Plasma phosphorylated tau 217 (p-tau217) outperformed p-tau181, p-tau231, and other blood-based biomarkers to identify which patients might benefit most from anti-amyloid Alzheimer’s drugs, a cohort study showed.

Plasma p-tau217 helped rule out two groups who would not likely benefit: those who were amyloid-negative, and those who were amyloid-positive but had a high tau burden, reported Oskar Hansson, MD, PhD, of Skåne University Hospital in Malmö, Sweden, and co-authors in JAMA Neurology.

The researchers applied a novel two cut-point strategy so that only people with ambiguous plasma p-tau217 values — 17.1% of participants — would need cerebrospinal fluid (CSF) analysis or PET scans to obtain a definitive amyloid-beta status.

“There is emerging evidence that anti-amyloid immunotherapies have the best benefit-risk ratio in amyloid-positive individuals who do not yet have too much tau tangle pathology throughout the neocortex,” Hansson told MedPage Today.

However, conducting amyloid-PET and tau-PET in all people with cognitive impairment would be costly, he pointed out.

“We now show that plasma p-tau217 can reliably identify many cognitively impaired individuals who are amyloid positive, indicating that advanced testing for detecting amyloid positivity with PET or CSF is not needed for most patients,” Hansson said.

“More novel, however, is that we show that the plasma test can also identify those amyloid positive patients who likely have a low tau load according to tau-PET imaging, and thereby, we can avoid doing tau-PET in those individuals,” he added.

Diagnostic tests for Alzheimer’s pathology aren’t perfect, and “the consequences of inaccuracy are much greater now that we are prescribing medications based on biomarker results,” noted Suzanne Schindler, MD, PhD, of Washington University in St. Louis, who wasn’t involved with the study.

“Even with amyloid PET, the clinically-used visual read disagrees with the quantitative research value about 5% to 15% of the time. For FDA-approved CSF biomarkers, about 10% to 15% of individuals have results that disagree with amyloid PET,” Schindler told MedPage Today.

Most discrepant results occur in people with borderline levels of pathology, she added, and that’s where a two cut-point strategy may have value.

“By applying two cut-offs, the positive individuals are more likely to have amyloid pathology, the negative individuals are less likely to have amyloid pathology, and the individuals with intermediate values can be identified,” she said. “Applying the two cut-off approach to blood tests could make results even more reliable than currently used single cut-off approaches for CSF tests and amyloid PET.”

Hansson and colleagues evaluated baseline data from the prospective Swedish BioFINDER2 study, including 912 people with a baseline diagnosis of subjective cognitive decline, mild cognitive impairment, or dementia recruited from 2017 to 2022.

Mean age was about 71 and 54.7% of the study population was male. Data were divided into a training set (80%) and a test set (20%).

The researchers assessed the performance of plasma p-tau217, p-tau181, p-tau231, N-terminal tau, glial fibrillary acidic protein, and neurofilament light chain to classify participants by amyloid-beta status (defined by amyloid-PET or CSF) and stage of tau accumulation (defined by tau PET).

Of the six blood-based markers, plasma p-tau217 was most strongly associated with amyloid-beta positivity, with an area under the receiver operating characteristic curve (AUC) of 0.94 (95% CI 0.90-0.97) in the test set.

Plasma p-tau217 values were classified into three categories — normal, “gray zone,” and abnormal — with the gray zone defined by the cut points 0.159 ng/L and 0.219 ng/L. Using the two cut-point approach to assess participants with ambiguous p-tau217 values led to an overall sensitivity of 0.94 (95% CI 0.90-0.98) and a specificity of 0.86 (95% CI 0.77-0.95).

When plasma biomarkers were evaluated to differentiate low/intermediate tau versus high tau among amyloid-positive participants, p-tau217 again performed best with an AUC of 0.92 (95% CI 0.86-0.97).

At a false-negative rate less than 10%, plasma p-tau217 could avoid 56.9% of tau-PET scans needed to identify high tau PET among amyloid beta-positive participants, Hansson and co-authors suggested. The findings were validated in an independent cohort of 118 people.

BioFINDER2 participants were consecutively recruited patients from Swedish memory clinics, and study results may not apply to primary care or more ethnically diverse populations, the researchers acknowledged.

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