25 Jan 2024

Not so long ago, a blood test for Alzheimer’s disease seemed a pipe dream. Now, after years of study, the field is awash with sensitive assays that signal the proteopathic culprits Aβ and tau coalescing in the brain. As these blood tests vie for regulatory approval, they stand poised to deliver more accurate diagnoses and, by extension, effective treatments, to people beyond the reach of tertiary care memory clinics or costly scans. Many see primary care clinics as the best place to make good on this promise. And yet, before family doctors start ordering up blood tests, critical questions loom. Around the globe, researchers are gearing up to address them.

For one, researchers are gauging how the plasma tests—largely developed within highly curated research cohorts—perform among the much more diverse swath of patients visiting primary care doctors. Researchers are tracking how well the biomarkers line up with gold-standard tests such as amyloid-PET, and how consistently they predict cognitive decline in primary care patients. They are also surveying general practitioners to gauge what they know and how they feel about using these blood tests, and if and how they might use them to guide diagnosis or referrals.

Meanwhile, some scientists believe that blood tests are not ready for use in primary care settings, because there, they stand a high chance of being misinterpreted. More work needs to be done to understand how the biomarkers work in memory clinics, where the blood results can be considered by specialists in a broader context of other data. These scientists study how the blood biomarker results influence patient diagnoses, treatment, and care, and to what extent the blood tests can replace more cumbersome or expensive diagnostics.

Read on to learn how global efforts could move AD blood tests from the highly controlled confines of research institutions out into the real world.

Primary Care: The Sweet Spot for AD Blood Tests?
To many scientists, access is the most important advantage blood-based biomarkers have over costlier or more invasive diagnostics, such as PET scans and CSF analysis. Primary care seems the optimal place to capitalize on that. That said, researchers and clinicians agreed that a sizable knowledge gap separates the world of primary care and the leading edge of biomarker science. Closing it is essential, particularly given the dearth of access to specialty memory clinics, believes Michael Schöll of the University of Gothenburg, Sweden. Schöll is about to start a blood-based biomarker study in primary care clinics in Sweden, which aims to integrate the markers into the country's healthcare system. Raising awareness of the biomarkers among doctors is no small part of it. “Half of what we do is education,” he said.

Randall Bateman of Washington University in St. Louis views the expanded use of blood biomarkers as essential to vanquishing AD. With the recent approval of amyloid-targeted therapies, and lengthy queues for precious few memory clinics, the need to implement AD blood tests at the primary care level has become urgent, Bateman told Alzforum. Beyond Schöll and Bateman, researchers around the globe are preparing studies that will test biomarkers in primary care clinics.

Bateman, a co-founder of blood-based biomarker frontrunner C2N Diagnostics, will lead SUNBIRD. This upcoming study aims to integrate and validate blood biomarkers in a dozen primary care clinics in the St. Louis area. SUNBIRD is the primary care version of an ongoing community-based study called SEABIRD, which is validating blood-based biomarkers, including Aβ42/40 and several p-tau epitopes, in some 1,100 local participants. In this cohort of mostly cognitively normal people, plasma p-tau217 identified those who had amyloid plaques in their brains (Jul 2020 conference news).

SUNBIRD aims to enroll 1,000 people aged 60 and older, about 80 percent of whom will have cognitive symptoms, directly from primary care clinics instead of from the community at large. SEABIRD participants can enroll through primary care clinics, as well. There, Bateman’s team will administer brief cognitive screens and collect blood samples. Patients found to be impaired will be offered amyloid- and tau-PET scans as well as more extensive neuropsychological tests for comparison with the blood biomarkers. Then, the researchers will support the primary care doctors in interpreting the results of these tests and disclose them to participants.

