Original Source: JAMA Network
Until fairly recently, the question of whether amyloid plaque—a hallmark of Alzheimer disease—was present in the brains of individuals with cognitive impairment could be settled only after their death.
Clinicians had to fly blind because the symptoms of Alzheimer disease, the most common cause of dementia, overlapped with those of other causes. But it didn’t matter as much as it does today, given that long-used medications to treat cognitive impairment symptoms, such as cholinesterase inhibitors, approved to treat dementia due to Alzheimer or Parkinson disease, could also be prescribed off label for patients with vascular or Lewy body dementia, conditions that aren’t always associated with brain amyloid.
However, with the advent of antiamyloid monoclonal antibodies in the last couple of years, determining whether individuals with dementia have amyloid plaques in the brain has become imperative for patients considering those treatments, which can offer a modest benefit but are expensive and cumbersome and carry a risk of a potentially serious adverse effect.
Two tools, positron emission tomography (PET) scans and lumbar punctures to collect a small amount of cerebrospinal fluid, have been found to be effective for assessing amyloid plaques in the brain, but they’re also expensive and hard to access for some patients.
“Not having easy access to a brain amyloid test can prevent a person from being considered for a treatment,” noted geriatrician Heather Wilson, MD, MHS, codirector of the Duke-UNC Alzheimer’s Disease Research Center.
Moreover, PET requires that patients be injected with a radioactive tracer and lie still in a scanner for 15 or 20 minutes. A lumbar puncture, or spinal tap, is invasive and can leave patients with a headache or back pain.
The lack of a simple test for amyloid pathology in the brain has contributed to an Alzheimer disease misdiagnosis rate of 25% or higher among patients with cognitive impairment seeking care in a specialty setting. Uncertainty about their diagnosis can add to patients’ and family members’ anxiety.
In the last few years, though, a new tool became available. Blood biomarker tests, which typically measure ratios of amyloid-β and tau proteins, are more accessible and acceptable to patients. A recent Alzheimer’s Association survey found that more than 9 out of 10 adults aged 45 years or older said they would definitely or probably want to take a simple test, such as a blood biomarker test, if it were available. Early access to treatment and care was the main reason they cited for wanting a simple test for amyloid pathology.
Up until now, however, no blood biomarker test had been reviewed and cleared or authorized by the US Food and Drug Administration (FDA).
But on May 16, the FDA for the first time cleared a blood biomarker test to detect brain amyloid plaques. The Fujirebio Diagnostics Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test is indicated for use in adults 50 years or older—the FDA’s announcement about the test erroneously states that it’s only for people 55 years or older—who are exhibiting signs and symptoms of Alzheimer disease. The FDA reviewed the test through a pathway in which a manufacturer has to demonstrate that a new device is substantially equivalent to a device that is already legally marketed. In this case, that device was Fujirebio’s previously authorized Lumipulse G β-amyloid Ratio (1-42/1-40) test, which uses cerebrospinal fluid samples.
Matthew Bell, vice president for sales and marketing at Fujirebio in Malvern, Pennsylvania, said that the company expected to begin shipping the test, available for use by any Clinical Laboratory Improvement Amendment (CLIA)–certified laboratory, in June.
Alzheimer disease experts applauded the first FDA-cleared blood biomarker test, but they also raised concerns about its potential for misuse.
The relatively inexpensive blood test could help identify patients earlier in the course of their Alzheimer disease, when the likelihood that antiamyloid therapies could slow its progression is thought to be greater. On the other hand, a relatively inexpensive blood test is more likely to attract the worried well who can’t remember where they put their keys and primary care physicians who lack the time to conduct a diagnostic workup for cognitive impairment.
“The test is intended for use by specialists to assess patients who are presenting with a cognitive complaint and are being evaluated for amyloid pathology,” Bell explained. However, he added, although the test’s intended use is clearly outlined in the package insert, “we don’t have the ability to prevent clinicians from using the test off label.”
Where Do Blood Biomarker Tests Fit In?
Whether the Lumipulse test or any other blood biomarker test can replace amyloid PET scans and lumbar punctures remains to be seen.
As dementia specialists await clinical practice guidelines, they are using blood biomarker tests in 2 situations. One is to rule out or rule in amyloid pathology to aid in the diagnosis of individuals with Alzheimer disease symptoms. The other is to determine which patients considering antiamyloid therapy should be referred to PET or cerebrospinal fluid testing for confirmation of amyloid pathology.
Clinical trials have shown that the antiamyloid therapies lecanemab (Leqembi) and donanemab (Kisunla) effectively remove amyloid plaques, but some clinicians say that doesn’t always translate into clinical benefit. Lecanemab, which received traditional FDA approval in July 2023, requires that patients travel to an infusion center for treatment every 2 weeks for 18 months, at which point they might be able to switch to maintenance treatments every 4 weeks. Donanemab, which received traditional FDA approval in July 2024, requires treatments every 4 weeks at an infusion center, but stopping can be considered if amyloid PET scans show that plaques have been reduced to minimal levels.
