Plasma p-tau217 detects Alzheimer's disease in preclinical stage

Plasma phosphorylated tau 217 (p-tau217) can identify pathological changes characteristic of Alzheimer’s disease (AD) in older adults without cognitive impairment, according to a meta-analysis.

Pooled data from 18 publications involving 7,834 individuals, including 2,533 who were amyloid-positive (mean age 70.9 years) and 5,301 who were amyloid-negative (mean age 68.2 years), showed that p-tau217 was able to differentiate between asymptomatic amyloid-positive and asymptomatic amyloid-negative individuals with high accuracy (area under the curve [AUC], 0.87, 95 percent confidence interval [CI], 0.85-0.90) and a large effect size (Hedges g, 1.50, 95 percent CI, 1.33–1.68). [JAMA Neurol 2025;doi:10.1001/jamaneurol.2025.4721]

Similar effect sizes were obtained across subgroups defined by amyloid-PET cutoff method (standard uptake volume ratio vs Centiloid) and study setting (community-based vs clinic and community and clinical trials), as well as in sensitivity analyses.

“These findings support the clinical utility of plasma p-tau217 as a scalable, minimally invasive tool for early identification of AD, particularly in settings where timely intervention with disease-modifying therapies may offer the greatest benefit in slowing or preventing disease progression,” the authors said.

Currently, the use of p-tau217 assays is limited to individuals who are symptomatic for AD. The authors pointed out that once an effective preventative therapy becomes available, the findings of the present meta-analysis could help justify the use of p-tau217 as a routine screening measure in asymptomatic individuals.

“There is confidence that plasma p-tau217 assays will soon become standard tools in screening for AD. Plasma p-tau217 has also shown to be superior to other p-tau assays in its ability to reliably detect changes in individuals with preclinical and prodromal AD, highlighting its ability to track disease progression and possibly the efficacy of amyloid-related interventions,” they said. [EBioMedicine 2025;112:105545; Nat Med 2022;28:2555-2562]

Additionally, given the different p-tau assays available on different platforms, p-tau217 has the best cross-platform reliability relative to p-tau181 and p-tau231, according to a recent large-scale validation study. [Alzheimers Dement 2025;21:e14508]

The promise and peril of AD testing

In an accompanying editorial, Dr Joshua Grill from the University of California, Irvine in Irvine, California, US, acknowledged that blood-based biomarker tests such as the p-tau217 assay is now a reality. [JAMA Neurol 2025;doi:10.1001/jamaneurol.2025.4726]

“Though not a replacement for careful evaluation, they will increase access to confident diagnoses for individuals with cognitive impairment, accelerate timelines to starting new therapies for some, and facilitate for many more the transition from what is frequently an ambiguous diagnostic journey to a phase of proactive disease management,” Grill said.

Specifically, “plasma p-tau217 will be a boon to the care of individuals with cognitive impairment, [but its] use in individuals without cognitive impairment—the population in the meta-analysis—is more complex,” in light of persisting issues about optimal diagnostic delivery, healthcare system requirements and burden, inadequate legal protections, and AD stigma, he continued.

Grill also highlighted the concerning proliferation of companies marketing direct-to-consumer (DTC) blood-based biomarker tests for AD. He stressed that these tests circumvent the necessary initial expert clinical evaluation and counselling for any older adult with cognitive concerns.

Grill noted that some of the companies offer other tests such as neurofilament light chain and glial fibrillary acidic protein (for which fewer and less convincing data are available), are not transparent about the specific assays being used, fail to disclose the cutoff values used to determine if the result is positive or negative, and sell treatments that lack evidence for AD risk reduction or delayed symptom onset.

“Physicians are likely to see an influx of older unimpaired adult patients bringing DTC blood-based biomarker test results to the clinic, asking about interpretation, prognosis, and opportunities for treatment. This could overburden available experts, delay access to diagnosis and treatment for impaired patients, and put many nonexpert clinicians in challenging positions for which they lack training,” he continued.

Grill called for regulation of the blood-based biomarker testing industry to protect consumers from low-quality tests, unproven therapies, and the risks that accompany the label of AD.

“The field has a tremendous opportunity but needs a strong plan for the effective and responsible introduction of blood-based biomarker test as a screening tool in individuals without cognitive impairment… Several key milestones are clearly in view and will be essential to the ethical implementation of powerful new tools,” he said.