TORONTO — An expert panel convened by the Alzheimer’s Association has released the first clinical guidelines to help clinicians choose the most appropriate blood-based biomarker (BBM) test to aid in the diagnosis of Alzheimer’s disease (AD).
The evidence-based guideline recommends that tests with ≥ 90% sensitivity and specificity can serve as a substitute for amyloid PET or cerebrospinal fluid (CSF) biomarker testing.
Tests with ≥ 90% sensitivity but only ≥ 75% specificity should be used as a triaging test. In this case, a negative result rules out AD pathology with high probability and a positive result should be confirmed with CSF or PET testing.
Evidence-based guidelines are key to standardizing the use of BBMs in clinical practice, Rebecca M. Edelmayer, PhD, vice president of scientific engagement for the Alzheimer’s Association, told Medscape Medical News.
“The whole purpose of developing the clinical practice guideline is to try to create pragmatic recommendations for clinicians on how to choose the right test for the right patient at the right time,” Edelmayer said.
This new guideline is the first step in a developing process, she added. “The blood-based biomarker area is still a burgeoning field.”
The findings were presented on July 29 at the Alzheimer’s Association International Conference (AAIC) 2025 and published online simultaneously in Alzheimer’s & Dementia.
Meeting a Need
With the approval of anti-amyloid beta (Aβ) therapies to treat early symptomatic disease, more rapid and accurate diagnosis of AD is becoming increasingly important. A number of different BBM tests are available to clinicians, but the lack of clinical practice guidelines has hindered more widespread use of the diagnostic tools, guidelines authors wrote.
A panel of clinical experts, researchers with experience and technical knowledge surrounding BBM, and guideline methodologists conducted a systematic review of the literature to assess the accuracy of BBMs in detecting amyloid pathology for triaging (≥ 90% sensitivity, ≥ 75% specificity) and confirmatory (≥ 90% sensitivity and specificity) diagnostic workup.
After a review of 1050 papers, 49 observational studies of 31 different BBM tests were selected for inclusion.
The BBMs of interest included plasma phosphorylated-tau (p-tau) and Aβ tests measuring these analytes: p-tau217, the ratio of p-tau217 to non-p-tau217 ×100 (%p-tau17), p-tau181, p-tau231, and the ratio of Aβ42 to Aβ40. The reference standard tests included CSF, amyloid PET, or neuropathology examination.
The relatively low-cost BBM tests are minimally invasive compared with PET and CSF tests and can significantly reduce the physical discomfort and anxiety often associated with lumbar puncture or PET imaging procedures, the authors wrote.
The systematic review focused on single analytes, not combinations of different analytes, sometimes referred to a “blood panel,” noted Edelmayer.
Using predefined decision thresholds, the panel determined whether tests have sufficient diagnostic accuracy to be used as a triaging test where a positive test is to be confirmed by PET or CSF, sufficient diagnostic accuracy as a confirmatory test to replace PET or CSF, or insufficient diagnostic accuracy to recommend current use in clinical practice.
The recommendations are focused on individuals with either mild cognitive impairment or dementia who are undergoing diagnostic assessment by providers trained and experienced in memory disorders, where AD is the suspected underlying etiology.
The guideline does not endorse specific tests or rank them.
“We just don’t have enough data at this time,” said Edelmayer. “We’re not ready to pick one single test out of a lineup of tests to say this test is performing much better in a comparative analysis and through systematic review evidence than another test.”
Accurate Predictors
Researchers now have a clearer picture of how AD pathology evolved over time, with changes in some tau biomarkers occurring very early on, said Edelmayer.
“What we’ve learned from all of the evidence so far is that some of these biomarkers, like tau 217, tend to be very accurate predictors of Alzheimer’s disease biology in the brain, and they can be used to aid in the diagnostic process early on, sometimes even before tau tangle formations can be visualized with brain imaging.”
The guideline authors noted some limitations of the evidence. For example, undesirable effects of BBM testing could include false positive or false negative results, which could delay accurate diagnosis and treatment.
The authors also cautioned that there’s significant variability in the accuracy of diagnostic tests and many commercially available BBM tests do not meet accuracy thresholds.
Edelmayer stressed this is the first iteration of the clinical practice guideline and the expert panel is already working on next steps, including determining if these biomarkers can be used as confirmatory or triage tests in cognitively unimpaired people and in a primary care setting.
The tests aren’t a substitute for comprehensive clinical evaluation by a healthcare professional, said David Knopman, MD, a clinical neurologist and researcher at the Mayo Clinic in Rochester, Minnesota, who commented on the new guidelines for Medscape Medical News.
“The use of any AD-specific biomarker is dependent on the context,” he said. “For example, the history or no history of cognitive impairment, the objective cognitive assessment, and the presence or absence of features of non-AD biologics.”
While he noted the guideline was reasonable for the separate functions of triaging and confirming AD biology, as with any such document, no matter how thoughtfully constructed, there’s the risk that people ignore stipulations in the recommendation.
“So people without cognitive impairment will be captured. There’s also the risk that the memory disorder clinic is not well versed in non-Alzheimer causes of memory impairment,” he said.
Edelmayer is an employee of the Alzheimer’s Association. Knopman reported no relevant conflicts of interest.
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