After successful treatment for Alzheimer’s disease, a blood test for amyloid plaques and tau tangles lurking in the brain has been one of the most urgently needed in the field. And in recent years he began to be satisfied. Whether by plasma Aβ42/Aβ40 or, more surprisingly, by an increasing number of phospho-tau species, the presence of amyloid plaques in the brain can now be detected in the blood. That said, these findings come from research cohorts and, recently, clinical trials, with homogeneous, predominantly white populations selected using various inclusion criteria. How will these biomarkers behave in the real world, where people have diverse genetic, social, and cultural backgrounds and live with different comorbidities? As the number of biomarkers and tests to measure them continues to grow, questions of implementation are beginning to arise. How to choose among these tests? What kind of patient should get them? Should they be limited to memory clinics? Should any primary care physician be able to order them? And how best to interpret the results and inform the patient?

  • A group of experts urges that blood biomarkers be used for symptomatic people in specialist clinics, for now.
  • Direct comparisons of blood biomarkers in different cohorts suggest that many amyloid detection tests work well.
  • Comorbidities such as renal dysfunction can skew the results.

The Alzheimer’s Association’s international conference, held July 31-August 4 in San Diego and online, showcased these and other looming issues facing the field as a whole. Blood biomarkers were a hot topic at the meeting. More than 100 presentations presented findings linking various markers and tests to amyloid plaques, tau tangles, and cognitive decline, while addressing practical questions about how to incorporate them into clinical practice. Below, learn how AAIC scientists came up with guidelines for the recommended use of these tests and charted a course from exploration to implementation. In Part 2, learn how direct comparisons of biomarkers in community cohorts reveal an abundance of robust testing. Part 3 of this story summarizes the logistical, technical, and ethical dilemmas of moving testing into doctors’ offices, including early probes into how common comorbidities might skew biomarker test results.

Recommendations for proper use
Oskar Hanson from Lund University, Sweden, led the way by highlighting recently published recommendations for appropriate use of blood biomarkers (Hansson et al., 2022). The recommendations are a first attempt at organizing a rapidly advancing field. Hansson said it could take several more years before the field can settle on stricter criteria like those published for the amyloid-PET and CSF biomarkers. Until then, Hansson estimates that these recommendations could be changed every nine to twelve months.

At this point, how do the leading biomarker scientists suggest using the tests? In clinical trials, blood biomarkers could be used for screening purposes, either to select participants for trials in AD or to exclude participants from trials in other neurodegenerative diseases, such as dementia. frontotemporal. For now, amyloid-PET or CSF should be used to confirm a person’s amyloid status, although it may soon be possible to use plasma biomarkers as stand-alone proxies for brain amyloid. The authors also recommend using blood biomarkers to track people’s response to treatment in trials and to inform decisions about moving from early to late trials. That said, the authors believe that blood tests should not be used as primary outcomes for pivotal trials.

What about in clinical practice? For now, the guidelines would limit the use of blood biomarkers to people with cognitive symptoms who are seen in specialist memory clinics and ideally receive follow-up with amyloid-PET or CSF to confirm that they really have amyloid plaques in the brain.

At her memory clinic in Lund, Hansson plans to use blood tests in the near future to reduce the number of lumbar punctures performed. Currently, about 80% of people who visit the Lund Memory Clinic receive a wood puncture for CSF analysis, he said. This is also the case at other large sites in Sweden, such as Sahlgrenska Hospital at the University of Gothenburg. Using blood, CSF, and amyloid-PET data previously collected from patients visiting the clinic, Hansson and colleagues first sorted people into high, intermediate, or low likelihood of amyloid positivity on the based on an algorithm combining plasma p-tau217 and ApoE4 status. By limiting CSF analysis to patients with an intermediate likelihood of amyloid positivity based on the blood-based algorithm, Hansson predicted that clinicians could avoid two-thirds of spinal taps they currently perform. while maintaining 91% accuracy in detecting amyloid. Narrowing this window of uncertainty further could save even more patients the hassle of a lumbar puncture, with minimal decline in amyloid detection accuracy, Hansson reported.

So long, LP? Plasma p-tau217 plus ApoE4 status predicts the likelihood that a person with MCI will have cerebral amyloid. When lumbar puncture for CSF Aβ42/40 measurements is performed on people with an intermediate probability (yellow), two-thirds of those pesky punches could be avoided while capturing amyloid positivity with 91% accuracy. [Courtesy of Oskar Hansson, Lund University.]

“Of course, the real game changer will be the use of blood biomarkers in primary care,” Hansson told the audience. The current restriction to specialized memory clinics stems in large part from the need to pursue studies in more diverse settings.

Hansson called these early recommendations conservative by design because much work remains to be done before blood biomarkers can be widely available. Besides evaluation in diverse populations, blood tests require side-by-side comparisons of different tests and careful consideration of potential confounders that may influence the results. They need prospective evaluation in trials, in specialty clinics, and in primary care, and the healthcare logistics of equitable biomarker deployment have yet to be resolved.

Road to implementation. Getting blood biomarkers to a medical clinic near you requires many steps, including prospective studies in different populations. [Courtesy of Teunissen et al., Lancet Neurology, 2022.]

Charlotte Teunissen from the University Medical Center Amsterdam co-authored the appropriate recommendations for use. She stressed that much more needs to be done before patients can access it as part of routine medical care. Teunissen presented a recently released roadmap of five biomarker development phases. Phase 1 includes exploratory and preclinical studies of biomarkers, while Phase 2 includes the development and validation of clinical trials. In phase 3, researchers conduct retrospective and longitudinal studies. In phase 4, the “real-world performance” of biomarkers is tested in prospective studies, and phase 5 involves ironing out all the practical and ethical details of their use in clinics and primary care (Teunissen et al. al., 2022). For the most part, phases 1 and 2 are complete for Aβ, p-tau and NfL. Work on phases 1 and 2 for GFAP, and on phase 3 for all blood biomarkers, is ongoing. Phases 4 and 5 still need to be processed for all markers.

Teunissen and colleagues expect the use of blood biomarkers in memory clinics to peak within the next three to five years, while their implementation as diagnostic aids in primary care could be expected within the next five to 10 years.

“It’s a rushing field,” Teunissen said. “But we still have a lot of work to do.”

Many of the biomarker discoveries presented at AAIC focused on Phase 3 of Teunissen’s roadmap, as researchers took blood banked samples from different community cohorts to directly compare leading biomarker candidates. (see part 2 of this series). Others looked forward to the final two rounds and pondered the technical, practical, and ethical issues that are sure to arise as biomarkers become more widely available (part 3 in the series).—Jessica Shugart

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paper quotes

  1. .
    Alzheimer’s Association Appropriate Use Recommendations for Blood Biomarkers in Alzheimer’s Disease.
    Alzheimer’s dementia. July 31, 2022;
    PubMed.
  2. .
    Blood biomarkers of Alzheimer’s disease: towards a clinical implementation.
    Neurol Lancet. 2022 Jan;21(1):66-77. Online publication 2021 November 24
    PubMed.

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