PHILADELPHIA – Physicians are starting to develop and implement beta-amyloid testing strategies into their practices to catch the early signs of Alzheimer's disease in their patients and determine whether they're a fit for the latest drugs.
New drugs like Eisai and Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab) that modestly slow Alzheimer's disease progression have brought hope to a field historically lacking treatment options. But these drugs require testing for aggregation of the protein beta-amyloid, a hallmark sign of the neurodegenerative disease targeted by this new class of drugs, which hasn't been standard practice in dementia care.
During a session at the Alzheimer's Association International Conference this week, Suzanne Schindler, an associate professor of neurology and a dementia specialist within the Knight Alzheimer Disease Research Center at the Washington University School of Medicine in St. Louis, shared that beta-amyloid testing has increased sevenfold at the university's Memory Diagnostic Center over the past three years. In 2021, the center performed on average six biomarker tests per month, but more recently, that number has shot up to 44 per month. "We really are at a transformative time in the field," Schindler said.
Historically, most Alzheimer's patients didn't undergo a comprehensive evaluation that included biomarker testing, since management of their cognitive problems wouldn't change based on the results, according to Schindler. Today, WashU physicians are primarily performing beta-amyloid testing to determine the appropriateness of prescribing an anti-amyloid treatment like Leqembi or Kisunla, but also to aid in diagnosis.
The primary methods of determining the presence of beta-amyloid involves PET imaging or analyzing cerebrospinal (CSF) fluid from a spinal tap. Both methods have proven accuracy but can be expensive and require specific equipment and trained staff. Many physicians believe that blood testing will eventually become the preferred method, but the approach currently requires additional clinical validation. Further, these tests at present aren't always covered by insurance, and not all physicians are aware of them.
Initially, WashU's Memory Diagnostic Center only offered CSF tests, since Medicare at the time limited coverage for amyloid PET to certain research studies. The US Centers for Medicare & Medicaid Services removed that requirement last fall but left it up to its Medicare administrative contractors to determine the specific coverage parameters.
More recently, the Memory Diagnostic Center has been offering all three of the major biomarker testing modalities. Blood testing is primarily done using C2N Diagnostics' PrecivityAD2, which launched last year as a laboratory-developed test and incorporates blood-based biomarkers amyloid-beta 42/40 ratio and percent of phosphorylated-tau (p-tau) 217.
In recent months, 37 percent of tests conducted at the clinic were amyloid PET, 34 percent were CSF analysis, and 28 percent were blood tests. "We like that we have multiple biomarker modalities available," Schindler said. "This allows us to select what we think is the optimal test for an individual patient."
Physicians weigh multiple factors when deciding what test is appropriate for a given patient, Schindler said, and she and her colleagues are close to publishing a paper on those considerations in the journal Alzheimer's & Dementia. For example, a patient with claustrophobia likely won't want to undergo an amyloid PET scan, while a patient who previously had lumbar back surgery may have difficulty undergoing a spinal tap for CSF analysis. Similarly, some comorbidities like chronic kidney disease or liver cirrhosis may inhibit the accuracy of blood tests.
Insurance coverage and cost are also concerns. Some health plans don't cover biomarker testing, in which case PET imaging and CSF analysis may be out of reach. On the other hand, certain health plans require PET imaging or CSF analysis to confirm beta-amyloid pathology before they'll cover anti-amyloid treatments and won't accept blood test results. Medicare has covered Leqembi for patients at the Memory Diagnostic Center after doctors used blood tests to gauge beta-amyloid positivity, Schindler noted, but private insurers haven't been as willing.
Guidelines bodies, too, are beginning to incorporate blood tests into Alzheimer's diagnostic criteria. Last month, a workgroup organized by the Alzheimer's Association issued updated guidelines, in which it said certain blood tests proven to be at least as accurate as approved CSF assays could be used for diagnosing the disease. It proposed amyloid-beta 42, p-tau 217, p-tau 181, and p-tau 231 as fluid biomarkers tested for in CSF or blood samples.