“It was the confluence of a good plasma biomarker, pTau217, and lecanemab and donanemab becoming commercially available that really raised the level of interest in the plasma biomarker,” noted Mayo Clinic neurologist David Knopman. “And well it should, because the therapeutic decision is a really big one.”
Both antiamyloid therapies are indicated for people with mild cognitive impairment or mild dementia with confirmed amyloid pathology. Both also carry a black box warning, the FDA’s strongest type, about the risk of amyloid-related imaging abnormalities, or ARIA, characterized by swelling or bleeding in the brain. ARIAs are usually asymptomatic but can cause confusion, altered mental status, and disorientation and in rare cases can be life-threatening. A real-world study of patients treated with lecanemab, published in May in JAMA Neurology, found an ARIA rate similar to that seen in the drug’s phase 3 trial. Of 194 patients who received at least 4 infusions and 1 magnetic resonance imaging scan to check for ARIA, 42 (22%) had developed the condition. Of the 42, 11 were symptomatic, and 2 of them had clinically severe symptoms.
Confirmation of amyloid pathology is required before patients begin antiamyloid therapy. In that case, “PET scanning remains the diagnostic test of choice,” Knopman said.
But if a patient with cognitive impairment wants only to know whether they have Alzheimer disease, not whether they’re a candidate for antiamyloid therapy, he says, blood biomarker tests are sufficient. Among such patients, Knopman explained, blood biomarker tests have provided “added knowledge of the underlying cause of their illness. The value that patients and families derive from certainty about their diagnosis cannot be underestimated.”
Whitson’s perspective is similar to that of Knopman’s.
The arrival of FDA-approved therapies that require a brain amyloid test to determine eligibility for treatment “has driven interest in making the blood tests available even more quickly, because now the stakes are higher,” she said. “Some patients really don’t want to know if they have a disease or risk factor if there’s not a treatment for it. For them, the utility is really driven by the treatment options.”
But, Whitson added, “it is also true that the utility of brain amyloid testing is not limited to how the test result will change management or a treatment decision. When we consider the utility of a test, we should consider all the ways that the knowledge can be valuable to the patient or their family.”
Among people with cognitive impairment who aren’t considering antiamyloid therapy, the blood biomarker tests’ usefulness varies from individual to individual, she said. Some find that the test results help them plan for the future, Whitson noted.
Neurologist S. Ahmad Sajjadi, MD, PhD, chief of the Memory Disorders Division at the University of California at Irvine, says he hadn’t routinely offer testing for amyloid pathology to patients with Alzheimer-type dementia unless they were interested in antiamyloid therapy. “Most of the patients don’t even ask for it,” he noted.
However, that may change with the newly cleared plasma test, Sajjadi said. “Having a PET scan or having a lumbar puncture is not an inconsequential thing,” he explained. “With the blood test, of course, it’s going to be a different story.”
Fujirebio acknowledges that some people who take its plasma test will still need a PET scan or a lumbar puncture to confirm whether they have amyloid pathology. The test has 2 cut points; those who score above the higher cut point can be confident that they have amyloid pathology, whereas those who score below the lower cut point can be confident that they don’t have amyloid pathology, according to the company. But 20% of patients fall in the gray area between the 2 cut points, so their results are indeterminant and require further testing.
The study reviewed by the FDA before it cleared the blood biomarker test collected plasma samples from 499 adults, aged 52 to 93 years, with cognitive impairment who’d previously had amyloid pathology confirmed by an amyloid PET scan or cerebrospinal fluid testing. All the samples were assessed with the assay and compared with the patients’ amyloid PET scans or cerebrospinal fluid test results.
About 92% of individuals with a positive plasma test result were found to have amyloid plaques by PET scans or cerebrospinal fluid testing, whereas about 97% of those with a negative plasma test result were found not to have amyloid plaques by those methods.
Only blood biomarker tests of amyloid pathology that perform at least as well as cerebrospinal fluid tests, with a sensitivity and specificity of around 90% or more, should be used as a confirmatory test without a follow-up amyloid PET or cerebrospinal fluid test, according to 2024 guidelines published in Nature Reviews Neurology by the Global CEO Initiative on Alzheimer’s Disease.
The initiative, founded in 2013, is a partnership of individuals in academia, patient advocacy organizations, pharmaceutical companies, and other private industry groups. In 2022, the initiative convened a work group to help prepare for the widespread adoption of blood biomarker tests in clinical practice. Work group members included practicing clinicians and health systems.
For use as a triaging test before deciding whether to proceed with a confirmatory amyloid PET or cerebrospinal test, blood biomarker tests should have a sensitivity of at least 90% with a specificity of at least 85% in primary care, the work group recommended. Depending on the availability of confirmatory tests, specificity could be as low as 75% for use as a triaging test in secondary care.