In addition to plasma Aβ42/40 and p-tau-217, which track with amyloid plaques, SUNBIRD will also measure plasma MTBR-tau-243, a tau fragment that correlates with tau-PET and impending cognitive decline (Aug 2023 conference news). Because amyloid plaques can brew for years without causing memory problems, the presence of plaques alone does not cement a diagnosis of AD, Bateman emphasized. A positive MTBR-tau-243 test could strengthen a physician's confidence that a patient’s current cognitive problems are due to AD, he said. He views blood biomarkers as a tool to empower primary care physicians to make more informed diagnoses, and to refer patients for further screening and potentially treatment with amyloid-lowering drugs. Pending NIH funding, SUNBIRD is slated to begin in March, Bateman said.

Several European studies are investigating how the blood tests might fit into the continent's multifarious healthcare systems. In the Netherlands, Charlotte Teunissen of Amsterdam University Medical Center and colleagues have just begun the CANTATE primary care study. It aims to enroll 400 participants age 50 and older who come into any of 40 participating primary care clinics with cognitive complaints. Following cognitive screens and blood draws in the clinic, blood biomarkers including Aβ peptides, NfL, GFAP, and p-tau-181 will be measured via Quanterix’s Simoa assays, and the results—expressed as an AD probability score based on the combined readings—will be shared with general practitioners. Six months later, Teunissen and colleagues will follow up with the doctors. They'll assess how the plasma biomarker results aligned with their working diagnosis, with the patient’s cognitive and functional status, and if and how the blood test influenced the patient’s subsequent care.

When CANTATE first started, many primary care physicians were hesitant to incorporate blood biomarkers into their practice, Amsterdam UMC’s Thomas Claessen told Alzforum. Some were unaccustomed to viewing AD as a biological construct, let alone with the concept of using biomarkers to inform their diagnosis of the disease. This reticence prompted the scientists to start a second line of research to survey attitudes of primary care physicians about the biomarkers. The surveys indicate that after learning what the biomarkers reflect, some doctors believe they can help patients and their families plan for the future, for example by preparing for likely symptoms and arranging appropriate care. However, others questioned the purpose of a biological diagnosis in the absence of treatments, and worried about the consequences of telling a person they have amyloid plaques in their brain without a way to reduce them. Many said that they might change their minds once such a treatment becomes available in the Netherlands. The European Medicines Agency is considering lecanemab, and is expected to render a decision before summer 2024. If it approves, having blood biomarkers integrated into primary care will help funnel the appropriate patients toward this treatment.

Primary care physicians are asking what the diagnostic and prognostic value of the blood tests is, hence this is a key question for CANTATE to answer, explained Argonde van Harten of Amsterdam UMC. In research cohorts, the most sensitive combinations of plasma biomarkers, such as Aβ42/40 and p-tau217, detect amyloidosis with an accuracy well above 90 percent (see, for example, Jan 2024 news). However, these participants typically have fewer comorbidities that contribute to symptoms. “We want to know the spectrum of functional and cognitive impairment that primary care physicians encounter, and how blood biomarkers track with that,” van Harten said.

Van Harten understands why primary care doctors are not yet integrating AD blood tests into their practices. These busy doctors must keep up with developments in multiple fields while managing heavy caseloads. Without an amyloid-lowering drug in hand, no wonder new, difficult-to-interpret blood tests are not their priority, she said. She hopes this study will prepare primary care physicians to use the markers while treatments are wending their way through the regulatory process.

Up north in Sweden, scientists are also readying AD blood tests for primary care. General practitioners in that country make the majority of AD diagnoses, and most patients never set foot inside the country’s few memory clinics, explained Oskar Hansson of Lund University. He and Sebastian Palmqvist head BioFINDER-primary care, an ongoing study to validate a barrage of blood biomarkers tests in participants from 25 such clinics across southern Sweden. The study has so far enrolled more than half of its planned 1,200 participants, who come to see their doctor with cognitive symptoms ranging from subjective cognitive decline to dementia.

Compared to the Swedish BioFINDER memory clinic cohort, enrollees from primary care average three to four years older, in their early 70s, and are likelier to have comorbidities such as vascular problems, Palmqvist said. About a third have chronic kidney failure. Recent studies suggest that comorbidities, and some of the medications used to treat them, might skew AD biomarker levels—something the scientists are investigating in this population (Aug 2022 conference news; Dec 2023 news). All participants will be asked to return for follow-up at the memory clinic, where they will undergo extensive neuropsychological testing, CSF biomarker measurements, and PET.