Some hospitals are trying to incorporate beta-amyloid blood testing within primary care. For example, Indiana University School of Medicine is investigating the feasibility and acceptability of using blood tests for early Alzheimer's detection at a subset of primary care clinics. That pilot research program is part of the Davos Alzheimer's Collaborative's Healthcare System Preparedness Early Detection Flagship program launched in 2022.
Primary care providers are well positioned to deliver population-based care and are familiar with conducting outreach to encourage patients to come in for routine screening and testing, said Deanna Willis, vice chair of research and a professor in the family medicine department at Indiana University School of Medicine, at the conference.
In the pilot, seven primary care clinics and nearly 60 primary care physicians integrated a digital cognitive assessment from digital health company Linus Health into routine patient visits. Patients with abnormal results, who weren't already diagnosed with dementia, could enroll in a study and receive blood-based biomarker testing using C2N's PrecivityAD test, which estimates beta-amyloid positivity by measuring a combination of amyloid-beta 42/40 ratio, apolipoprotein E levels, and the patient's age. Patients could also schedule an appointment with a brain health nurse navigator who would coordinate an evaluation on the Montreal Cognitive Assessment and provide information on specialty care and community resources.
Of the about 100 patients who were eligible for blood testing based on their digital cognitive assessment, 26 patients agreed to undergo the testing and participate in the research study, while 62 patients declined. An additional nine patients initially consented but didn't go to the lab for the blood draw.
Among other avenues, Willis said she'd like to further explore the role primary care team members can play in disclosing and discussing test results. Within the pilot, physicians had the option to deliver blood test results to patients themselves or to defer to a research team, who would deliver results over the phone. Physicians were split about 50-50 on the option they chose, and Willis said some physicians informally raised concerns that the study's requirement to deliver test results within seven days of receiving them inhibited their ability to schedule follow-up appointments to discuss results in person.
Winston-Salem, North Carolina-based Atrium Health Wake Forest Baptist is another hospital trying out a care pathway, called MindCare 360, in which clinicians use blood tests to screen patients who are at risk for Alzheimer's. The program was adapted from a process developed by the Global CEO Initiative on Alzheimer's Disease to implement blood-based biomarker testing to inform care for patients who may benefit from anti-amyloid treatment. A paper on this proposed pathway is also in press with Alzheimer's & Dementia.
The team at Atrium Health Wake Forest Baptist considered screening all senior patients over a certain age threshold but decided it wouldn't be feasible to do every year, said Michelle Mielke, chair of the epidemiology and prevention department at Wake Forest University School of Medicine and one of the leaders of the Global CEO Initiative's work on implementing blood-based biomarkers.
"Instead, we're focusing on individuals who are high risk," she said of the hospital's program, which is designed for patients with potential signs of early cognitive impairment, who are at least 55 years old, and who aren't currently diagnosed with dementia. These patients might have concerns about their cognitive functions or are identified by a machine learning risk prediction algorithm embedded in the hospital's electronic health record system.
Those patients deemed to be at high risk undergo cognitive testing at home and schedule a virtual visit with an advanced practice provider (APP), such as a nurse practitioner or physician assistant, who returns results and gathers additional information on the patient's medical history, medications, mental health, lifestyle, and other factors that could be affecting their cognition other than Alzheimer's. This practitioner guides the patient throughout the MindCare 360 program.
MindCare 360 relies on APPs to avoid giving more work to already stretched-thin primary care doctors. One of the core goals for the program was "not to add additional burden onto primary care physicians … and not impede primary care workflow," Mielke said.
Patients determined to have cognitive impairment then undergo blood testing to detect possible beta-amyloid pathology and other biomarkers of neurodegeneration, which is confirmed with a PET scan or CSF analysis. The APP discusses care plan options with the patient, which could involve a discussion of anti-amyloid treatment as well as referrals to other specialists and brain health counseling for patients who aren't deemed a good fit for those drugs.
Amid excitement around new anti-amyloid treatments, hospitals developing these care pathways must also consider that many patients will test beta-amyloid negative or decide not to receive these drugs after learning their risk-benefit profile. These patients could benefit from other medical or behavioral interventions. "Some of these individuals will be eligible for lecanemab or donanemab," Mielke said. "But the vast majority probably will not."