Science Daily

by Mass General Brigham

    A simple blood test could help identify people at increased risk of Alzheimer's-related cognitive decline years before they experience any noticeable problems with memory or thinking. In a large international study, researchers found that older adults with very high levels of a particular blood biomarker faced a 38% chance of developing cognitive impairment within five years. Over 10 years, the estimated risk rose to 78%, although the longer-term findings were based on substantially less data.

    The findings offer new insight into the potential of blood tests to predict future cognitive problems in people who currently show no signs of impairment. The research was led by scientists at the Mass General Brigham Neuroscience Institute and involved teams working across three continents. The results were presented at the Alzheimer's Association International Conference and simultaneously published in JAMA.

The study focused on phosphorylated tau 217 (p-tau217), a blood biomarker associated with Alzheimer's disease. A test measuring this marker recently received federal clearance, raising hopes that blood testing could make Alzheimer's detection more accessible. However, an important question has remained: Can these tests reliably predict whether someone with normal cognitive function will eventually develop symptoms

Blood Test Reveals Cognitive Decline Risk Years in Advance

    To investigate, researchers combined information from six observational studies and clinical trials conducted in North America, Japan, and Australia. Together, these studies included 2,684 older adults who showed no signs of cognitive impairment when they entered the research.

    At enrollment, participants provided blood samples that were analyzed for p-tau217. They also underwent positron emission tomography (PET) brain scans, allowing researchers to establish baseline measurements of brain health. Annual follow-up assessments were then used to monitor changes in memory, thinking, and other cognitive abilities.

    The combined data covered an unusually long period. Some participants entered one of the studies as early as 2004, while the most recent follow-up assessments took place in 2025.

    Across the studies, approximately 478 participants eventually developed cognitive impairment. When researchers compared these outcomes with the original blood test results, they found a strong relationship between higher p-tau217 levels and the likelihood of future cognitive problems.

    Among people with very high biomarker levels, the estimated probability of developing cognitive impairment reached 38% within five years. By 10 years, that figure increased to 78%. However, the researchers emphasized that substantially fewer observations were available for the 10-year period and beyond, making those longer-term predictions less certain.

A Powerful Alzheimer's Predictor Beyond Genetics and Brain Scans

    One of the most important findings was that p-tau217 provided information about future cognitive decline beyond what could be explained by other established risk factors.

    The biomarker remained significantly associated with cognitive impairment even after researchers accounted for amyloid-beta plaques, which are abnormal protein deposits in the brain that can be detected with PET imaging. Its predictive value also extended beyond known genetic risk factors (such as APOE4).

    This suggests that a relatively simple blood test could eventually provide doctors with additional information when estimating an individual's likelihood of developing cognitive difficulties.

"This is a critical step toward better understanding what p-tau217 can tell us about a person's risk for cognitive impairment," said lead author Rachel F. Buckley, PhD, a cognitive neuroscientist with the Mass General Brigham Neuroscience Institute. "What really sets this work apart is that it estimates an individual's level of risk for cognitive impairment. We harmonized data across six cohorts, creating a large and varied data set, and still found consistent results showing how p-tau217 informs risk over time."

    Rather than simply identifying biological changes associated with Alzheimer's, the research helps estimate how those changes translate into the probability of developing symptoms over a specific period.

Why Alzheimer's Blood Tests Are Not Yet Recommended for Healthy People

    Despite the promising results, the researchers caution that blood tests are not currently recommended for routine Alzheimer's risk screening in people without symptoms.

    One major reason is that preventive treatments capable of changing the course of the disease have not yet been established for otherwise healthy individuals identified as being at elevated risk.

"We do not yet have disease-modifying treatments for people who find out they are at high risk for developing cognitive impairment due to Alzheimer's disease, which is why we don't recommend currently available blood tests for asymptomatic individuals. Today, our medical advice would remain the same regardless of test results: exercise regularly, maintain a healthy diet, and prioritize sleep and overall wellness," said senior and corresponding author Reisa Sperling, MD, a neurologist with the Mass General Brigham Neuroscience Institute. "But the preventive care landscape could change rapidly if ongoing trials of disease-modifying therapies prove beneficial. In the future, these tests could help identify those who might benefit most from these treatments. Our long-term goal is to get us to where cholesterol testing is in predicting your risk of a heart attack."