To validate blood biomarkers for primary care, BioFINDER-PC researchers will send its participants' blood samples to several locations to compare different assays that measure Aβ peptide ratios and/or p-tau epitopes. These include C2N Diagnostics’ mass-spectrometry based assay, as well as tests developed by Eli Lilly and Janssen. A Lumipulse-based plasma biomarker test that measures Aβ42/40, p-tau217, and NfL has also been added to the mix; it will be run in Kaj Blennow’s lab at the University of Gothenburg. The scientists will then evaluate the various tests' concordance with CSF and PET.

Palmqvist told Alzforum that two messages are already emerging from this ongoing study. One: Collection and handling of blood samples in primary care clinics works just fine. It does not compromise accuracy. Two: Some tests are more swayed by comorbidities than others. At 90-95 percent concordance with CSF biomarker readings, C2N’s appears to be the most robust so far.

Notably, half the participants enrolled thus far are positive for CSF Aβ42/40 and p-tau-217, suggesting their prevalence of amyloidosis is quite high. This begs the question: How should primary care docs interpret a positive biomarker reading for their patients? Does everyone with such a reading have AD? “It takes experience to interpret that result for the person you have in front of you,” Palmqvist told Alzforum. “Just because you have an accurate blood test doesn’t mean that it should automatically be used in primary care.”

To this end, BioFINDER-PC, like CANTATE and SUNBIRD, will track how blood biomarker results match primary care diagnoses, and whether knowing the results influences that diagnosis. One concern, Hansson said, is that doctors may rely on the tests too heavily, diagnosing anyone who tests positive with AD without adequately exploring other reasons for their cognitive problem. At the other end of the spectrum, some doctors may not want to rely on the tests at all, Hansson said.

On Sweden's west coast, UGot's Schöll and colleagues are preparing a different study, called REAL AD. It tries to lay the logistical groundwork for widespread use of AD biomarkers to screen for preclinical AD. Having a screening pipeline in place will come in handy once disease-modifying therapies can be prescribed in Sweden, Schöll told Alzforum. The study will recruit participants from the community but will converge on primary care.

Getting Real. RealAD aims to recruit more than 3,000 people from Sweden’s Västra Götaland Region (VGR) to take online cognitive tests and give blood for biomarker testing. Clinical validation will be done with a subset of 440 volunteers. [Courtesy of Michael Schöll, University of Gothenburg.]

With the help of a Swedish PR firm, Schöll’s RealAD study is seeking up to 4,000 participants aged 50-80. They will take online cognitive assessments on the Neotiv digital platform, which detects subtle episodic memory deficits that start at the preclinical stage of AD (Dec 2021 conference news). After an initial round of remote testing, participants will be asked to visit any of 111 primary care clinics for a blood draw. It will be tested for an exhaustive panel of markers in Blennow’s lab at the University of Gothenburg. Eighteen months later, participants will be invited for another round of remote testing and blood biomarker measurement, followed by cognitive testing alone at 27 and 36 months. Schöll told Alzforum that, as of now, biomarker results will not be disclosed to participants.

A subset of 440 volunteers will undergo CSF or PET to validate the blood tests, though this is not the study's main focus. Rather, it’s to pave the way for blood-based biomarker integration into the Swedish healthcare system, and to understand how prevalent biomarker positivity is in a natural cohort. “It’s about creating this knowledge base, and about making healthcare providers aware that these biomarkers are around the corner,” Schöll said.

Biomarkers as Triage?
To the mind of Sid O’Bryant at University of North Texas Health Science Center in Fort Worth, Texas, blood biomarkers can shine in primary care not to diagnose AD, but to rule it out. He says that this use is what primary care doctors are excited about in his area.

