Plasma Phosphorylated Tau 217 Effectively Identifies Preclinical Alzheimer Disease

Plasma phosphorylated tau 217 (p-tau217) demonstrates strong accuracy in identifying amyloid β (Aβ) pathology among cognitively unimpaired individuals, according to study results published in JAMA Neurology.

While Aβ and tau accumulation are known hallmarks of Alzheimer disease (AD), identifying cognitively normal individuals with underlying pathology remains a major challenge for preclinical research and future treatment programs. Researchers therefore evaluated whether plasma p-tau217 could reliably classify Aβ status and improve efficiency in participant selection for clinical trials.

This cross-sectional cohort study analyzed data from 2916 cognitively unimpaired adults across 12 international cohorts in Australia, Canada, Europe, and the United States, collected between June 2009 and March 2024. Participants had a mean (SD) age of 66.9 (9.9) years, 57.2% were women, and 38.1% carried at least 1 apolipoprotein E ε4 allele. Overall, 33.3% (n=971) were classified as Aβ positive based on cerebrospinal fluid (CSF) or positron emission tomography (PET) results.

The use of plasma p-tau217 as a stand-alone tool or as part of a 2-step approach will reduce resource demands, and minimize unnecessary burdensome PET or CSF procedures, ultimately accelerating the development and implementation of early-stage AD therapeutics.

When used as a stand-alone test, plasma p-tau217 achieved an accuracy of 81% (95% CI, 80-82) and a positive predictive value (PPV) of 79% (95% CI, 74-84). However, sensitivity was limited, with plasma p-tau217 alone detecting only 46% of true Aβ-positive cases.

To address this, researchers tested a 2-step approach, in which individuals with positive plasma results underwent confirmatory CSF or PET testing. This workflow increased the PPV to 91% (95% CI, 86-95), while substantially reducing the number of confirmatory scans required.

Further, recruitment modeling for a hypothetical preclinical AD trial demonstrated that plasma-based strategies could cut costs by up to 92% relative to PET-only screening and minimize patient burden by reducing unnecessary lumbar punctures or imaging.

Study limitations include variability in biomarker assays across cohorts and a slightly higher prevalence of Aβ positivity compared with the general cognitively unimpaired population, which may affect generalizability.

“The use of plasma p-tau217 as a stand-alone tool or as part of a 2-step approach will reduce resource demands, and minimize unnecessary burdensome PET or CSF procedures, ultimately accelerating the development and implementation of early-stage AD therapeutics,” the study authors concluded.

Disclosures: This research was supported by the National Institutes of Health, the Alzheimer’s Association, the Vanderbilt Alzheimer’s Disease Research Center, the Swedish Research Council, the Swedish Alzheimer Foundation, Hjärnfonden, Fondation Recherche Alzheimer, Familjen Rönströms Stiftelse, Swedish State Support for Clinical Research, the Alzheimer Drug Discovery Foundation, the European Union’s Horizon Europe Research and Innovation Programme, and the National Institute for Health and Care Research University. Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.