New biomarkers are a hot topic in the field of neurodegenerative diseases. In Leuven, the team of neurologist and Alzheimer’s expert Prof. Dr. Rik Vandenberghe recently published a study that evaluated a new plasma p-tau181 assay. “The sensitivity and specificity of this biomarker are astonishing,” he says.

Currently available clinical tools to diagnose Alzheimer’s disease and other dementias are based on lumbar punctures (to collect cerebrospinal fluid), PET or MRI brain scans, and neurocognitive testing. Each of those has limitations that prevent them from being widely used today: lumbar punctures are a bit invasive and uncomfortable, brain scans are expensive, and cognitive problems typically occur late in the disease process so functional tests have limited value in preclinical screening.

In recent years, a lot of research attention was directed towards blood-based biomarkers. Being able to make an early diagnosis using a few droplets of blood would make larger scale screening of populations possible. It would allow us to identify people at a higher risk to develop dementia and to select the most suitable human subjects to participate in clinical trials.

Phosphorylated tau protein

One of the hallmarks of Alzheimer’s disease is the accumulation of an abnormally structured and dysfunctional protein called tau. In the diseased brain, this protein becomes ‘hyperphosphorylated’: its molecular structure gets altered by the addition of many phosphor groups. Alzheimer’s-associated tau is typically identified based on which sites of the protein are phosphorylated.

A very promising plasma biomarker is p-tau181, which detects tau protein phosphorylated at amino acid 181. A recent study at UZ Leuven and KU Leuven evaluated the biomarker in Alzheimer’s patients and healthy people with PET-confirmed amyloid pathology.

Prof. Dr. Rik Vandenberghe, neurologist and head of the memory clinic at UZ Leuven: “Our study confirmed that plasma p-tau181 levels are significantly higher in people clinically diagnosed with Alzheimer’s disease, so the assay can reliably identify AD cases. More remarkably, plasma p-tau181 levels were also elevated in people with asymptomatic amyloid pathology, who had a positive amyloid-PET brain scan but were otherwise cognitively healthy. The assay could recognize both groups of people with a high sensitivity and specificity, meaning that there were relatively few false positives and false negatives.”

Strong link with amyloid pathology

While the p-tau181 marker presumably reflects pathological forms of the tau protein, it is surprisingly well correlated with amyloid pathology in the brain. “It is fascinating that plasma p-tau181 levels correspond so well with someone’s amyloid-PET result, even better than with their tau-PET result. Moreover: p-tau181 plasma levels are so predictive on its own, that including amyloid plasma levels in the equation brings no added value. All of these findings are part of an open scientific question, but they do seem to indicate an underlying interaction between amyloid and tau pathologies.”

Impact on the ecosystem

The p-tau181 plasma assay is not only cheaper than PET scans and less invasive than CSF collection, it also appears to be more sensitive than genetic screening and more predictive than age, gender or APOE risk gene status. It is already being used in several clinical trials.

“The performance of this assay is so impressive, that I think it won’t be long until it will be used in the clinical practice. These biomarkers can have an enormous impact on disease detection. But an important open question is: how will these biomarkers be embedded in the diagnostic ecosystem, from primary care to specialized memory clinics? I believe that, if we want to make maximum use of these revolutions, we should not restrict their use to specialized tertiary care centres”, says Prof. Vandenberghe. “We need to look purely at the data: how good is the diagnostic accuracy in broader populations, outside the clinical trial cohorts? For example, what is the effect on comorbidities such as renal impairment on those biomarkers?”

Another important aspect is communication to the patient. “Shared decision making will become even more important. It’s not because a test has become accessible and practical in use, that patients are mentally prepared for the implications of a positive test result. We need to approach this much like today’s counseling for genetic testing. I think the challenge lies in feeding back the result to patients, more than in running the test.”

Actionable?

Plasma assays do have a disadvantage: they don’t appear very good at longitudinal measurements. To track disease progression over time, PET scans are still more accurate.

Finally, the broad implementation of new screening methods and their reimbursement by health insurance funds heavily depend on how ‘actionable’ they are. “Ideally a biomarker finding would result in a therapeutic action or other effect that clearly benefits the patient. For asymptomatic people, we can’t really call a diagnosis actionable. So today it makes no sense to start measuring this kind of biomarkers on a clinical scale in healthy people. But for people with symptoms, the impact can be significant: a positive biomarker result may make extensive neurocognitive examination or lumbar punctures redundant. It will be interesting to see how the field will evolve in the coming years”, concludes Prof. Vandenberghe.

• Read the publication of the study (De Meyer et al. 2022)