His team has designed a 21-protein panel to attempt just that. The panel includes a host of inflammatory and metabolic proteins that together can rule out clinically defined AD with an accuracy well above 90 percent (O’Bryant et al., 2016; O’Bryant et al., 2021). Neither Aβ nor tau are in it, as these proteins require more costly equipment to measure, O’Bryant said. His group test runs on the Luminex platform, which is widely used in clinics, making the test cheap and scalable. The panel’s high negative predictive value would ideally enable primary care doctors to rule AD out for a majority of their patients and focus on other health or lifestyle factors, or other neurodegenerative diseases, that might explain the cognitive problems that drove them to see their doctor. Along those lines, O’Bryant’s lab has also developed tests to rule out PD in primary care (O’Bryant et al., 2022). 

“Our hope is to get a series of tests available to help primary care providers have tools to make informed and timely decisions on which patients should be referred, and to whom they should be referred,” O’Bryant said.

Patients with abnormal biomarkers can be referred to memory clinics for confirmatory testing. O’Bryant considers Simoa- and mass-spec-based plasma biomarker tests of Aβ and p-tau epitopes, which have a high positive predictive value, to be second-line tests. People positive on these can be referred for even costlier tests such as PET scans if necessary. Triaging people with a cheap and quick first-line test will stem the tide of “worried well” who flood memory clinic wait-lists, reducing healthcare costs, O’Bryant said. It also greases the wheels for people who test positive on first-line triage panels to get the care they need.

O’Bryant argues that “rule-out AD triage” could be done anywhere people are seeing their doctors, even urgent-care clinics or emergency rooms, extending their reach to people who don’t have a primary care doctor.

O’Bryant’s group is currently analyzing data from a recently completed study, in which they tested two different versions of their blood biomarker panel in 500 people 65 or older who came to primary care clinics in the Dallas/Fort Worth area with cognitive concerns. After a brief cognitive screen and blood draw at their doctor’s office, enrollees visited O’Bryant's memory clinic for amyloid-PET scans and an extensive cognitive work-up. The researchers are validating their panels against gold-standard biomarkers, to find the best triage test in the primary care population.

The argument for using blood biomarkers to triage primary care referrals jibes with a report the RAND Corporation will release next week. It analyzed bottlenecks in U.S. healthcare that impede access to Alzheimer's treatments, and landed on primary care (see Feb 2024 news).

Premature for Primary Care? Even as many scientists steer blood biomarkers toward primary care, others see secondary and tertiary care as their appropriate place, at least for now. Nicolas Villain of Sorbonne University in Paris heads a study to position blood biomarkers as a first-line AD test in memory clinics. As in many other countries, in France patients with cognitive complaints are referred by their primary physicians to secondary specialists, such as geriatricians or general neurologists, who then refer them to tertiary memory clinics if an underlying neurodegenerative disease such as AD is suspected. Once there, all patients get lumbar punctures to measure CSF biomarkers. Villain would like to see blood draws supplant the spinal jabs whenever possible.

To see if this is feasible, Villain's team ask if ApoE genotype combined with plasma p-tau-217 can predict who among 400 memory clinic patients is positive on CSF-based biomarkers. Similar questions have been addressed in the Swedish BioFINDER research cohort (Brum et al., 2023; Nov 2023 conference news). The French cohort will include more people across a range of cognitive problems and comorbidities. The researchers will test blood samples as they come in, instead of retrospectively testing them in tightly controlled batches. The added variability from this will put the biomarkers to the test in a real-world cohort under real-world conditions, Villain said.

Why not do this in primary care? Villain believes blood biomarkers should only be used alongside cognitive testing, and interpreted by an expert who knows what the tests mean. If expanded to broad use too quickly, the chance of misdiagnosis is high. “Far from all people with an abnormal plasma p-tau-217 test will develop dementia during their lifetime,” Villain said. Since age, health, and lifestyle factors influence the emergence of AD symptoms, biomarkers need to be interpreted in context, he added.

That said, should a safe and effective treatment that prevents AD become available, Villain envisions AD blood tests being used, perhaps in combination with standardized, digital cognitive tests, to screen for AD in primary care. “The field may eventually go in this direction, but right now using blood biomarkers in primary care is premature,” he said.