    There are also important limitations to the research. Although the investigators brought together data from multiple studies and geographic regions, the participants may not fully represent the broader population. This potential selection bias could affect how well the findings apply to other groups.

    In addition, the analysis focused on predicting cognitive impairment over relatively limited periods rather than estimating a person's lifetime risk. Researchers say larger, more representative studies and longer follow-up periods will be needed to confirm the findings and improve the precision of individual risk predictions.

Could Blood Tests Help Prevent Alzheimer's Before Symptoms Begin

    The greatest potential benefit of this approach may emerge as scientists develop treatments designed to slow or prevent Alzheimer's-related cognitive decline before noticeable symptoms develop.

    Several clinical trials are already investigating whether disease-modifying therapies can benefit people who have biological signs of Alzheimer's but have not yet experienced cognitive impairment. If those treatments prove effective, blood biomarkers such as p-tau217 could help identify individuals most likely to benefit from early intervention.

    Such an approach could eventually make Alzheimer's prevention more similar to cardiovascular prevention, where cholesterol measurements help doctors estimate future heart attack risk and determine who may benefit from treatment.

    For now, the blood test offers researchers a way to identify higher-risk individuals who may be suitable candidates for prevention studies.

"Today, p-tau217 can help identify people at high risk for future Alzheimer's dementia for participation in prevention trials," said Sperling. "As these trials move forward, individualized estimates, including the biomarker's prognostic value, could guide earlier treatment and monitoring decisions."

    Authorship: In addition to Sperling and Buckley, Mass General Brigham authors include Diana L. Townsend, Colin J. Birkenbihl, Madison Cuppels, Gillian T. Coughlan, Mabel T. Seto, Jane A. Brown, Michael J. Properzi, Merle C. Hönig, Annie Li, Aaron P. Schultz, Jasmeer Chhatwal, Hyun-Sik Yang, Steven Arnold, Pia Kivisäkk, Brian Healy, Jorge Garcia Condado, Wai-Ying Wendy Yau, Michelle Farrell, Rebecca E. Amariglio, Dorene M. Rentz, Kathryn V. Papp, and Keith A. Johnson. Additional authors include Bryan D. James, Sid O'Bryant, Robert A. Rissman, Melissa Petersen, Jessica Z. K. Caldwell, Tobey Betthauser, Julie Elisabeth Oomens, Maria Carrigan, Sterling C. Johnson, Oliver Langford, Ron Brookmeyer, Timothy J. Hohman, Michael Donohue, and Paul S. Aisen.

    Disclosures: Buckley reported receiving grants from the National Institutes of Health (NIH) outside the submitted work. Sperling reported receiving grants from NIH (A4; R01 AG063689, U24AG057437), GHR Foundation, and Alzheimer's Association during the conduct of the study; consulting for AbbVie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Ionis, Immunobrain, Janssen, Novo Nordisk, Oligomerix, Prothena, Roche, Therini, and Vaxxinity; and public-private partnership clinical trial funding from Eisai and Eli Lilly outside the submitted work. Additional author disclosures are available in the JAMA paper's disclosures section.

    Funding: This study received partial funding from the National Institutes of Health (R01AG079142, DP2AG082342, U01 AG024904, R01AG054073, R01AG058533, R01AG070862, P41EB015922, U19AG078109, R01AG027161, R01AG021155, P30AG062715, U19AG010483, R01AG063689, P01 AG036694, P41EB015896, S10RR021110, S10RR023401, S10RR023043, P30AG062421), the U.S. Department of Defense (W81XWH-12-2-0012), Eli Lilly, the Alzheimer's Association, Accelerating Medicines Partnership, the GHR Foundation, an anonymous foundation, and private donors. Additional in-kind support was provided by Avid, Cogstate, Albert Einstein College of Medicine, Foundation for Neurologic Diseases, and Meso Scale Diagnostics.