Summary: For years, the gold standard for spotting early Alzheimer’s was the amyloid PET scan, which could detect brain plaques 10 to 20 years before symptoms appeared. However, a groundbreaking study has identified a “pre-early” warning sign.
Researchers found that a blood test for pTau217 (phosphorylated tau 217) can predict amyloid buildup and cognitive decline even when initial brain scans appear perfectly normal. This discovery could shift Alzheimer’s screening from expensive, invasive scans to a simple, scalable blood test during routine checkups.
Key Facts
- Scalable Screening: Unlike PET scans (which are expensive and involve radiation) or lumbar punctures (which are invasive), the pTau217 test is a simple plasma draw.
- Early Detection: The test identifies individuals who will eventually become “amyloid-positive” even when their current clinical scans show no abnormalities.
- HABS Study Data: The findings come from the Harvard Aging Brain Study (HABS), a prospective cohort that provides high-quality longitudinal data over nearly a decade.
- Clinical Translation: While not yet recommended for general routine use in healthy seniors, the test is already being used to streamline clinical trials for Alzheimer’s prevention.
- FDA Precedent: The FDA cleared the first blood test for Alzheimer’s in 2025, and this study provides the critical evidence needed to expand its use for long-term prediction.
Source: Mass General
A new study by investigators at Mass General Brigham has found that a blood test of plasma phosphorylated tau 217 (pTau217), an Alzheimer’s disease biomarker, can predict the progression of amyloid PET scan changes and cognitive decline in cognitively healthy older adults.
The findings may help push back the clock to enable simpler, earlier disease prediction and indicate who may be at risk for cognitive decline.
The results are published in Nature Communications.
“We used to think that PET scan detection was the earliest sign of Alzheimer’s disease progression, revealing amyloid accumulation in the brain 10 to 20 years before symptoms appear,” said lead author Hyun-Sik Yang, MD, a neurologist with Mass General Brigham Neuroscience Institute and an associate member of the Broad Institute of MIT and Harvard. “But now we are seeing that pTau217 can be detected years earlier, well before clear abnormalities appear on amyloid PET scans.”
Last year, the U.S. Food and Drug Administration cleared the first blood test for Alzheimer’s disease, paving the way for a cheaper, less invasive alternative to lumbar punctures and PET scans. The new study by Yang and colleagues adds important evidence about the predictive potential of these kinds of blood tests.
This prospective cohort study followed 317 cognitively healthy older adults from the Harvard Aging Brain Study (HABS) for an average of eight years. Participants, who ranged in age from 50 to 90 years, had blood tests for pTau217, repeated amyloid and tau PET scans and long-term cognitive testing.
The researchers examined whether baseline and changing pTau217 levels predicted future amyloid buildup, tau accumulation (the abnormal buildup of misfolded tau proteins inside brain neurons) and cognitive decline.
Researchers found that higher levels of pTau217 predicted a faster buildup of Alzheimer’s disease pathology, even when initial brain scans appeared normal. Increases in pTau217 frequently occurred before amyloid PET scans became positive, highlighting the biomarker’s ability to detect changes earlier.
Importantly, participants with low pTau217 levels at the start of the study were very unlikely to accumulate significant amyloid-beta on their PET scans over many years of follow-up.
“What stood out in our study is that even when amyloid scans appear normal in the clinic, the pTau217 biomarker can identify individuals who later become amyloid-positive,” said Yang. “It also shows that those with low pTau217 levels are likely to stay amyloid-negative for several years.”
While it’s too early to recommend pTau217 testing for older adults, Yang and his colleagues hope the study results will serve as a scalable screening tool for clinical trials targeting Alzheimer’s disease prevention and will help identify individuals at higher risk. Eventually, biomarker blood tests could be used for routine health maintenance and may offer a more affordable alternative to amyloid PET scans.
“As the field is evolving quickly, we’re excited to see discoveries on the research side being rapidly translated to clinical application,” said co-senior author Jasmeer Chhatwal, MD, PhD, a neurologist with Mass General Brigham Neuroscience Institute.