James Rowe of the University of Cambridge, U.K., agrees. Rowe is a proponent of plasma biomarkers but worries about potential misuse. He believes for now, blood tests should only be part of a full clinical assessment by a specialist. People with abnormal biomarkers could be misdiagnosed with AD, when perhaps other common, and treatable, conditions might underlie their current symptoms. The psychological and physical repercussions of such a diagnosis—in the absence of effective and available disease-modifying treatments—could be disastrous for some people, he said. The same goes for cognitively normal people who test positive for the biomarkers. “If you take a healthy person with a benignly high biomarker and change their health status to AD, you’ve done harm,” Rowe said.

While some researchers believe a negative AD blood test might steer a person toward proper diagnosis of other dementias such as FTD, Rowe thinks the opposite might happen in a primary care clinic, where few physicians are familiar with other dementias. “The doctor might say, ‘Your dementia test is negative,’ and send them on their way,” Rowe said.

Rowe wants to investigate how best to embed blood biomarkers within healthcare pathways where other causes of cognitive impairment are being considered. He also wants to study how blood biomarker tests affect the health, well-being, and care of the people who receive them.

Rowe and other U.K. scientists are vying for a £5 million grant to assess blood biomarker integration into the country’s national health service. Funded by the People’s Postcode Lottery—i.e., proceeds from the country's lottery—the Blood Biomarker Challenge, a collaboration between the Alzheimer’s Society, Alzheimer’s Research U.K., and the National Institute for Health and Care Research, focuses on validating biomarkers in secondary and tertiary care, not primary.

Jonathan Schott of University College London believes the inevitable arrival of disease-modifying drugs, such as lecanemab, is putting pressure on the U.K. healthcare system to integrate blood biomarkers into the pathway for diagnosis. “Drugs are forcing this issue onto people’s radars, but even without drugs, evidence is clear that there are benefits for an accurate diagnosis,” Schott added. While he foresees one day using blood biomarkers in primary-care settings for screening, validating them carefully in memory clinics and in diverse populations is the priority of the moment, he said.—Jessica Shugart

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References

News Citations

1. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics 29 Jul 2020
2. CSF MTBR-tau-243 Tracks Tangles, Plummets in Response to Antibody 31 Jul 2023
3. Paper Alert: p-Tau217 Blood Test Predicts Plaques, Tangles Over Time 24 Jan 2024
4. Blood Tests: Charting the Path to Primary Care 23 Aug 2022
5. Heart Failure Drug Drastically Skews Blood Aβ 28 Dec 2023
6. Bringing Alzheimer’s Detection into the Digital Age 9 Dec 2021
7. Moving Alzheimer’s Diagnosis to Primary Care Could Ease Bottlenecks 6 Feb 2024
8. Plasma p-Tau-217 Assays Work Well, But No Home Run for Diagnosis 30 Nov 2023

Paper Citations

1. O'Bryant SE, Edwards M, Johnson L, Hall J, Villarreal AE, Britton GB, Quiceno M, Cullum CM, Graff-Radford NR. A blood screening test for Alzheimer's disease. Alzheimers Dement (Amst). 2016;3:83-90. Epub 2016 Jun 25 PubMed.
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3. O'Bryant SE, Petersen M, Zhang F, Johnson L, German D, Hall J. Parkinson's Disease Blood Test for Primary Care. J Alzheimers Dis Parkinsonism. 2022;12(4) Epub 2022 Jul 22 PubMed.
4. Brum WS, Cullen NC, Janelidze S, Ashton NJ, Zimmer ER, Therriault J, Benedet AL, Rahmouni N, Tissot C, Stevenson J, Servaes S, Triana-Baltzer G, Kolb HC, Palmqvist S, Stomrud E, Rosa-Neto P, Blennow K, Hansson O. A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases. Nat Aging. 2023 Sep;3(9):1079-1090. Epub 2023 Aug 31 PubMed.

Other Citations

Further Reading

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