Because the quality and quantity of information about blood biomarker tests varied greatly, the work group did not endorse any particular test but instead recommended performance standards that could be applied to any of them, according to the consensus statement.
Increased Accessibility
Blood biomarker tests for amyloid pathology already present fewer logistical barriers than PET or lumbar punctures, and the newly cleared plasma test presents even fewer barriers than its competitors.
For one, any CLIA-certified laboratory can provide it, noted Fujirebio’s spokesman Bell. “It’s not limited to 1 specific laboratory.…There are a number of laboratories that are ready to go live with the test.”
LabCorp is working with Fujirebio to add the FDA-cleared test to its offerings, a spokesperson for the laboratory services company said in an email. LabCorp began offering its own pTau217/β-Amyloid 1-42 ratio test on April 2. (The webpage for the test mentions Fujirebio because it uses the company’s reagents, according to the spokesperson.)
Another reason the new test is expected to be more accessible than other biomarker tests is related to cost and insurance coverage. As the first blood biomarker test to receive FDA clearance, it is also due to become the first such test covered by Medicare, and private insurers usually follow Medicare’s lead. Medicare is expected to set the final coverage amounts by early January, said Bell, who estimated that if people were to pay out of pocket, the plasma test would cost in the low 3 figures, making it less expensive than its competitors.
Although they haven’t received FDA premarket approval, clearance, or authorization, Quest Diagnostics and C2N Diagnostics as well as LabCorp offer blood biomarker tests as “laboratory-developed tests.” The FDA generally hasn’t enforced applicable requirements for such tests because they used to be relatively simple and available only on a limited basis.
In May 2024, though, the agency announced that it would be providing greater oversight of laboratory-developed tests. Given all the recent staff changes and cuts at the FDA, it’s not clear if the agency is still intending to phase out its “general enforcement discretion approach” for such tests. The FDA no longer has a communications office, and its counterpart at the US Department of Health and Human Services did not reply to an email asking about the regulatory status of laboratory-developed tests.
Potential for Misuse
Whitson called the Lumipulse plasma test’s inherently greater accessibility a double-edged sword.
It’s beneficial “when it’s used in the right population to answer the right question,” explained Whitson. “The downside of that is we now have something that is accessible to a large part of the population.”
The Mayo Clinic’s Knopman called that terrifying. “The risk of overdiagnosis or misdiagnosis is huge and very worrisome,” he cautioned. “This is a test for biology, not for whether symptoms are present.”
The vast majority of people with concerns about their cognition talk first with primary care physicians, who may never have rotated through neurology and been exposed to dementia care or diagnosis, Knopman pointed out. These physicians might go ahead and order a blood biomarker test because it takes less time than evaluating patients for cognitive impairment, he said.
But, emphasized Sajjadi of the University of California at Irvine, “if you have somebody whom you cannot be sure has cognitive impairment, you have to refrain from testing. This is not a test to diagnose cognitive impairment.”
Autopsy studies suggest that 30% of cognitively normal people have amyloid plaques in their brain, Knopman noted. At present, Sajjadi said, “it’s difficult to know what to do with them. Once they get these tests, it kind of opens a can of worms.”
Among people diagnosed with cognitive impairment, Whitson said, she worries that a positive blood biomarker test will lead clinicians to assume, “Okay, everything’s due to the Alzheimer’s” and won’t check for other actional factors, such as thyroid dysfunction and poor vision.
On the other end of the spectrum from the worried well are nursing home residents who may be too cognitively impaired or frail to benefit from or even tolerate infusions of antiamyloid treatments, Whitson pointed out.
“I’m really trying to educate my geriatric colleagues, nursing home medical directors, that I don’t think blood biomarker testing would be in service to nursing home patients,” she said.
Whitson cochairs a committee convened by the Alzheimer’s Association to develop guidelines for the use of blood biomarker tests. She said the first iteration, aimed at specialists, will be presented in late July in Toronto at the 2025 Alzheimer’s Association International Conference.
“Clinical practice guidelines are needed because blood-based diagnosis for amyloid is a game-changer,” Whitson noted. “It has an incredible possibility for good and an incredible possibility for really well-intentioned misuse and harm.”
Article Information
Published Online: June 13, 2025. doi:10.1001/jama.2025.9013
Conflict of Interest Disclosures: Dr Whitson reported consulting for DrivenData on the Pioneering Research for Early Prediction of Alzheimer’s and Related Dementias EUREKA Challenge and serving on the board of the American Geriatrics Society and as cochair of the Alzheimer’s Association Clinical Practice Guideline Panel on Blood-Based Biomarkers for Alzheimer’s Disease. Dr Knopman reported receiving research funding from the National Institutes of Health (NIH). Dr Sajjadi reported receiving research funding from the NIH and honoraria for continuing medical education talks and consultation work with Guidepoint.