23 Aug 2022

Part 1 of 3

Second to an effective treatment for Alzheimer’s disease, a blood test for amyloid plaques and tau tangles lurking in the brain has been one of the field’s most urgent needs. And in recent years, it has started to be met. Whether by plasma Aβ42/Aβ40 or, more surprisingly, by a growing number of phospho-tau species, the presence of amyloid plaques in the brain can now be detected in the blood. That said, these discoveries come from research cohorts and, recently, clinical trials, with homogenous, largely white populations selected by way of various inclusion criteria. How will these biomarkers perform out in the real world, where people have diverse genetic, social, and cultural backgrounds, and live with different comorbidities? As the number of biomarkers, and assays to measure them, both continue to grow, implementation questions start to press in. How to choose among these tests? What type of patient should get them? Should they be restricted to memory clinics? Should any primary care doctor be able to order them? And how best to interpret results, and tell the patient?

The Alzheimer’s Association International Conference, held July 31-August 4 in San Diego and online, showcased these and other looming questions that confront the field at large. Blood-based biomarkers were a hot topic at the meeting. More than 100 presentations featured findings linking various markers and assays to amyloid plaques, tau tangles, and cognitive decline, while also grappling with practical matters of how to get them into clinical practice. Below, read on about how scientists at AAIC offered guidelines for recommended use of these tests, and charted a course from exploration to implementation. In Part 2, learn how head-to-head comparisons of the biomarkers in community-based cohorts reveal an abundance of robust assays. Part 3 of this story summarizes the logistical, technical, and ethical dilemmas of moving the tests into doctors' offices, including early probes into how common comorbidities might skew biomarker test results.

Recommendations for Appropriate Use
Oskar Hansson of Lund University, Sweden, set the stage by highlighting newly published recommendations for appropriate use of blood-based biomarkers (Hansson et al., 2022). The recommendations are a first stab at organizing a rapidly advancing field. Hansson said it may take several more years before the field can settle on more stringent criteria like those published for amyloid-PET and CSF biomarkers. Until then, Hansson estimates that these recommendations may be tweaked every nine to 12 months.

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

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

In his memory clinic at Lund, Hansson envisions using the blood tests in the near future to reduce the number of lumbar punctures performed. Currently, about 80 percent of people who visit the Lund memory clinic receive a lumber puncture for CSF analysis, he said. This is the case in other large sites in Sweden, as well, such as at University of Gothenburg's Sahlgrenska Hospital. 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 probability of amyloid positivity based on an algorithm that combined 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 projected that clinicians could avoid two-thirds of the lumbar punctures they now perform while maintaining an accuracy of 91 percent in detecting amyloid. Further narrowing that window of uncertainty could spare even more patients the hassle of a lumbar puncture, with a minimal dip in amyloid detection accuracy, Hansson reported.

“Of course, the real game-changer will be using blood biomarkers in primary care,” Hansson told the audience. The current restriction to specialized memory clinics stems largely from the need for further studies in more diverse settings.

Hansson called these first recommendations cautious by design, because much work remains to be done before blood biomarkers can be made widely available. Besides evaluation in diverse populations, blood tests need side-by-side comparisons of different assays and scrutiny of potential confounders that might influence results. They need prospective evaluation in trials, in specialist clinics, and in primary care, and the healthcare logistics of deploying biomarkers equitably still need to be solved.

Road to Implementation. The path of blood-based 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 of Amsterdam University Medical Center co-authored the appropriate-use recommendations. She stressed that much work remains before patients will be able to access them in the course of routine medical care. Teunissen outlined a recently published roadmap of five phases of biomarker development. Phase 1 involves exploratory, preclinical studies of biomarkers, while phase 2 includes the development and validation of clinical assays. In phase 3, researchers conduct retrospective and longitudinal studies. In phase 4, “real-world performance” of biomarkers is put to the test 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., 2022). For the most part, phases 1 and 2 have been completed 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 addressed for all markers.

Teunissen and colleagues expect use of blood-based biomarkers in specialist memory clinics to be in full swing within the next three to five years, while implementing them as diagnostic aids within primary care could be expected within the next five to 10 years.

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

Many of the biomarker findings presented at AAIC focused on Phase 3 of Teunissen’s roadmap, as researchers pulled banked blood samples from different community cohorts to compare the top biomarker contenders directly to each other (see Part 2 of this series). Others looked forward to the two final phases, and delved into the technical, practical, and ethical issues that are sure to arise as the biomarkers become more widely available (Part 3 of the series).—Jessica Shugart

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References

News Citations

1. Blood Tests Go Head-to-Head in Community Cohorts 23 Aug 2022
2. Blood Tests: Charting the Path to Primary Care 23 Aug 2022

Paper Citations

1. Hansson O, Edelmayer RM, Boxer AL, Carrillo MC, Mielke MM, Rabinovici GD, Salloway S, Sperling R, Zetterberg H, Teunissen CE. The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease. Alzheimers Dement. 2022 Dec;18(12):2669-2686. Epub 2022 Jul 31 PubMed.
2. Teunissen CE, Verberk IM, Thijssen EH, Vermunt L, Hansson O, Zetterberg H, van der Flier WM, Mielke MM, Del Campo M. Blood-based biomarkers for Alzheimer's disease: towards clinical implementation. Lancet Neurol. 2022 Jan;21(1):66-77. Epub 2021 Nov 24 PubMed.

Further Reading

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