'Tau Blood Test May Detect Alzheimer’s Disease Risk Years Before Brain Changes'

 A tau blood test may be able to predict Alzheimer’s disease (AD) years before brain scans reveal pathology or symptoms develop.

In a longitudinal cohort of cognitively healthy older adults, investigators found elevated baseline levels of plasma phosphorylated tau 217 (pTau217) predicted faster accumulation of AD pathology on imaging.

“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,” study investigator Hyun-Sik Yang, MD, neurologist at Neuroscience Institute, Mass General Brigham, in Boston, said in a statement.

“We used to think that PET scan detection was the earliest sign of Alzheimer’s disease progression, revealing amyloid accumulation in the brain 10-20 years before symptoms appear. But now we are seeing that pTau217 can be detected years earlier, well before clear abnormalities appear on amyloid PET scans,” Yang said.

Equally important, Yang added, is that the data show that individuals with low baseline pTau217 levels are likely to stay amyloid-negative for several years.

The study was published online on April 14 in Nature Communications.

Early Predictive Power

To test the early predictive power of plasma pTau217, the researchers followed 317 cognitively unimpaired older adults from the Harvard Aging Brain Study for an average of 8 years, with repeated blood tests, amyloid and tau PET scans, and cognitive testing.

Baseline plasma %pTau217 was strongly associated with baseline brain amyloid-beta burden measured by amyloid-beta PET. The biomarker classified amyloid-beta status with high accuracy (area under the curve, 0.94), with sensitivity and specificity of 0.89 and 0.90, respectively, at the 4.2% threshold recommended in the assay used for the study.

Higher baseline plasma %pTau217 was associated with a longitudinal increase in brain amyloid-beta measured by PET. Even among individuals who were amyloid-negative at baseline, higher pTau217 predicted future increases; those in the highest tertile were less likely to remain amyloid-negative at 6 years than those in the lowest tertile (72% vs 98%).

Notably, the investigators reported, the trajectory of %pTau217 and amyloid-beta Centiloid over time followed a “sigmoid curve, suggesting that plasma %pTau217 increases before substantial cortical amyloid-beta accumulation.”

Participants who were amyloid-beta-negative and had very low pTau217 (below ~2.6% in this cohort) rarely became amyloid-beta-positive, suggesting this subgroup may be low risk and might not require amyloid-beta PET until pTau217 rises, the researchers said.

Higher baseline plasma %pTau217 also predicted tau accumulation in the brain — even when amyloid levels were still low, suggesting it captures very early disease processes.

In terms of cognition, across the full cohort, higher plasma pTau217 was associated with faster decline on a composite cognitive score. However, this relationship was largely driven by individuals who already had elevated amyloid; among amyloid-negative participants, pTau217 did not significantly predict cognitive decline over the follow-up period.

Further analysis suggested a cascade in which elevated baseline pTau217 leads to amyloid accumulation, which then drives tau buildup, ultimately resulting in cognitive decline.

Not Ready for Prime Time

While promising, the results do not yet support widespread clinical screening using pTau217 alone without confirmatory testing, the authors said.

“For now, pTau217 as a screening test, would not be advised because we don’t know the clinical benefit of doing that and because there’s no intervention that has been shown to be effective in this early stage,” Yang told Medscape Medical News.

“However, in research, if we screen people, and they have very low pTau217, the question is — do we even need to repeat an amyloid PET or do we even need to enroll them in Alzheimer’s studies? That’s something that we need to look into,” Yang said.

Reached for comment, Maria C. Carrillo, PhD, chief science officer and medical affairs lead at the Alzheimer’s Association, said this new study “adds to growing scientific evidence” that the plasma biomarker pTau217 is a strong indicator of AD disease pathology buildup in the brain.

What’s novel here, said Carrillo, is that plasma pTau217 may detect initial buildup of AD-related brain changes before they can be detected by current “gold standard” tests, such as PET scans.

“As the Alzheimer’s Association and all other stakeholders in this field anticipate results of clinical trials of disease modifying treatments in people with preclinical Alzheimer’s, the urgency for accurate, dependable, and accessible diagnosis at this earliest stage of the disease is high,” Carrillo told Medscape Medical News.

To help dementia specialists navigate the fast-changing landscape of blood testing, the Alzheimer’s Association recently released its first-ever clinical practice guideline for use of AD blood tests in specialty care settings.

“The guideline gives specialists evidence-based advice on who should get tested, which test to use, and how to interpret the results. It will be updated as new research emerges,” Carrillo said.

The study was supported by grants from the National Institute on Aging and the Shelby Cullom Davis Charitable Fund. Disclosures for study authors are available in the original study publication. Carrillo had no relevant disclosures.

https://www.medscape.com/viewarticle/tau-blood-test-detects-alzheimers-disease-risk-years-before-2026a1000cn0