“By anticipating who’s going to turn amyloid-positive in the future, we are trying to push back the clock to enable earlier Alzheimer’s disease prediction.”
Authorship: In addition to Yang and Chhatwal, Mass General Brigham authors include Juliana A. U. Anzai, Wai-Ying Wendy Yau, Brian C. Healy, Andrea M. Roman Viera, Courtney Maa, Dylan Kirn, Michael J. Properzi, Jean-Pierre Bellier, Aaron P. Schultz, Michelle E. Farrell, Heidi I. L. Jacobs, Rachel F. Buckley, Kathryn V. Papp, Gad A. Marshall, Rebecca E. Amariglio, Dorene M. Rentz, Lei Liu, Dennis J. Selkoe, Keith A. Johnson, and Reisa A. Sperling. Additional authors include Philip B. Verghese and Joel B. Braunstein.
Disclosures: Philip B. Verghese and Joel B. Braunstein are full-time employees of C2N Diagnostics LLC. Other authors declare no directly relevant conflict of interest.
Funding: This work was supported by grants K23 AG062750, K23 AG084868, P01 AG036694 (Harvard Aging Brain Study), and R01 AG071865 from the National Institute on Aging, as well as the Shelby Cullom Davis Charitable Fund’s philanthropic gift.
Key Questions Answered:
A: Because a “normal” scan only tells you what is happening now. The pTau217 blood test tells you what is happening next. It can detect the very first molecular ripples of Alzheimer’s years before they clump together into the plaques that a PET scan is able to see.
A: We are getting close. The FDA cleared the first Alzheimer’s blood test last year, but it is currently used mostly for people already showing symptoms. This study proves it works for healthy people too, which will likely lead to it becoming a routine screening tool for those over 50.
A: It indicates a much higher risk of “amyloid positivity” and cognitive decline. However, the real value of this early warning is prevention. Identifying risk a decade earlier gives patients a massive head start on lifestyle changes and new preventative therapies currently in clinical trials.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Plasma phosphorylated tau 217 and longitudinal trajectories of Aβ, tau, and cognition in cognitively unimpaired older adults” by Hyun-Sik Yang, Juliana A. U. Anzai, Wai-Ying Wendy Yau, Brian C. Healy, Andrea M. Román Viera, Courtney Maa, Dylan Kirn, Michael J. Properzi, Jean-Pierre Bellier, Aaron P. Schultz, Michelle E. Farrell, Heidi I. L. Jacobs, Rachel F. Buckley, Kathryn V. Papp, Gad A. Marshall, Rebecca E. Amariglio, Dorene M. Rentz, Lei Liu, Dennis J. Selkoe, Philip B. Verghese, Joel B. Braunstein, Keith A. Johnson, Reisa A. Sperling & Jasmeer P. Chhatwal. Nature Communications
DOI:10.1038/s41467-026-71269-3
Abstract
Plasma phosphorylated tau 217 and longitudinal trajectories of Aβ, tau, and cognition in cognitively unimpaired older adults
Plasma phosphorylated tau 217 (pTau217) is an excellent biomarker of Alzheimer’s disease (AD) pathology, but it remains uncertain whether pTau217 can predict amyloid-β (Aβ) and tau accumulation prior to Aβ positron emission tomography (PET) positivity.
Here, we leverage data from a well-characterized prospective cohort of cognitively unimpaired older adults to examine mass spectrometry-based plasma %pTau217 (pTau217/non-phosphorylated-Tau217×100) relative to changes in Aβ/tau PET and cognition.
A higher baseline %pTau217 was associated with faster Aβ and tau accumulation on PET, which then led to greater cognitive decline. Among individuals Aβ PET-negative at baseline, higher %pTau217 levels presaged increases in Aβ and tau PET signals.
Together, our results suggest that very low %pTau217 in cognitively unimpaired older adults is associated with a minimal risk of AD pathology accumulation and cognitive decline.
