p-Tau217 May Predict Cognitive Decline Years Before Symptoms

LONDON — Plasma phosphorylated (p)-tau217 levels may help estimate the risk for developing cognitive impairment up to a decade before symptoms appear in cognitively normal older adults.In an analysis of more than 2600 cognitively unimpaired adults, individuals with very high plasma p-tau217 levels had an estimated 38% risk of developing cognitive impairment within 5 years and a 78% risk within 10 years. The biomarker also provided prognostic information beyond amyloid PET imaging, suggesting it may improve estimates of an individual’s risk for cognitive impairment.“Very high levels of plasma p-tau217 provide meaningful information about future risk for cognitive impairment among older adults who are initially cognitively unimpaired,” lead investigator Rachel F. Buckley, PhD, associate professor of neurology at Mass General Brigham Neuroscience Institute and Harvard Medical School in Boston, told Medscape Medical News.The findings “move us toward individualized p-tau217-based risk estimates for future cognitive impairment over clinically meaningful timeframes, which will be critical as prevention strategies hopefully become a reality in the near future,” she added.The findings were presented on July 15 at the Alzheimer’s Association International Conference (AAIC) 2026 and were simultaneously published online in JAMA.Long-Term Risk Prediction Blood-based biomarkers offer a less invasive way of assessing Alzheimer’s disease (AD)-related pathology compared with cerebrospinal fluid (CSF) testing or amyloid PET imaging. Although plasma p-tau217 has demonstrated high accuracy for detecting AD-related pathology, less is known about its ability to predict long-term cognitive decline in cognitively unimpaired adults.To estimate the long-term risk for progression to cognitive impairment and cognitive decline associated with plasma p-tau217 levels, the investigators pooled harmonized data from 2684 cognitively unimpaired adults (median age, 69.6 years; 63% women) enrolled in six longitudinal AD cohorts. Participants were followed for a median of 5.4 years, with some followed up to 13.5 years.During follow-up, 478 participants developed cognitive impairment, defined as mild cognitive impairment, dementia, or two consecutive visits with a Clinical Dementia Rating score of 0.5 or higher.Higher plasma p-tau217 levels were associated with more rapid cognitive decline, with the strongest associations observed among participants with elevated amyloid burden on PET imaging. Each standard deviation increase in plasma p-tau217 was associated with a 38% higher risk of progressing to cognitive impairment (hazard ratio [HR], 1.38; 95% CI, 1.30-1.46; P < .001), independent of age, sex, education, and APOE epsilon 4 status.Across p-tau217 categories, estimated risks increased with higher p-tau levels. Participants with high, but not very high, plasma p-tau217 levels had an estimated 24% risk for cognitive impairment within 5 years and a 62% risk within 10 years. Those with intermediate plasma p-tau217 levels had a 15% risk at 5 years and a 45% risk at 10 years.Plasma p-tau217 remained independently associated with a 32% higher risk for future cognitive impairment even after accounting for amyloid PET burden (HR, 1.32; 95% CI, 1.24-1.41; P < .001).“p-tau217 appears to provide additional information beyond amyloid PET alone, even though it is itself a sensitive marker of amyloid PET burden,” Buckley said.One possible explanation, she said, is that plasma p-tau217 reflects the downstream biological effects of amyloid pathology rather than just the presence of amyloid itself.“In other words, the extent to which amyloid is ‘perturbing tau’ and potentially producing downstream effects on synaptic function that are more directly linked to cognitive decline,” she said.More Validation Needed Additional research is needed before plasma p-tau217 can be incorporated into routine clinical practice, Buckley noted.Future studies should validate these risk estimates in larger and more representative populations, extend follow-up to refine long-term predictions, and establish clinically meaningful thresholds across different p-tau217 assays, she said.Researchers also need to better understand how factors such as age, kidney function, vascular disease, race and ethnicity, and competing mortality risks influence plasma p-tau217 levels and long-term risk estimates.Current clinical practice guidelines do not recommend plasma p-tau217 testing in cognitively unimpaired individuals outside research studies or clinical trials, Buckley and colleagues noted.Ultimately, Buckley envisions plasma p-tau217 as one component of a broader AD risk prediction model rather than a stand-alone screening test.“As soon as preventive treatments become available for cognitively unimpaired older adults, p-tau217 will help identify individuals who may benefit from closer monitoring, additional biomarker testing, prevention trial enrollment, or early intervention strategies,” she said.Toward Early Detection The analysis is “one of the most comprehensive” evaluations of plasma p-tau217 to date because of its large sample size, inclusion of six major research cohorts, and long-term follow-up, Sheena Aurora, MD, vice president of medical affairs for the Alzheimer’s Association, who was not involved in the study, told Medscape Medical News.The findings represent an important step toward earlier identification of AD risk, she said.“One of the first steps of finding a cure is to detect early. What’s exciting here is that it could even detect disease before the symptoms start,” Aurora added. However, she cautioned that the blood-based biomarker is not yet ready to be used this way. “At the moment, even if we detect someone’s risk, we don’t know what the other factors are that could lead to developing symptoms. The other critical issue is what to do if somebody has elevated p-tau217. We don’t have treatment for that,” she noted.Aurora said the findings offer hope that AD will eventually be detected during its asymptomatic stage. “We are hopeful for a future” in which that is possible, she said. Funding for the study was provided by the National Institutes of Health, the Alzheimer’s Association, Wellcome Leap, and Cure Alzheimer’s Fund.