The primary method of diagnosis is currently a scan of the brain called an Aβ-PET which uses radioactivity to show the location and concentration of misfolded Aβ in the brain. These PET scans cost thousands of dollars and are generally not covered by insurance. Alternatively, lumbar punctures (LP) to collect cerebrospinal fluid (CSF) can also determine an AD diagnosis, and while less costly than a PET scan, are more invasive with a higher degree of potential side effects. Due to the risks and discomfort involved for the patient with an LP it is not a routine practice. A long-awaited, simpler, safer, and less costly diagnostic test for AD may finally be on the horizon, and in the form of a simple blood test.
Blood-based testing for Aβ had already shown promise, but Aβ alone couldn’t accurately predict an AD diagnosis. To add further complexity to the issue, multiple forms of tau are present throughout the body in varying concentrations that don’t all accurately correlate to the amount of misfolded tau in the brain. For example, one such sub-type called p-tau181 had elevated levels in the blood of participants with AD and mild cognitive impairment (MCI). Unfortunately, this alone doesn’t mean that the concentration of p-tau181 in the blood sufficiently correlates to p-tau181 levels in the brain and CSF to be a useful diagnostic tool for AD. Furthermore, increased concentration of this protein, while correlated with presence of AD and MCI, was not as closely tied to the other piece of the puzzle, Aβ pathology, as was desired. Testing for tau has been quite elusive; until now that is!
Another sub-type called p-tau217, which does correlate well with Aβ pathology, was recently investigated to determine if it could be an effective blood-based biomarker for AD. At first, blood concentrations of p-tau217 were so low that they were undetectable. Luckily, scientists were able to purify and concentrate the sample to 800-fold, allowing for accurate detection of both p-tau181 and p-tau217 in the blood. Concentrations of both tau proteins correlated well to tau levels in CSF, and more importantly, were elevated in Aβ-positive individuals (those with the other biomarker of AD) in comparison to Aβ-negative individuals. This determined that it was more accurate to detect potential AD by using p-tau217 than p-tau181. A second study also confirmed that p-tau217 was an effective blood biomarker.
In this study, researchers used the p-tau217 blood test to attempt to determine the presence of AD in patients who had a prior diagnosis of AD by Aβ-PET, CSF, or post-mortem analysis of the brain directly. In this way, they could determine whether or not it was truly an effective test and where any shortcomings might be. Interestingly, this tau blood test was able to distinguish those with AD from patients with other neurodegenerative disorders quite accurately. In patients with a PSEN1 mutation who remain asymptomatic much longer than those without the mutation, this test predicted an AD diagnosis roughly 20 years before onset of symptoms. This means that not only could this blood test become the new gold standard for AD diagnosis, but it could also become a preventative test to determine risk for AD. With this premature detection researchers could easily and accurately find participants for preventative AD trials which, hopefully, will lead us more quickly to a disease modifying treatment for AD, preventing symptom onset.