Summary: Blood tests from participants in an Alzheimer’s research program detected elevated levels of a specific form of tau protein — phosphorylated tau 217 — that closely tracked the presence of amyloid plaques in the brain. Individuals with amyloid accumulation had as much as two to three times the amount of this tau species in their blood compared with those without amyloid, and these elevated levels were measurable even in people who showed no cognitive symptoms.
Source: WUSTL
Researchers at Washington University School of Medicine in St. Louis report that a particular form of the tau protein can be measured in blood and is strongly associated with amyloid plaque buildup in the brain — a hallmark of Alzheimer’s disease that begins to develop decades before clinical symptoms appear. The work, published July 28 in the Journal of Experimental Medicine, points to phosphorylated tau 217 as a promising marker for detecting Alzheimer’s pathology in the preclinical stage.
“Identifying a tau species that reliably reflects changes driven by amyloid plaques could help predict who has, or is likely to develop, Alzheimer’s disease,” said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and senior author of the study. “A blood-based diagnostic that detects early disease biology would accelerate research and clinical trials and improve how we screen patients in clinical practice.”
Alzheimer’s disease typically begins with a long, silent phase that can last 20 years or more, during which amyloid plaques gradually accumulate in the brain without producing clear cognitive symptoms. Because this preclinical window presents the best opportunity for preventive treatment, scientists have long sought affordable, scalable tests that identify people harboring these early brain changes before memory or thinking problems emerge.
While positron emission tomography (PET) scans can visualize amyloid plaques, they are costly and not practical for widespread screening. Blood tests that reliably indicate the presence of amyloid-related brain changes would therefore be a major advance. The Washington University team had already been developing a blood assay to detect amyloid itself, and in the current study they investigated whether a specific tau form in blood could serve as a complementary indicator of amyloid-associated brain changes.
Earlier work by the group showed that particular tau species appear in cerebrospinal fluid (CSF) of people with amyloid plaques. Because lumbar puncture to obtain CSF is invasive and not always acceptable to participants, the investigators explored whether those same tau forms could be detected in blood, where proteins from the central nervous system can sometimes be measured.
The team analyzed blood samples and brain imaging from two independent cohorts enrolled at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center. In the initial cohort of 34 people, 19 had no amyloid on PET scans, five had amyloid but no cognitive symptoms, and 10 had both amyloid and cognitive impairment. Using mass spectrometry to profile tau species in plasma, the researchers found that levels of phosphorylated tau 217 (p-tau217) correlated with amyloid plaque presence. Individuals with amyloid had approximately two to three times higher blood p-tau217 than those without amyloid, and these elevated concentrations were detectable even among cognitively normal participants who nonetheless had brain amyloid.
To confirm the initial results, researchers repeated the analysis in a validation group of 92 participants: 42 amyloid-negative individuals, 20 who had amyloid but remained cognitively unimpaired, and 30 who had both amyloid and cognitive symptoms. In this larger set, blood p-tau217 distinguished people with brain amyloid from those without with better than 90% accuracy. Restricting the analysis to only cognitively normal participants, blood p-tau217 differentiated those in the asymptomatic, amyloid-positive stage from amyloid-negative controls with about 86% accuracy.
“This is an exploratory study, but p-tau217 appears to be a strong candidate for an early diagnostic blood marker,” said first author Nicolas Barthélemy, PhD. “We observed a substantial separation between amyloid-positive and amyloid-negative groups, including among people who were cognitively normal. The current assay required a relatively large blood volume, but we are optimizing sample preparation and concentration to reduce that requirement. Those improvements will bring us closer to a practical tau-based blood test to identify people at risk for Alzheimer’s dementia before clinical symptoms appear.”
About this Alzheimer’s disease research article
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WUSTL
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Judy Martin Finch – WUSTL
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Original Research: The study appears in the Journal of Experimental Medicine.