Article In Brief
Neurologists will need to know whether a patient considering the new Alzheimer's disease drug lecanemab actually has signs of amyloid along with clinical symptoms indicative of the disease. They review the opportunities and limitations afforded by available biomarkers for the disease.
The anticipated arrival of the new Alzheimer's disease (AD) drug, lecanemab, is expected to increase demand for testing for AD biomarkers, but experts say that the decision to prescribe the drug won't be as easy as looking for a positive or negative test result.
The US Food and Drug Administration (FDA) granted expedited approval to lecanemab in January. In clinical testing, the monoclonal antibody that targets amyloid-beta plaque offered a modest though significant benefit in slowing cognitive decline in patients with mild cognitive impairment or mild dementia due to AD.
Physicians will need to know that a patient considering the drug does in fact have signs of amyloid along with clinical symptoms indicative of AD, experts told Neurology Today. Biomarker testing modalities include brain imaging using a PET scan, cerebrospinal fluid (CSF) assays, and blood-based biomarkers, though such blood tests are considered to be in the developmental stage and confined mostly to research.
But arriving at the right answer for patients considering the drug will not be straightforward. “There are a lot of nuances to the meaning of biomarker results, and their interpretation is very dependent on clinical context,” said David A. Wolk, MD, FAAN, professor of neurology and director of the Alzheimer's Disease Research Center at the University of Pennsylvania. “I do worry that less-experienced clinicians will treat these measures as definitive without considering these nuances.”
For instance, amyloid may be present in the brain in preclinical stages of AD, and autopsy studies have shown that some people have AD pathology in their brain without ever developing the cognitive symptoms of AD during their lifetime.
At the same time, “some patients with cognitive symptoms may have a PET scan (positive for amyloid), but it may also reflect preclinical disease, and something else might be driving their symptoms—for example, they may be depressed, have poor sleep, or have significant vascular cognitive impairment,” Dr. Wolk said in an email interview. “So, there will need to be a lot of education about these measures and their limitations.”
“There have been major improvements in the blood tests, and in the very near future, they are likely to agree as closely with PET scans as CSF tests do.”—DR. SUZANNE E. SCHINDLER
In a paper published Jan. 31 in Neurology, Dr. Wolk and colleagues detailed the many issues surrounding AD biomarker testing, including interpretation of test results and what they mean for an individual patient's case and disclosure of information to patients.
Up to now, AD biomarker testing has been conducted mostly in research settings, which tend to have well-defined protocols, but as therapies such as lecanemab come along, “lowered barriers to testing and increased medical actionability of results will speed up uptake of AD biomarker testing, including in clinical settings beyond specialized memory centers,” the paper said.
While the accelerated FDA approval of lecanemab was based on phase 2 clinical trial results, phase 3 findings were reported in the New England Journal of Medicine in January. The phase 3 study included 1,795 persons with early AD (mild cognitive impairment or mild dementia due to AD) with evidence of amyloid on PET or CSF testing. The participants received either lecanemab or a placebo.
Researchers concluded that “lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months.” But the drug was associated with adverse events,” most commonly amyloid-related imaging abnormalities (ARIA), which can present as brain swelling and spots of bleeding.
Factors to Consider
Ian M. Grant, MD, assistant professor of neurology at Northwestern University, said doctors will need to discuss biomarker testing for amyloid with patients considering lecanemab.
“We also need to discuss the side effects of the medication, particularly swelling and bleeding in the brain that can occur in up to 1 of 6 people,” he said, noting that people positive for the APOE4 gene seem particularly at risk for the side effect.
“Assuming people meet the basic criteria, a lot of the discussion will come down to the goal of an individual's care,” he said. “The medication has to be given every other week in an infusion center, which will take one to two hours of their time, and it will require fairly regular MRIs of the brain.” Dr. Grant noted that that sort of scheduling demand may not appeal to some patients, who may prefer to spend their time travelling or being with family.
The drug is expensive, Dr. Grant said, and it is not yet clear whether Medicare or other health insurers will pay for it. Eisai—which collaborated with Biogen to develop lecanemab and is now pursuing traditional approval from the FDA to market the drug—said the drug will cost $26,500 annually, which Dr. Grant noted does not include infusion costs. There will also be costs for biomarker testing, with the scope of coverage varying among insurance.
“I think, from a scientific standpoint, it's exciting to finally see some moving forward of the needle, to see some evidence of an effect even if it's not a big effect,” Dr. Grant said. But he cautioned against over-enthusiasm for lecanemab until more is learned. “We have to try to help our patients understand that it's not a cure. It is not going to make their disease go away.”
Blood Testing Would Be Optimal
Checking blood-based biomarkers would likely be the easiest and cheapest way to screen for amyloid, though the tests are evolving and not considered the final word on an AD diagnosis.
“Blood biomarkers are likely to have a major impact on our field, but we still have limited clinical experience with them,” Dr. Wolk said. “While they perform well in research cohorts, they will likely be treated as, at most, screening measures for a more definitive test, such as amyloid PET.”
Dr. Wolk said that, for now, he would do an amyloid PET scan in patients considering lecanemab, which he will then repeat periodically to see if there is “target engagement. “Depending on a patient's insurance coverage, he added, “CSF testing is also a reasonable choice” for determining a patient's amyloid status prior to deciding whether to start lecanemab.
Dr. Wolk said he also would recommend doing an MRI upfront to look for evidence of amyloid angiopathy (microhemorrhages and/or superficial siderosis), which he thinks would be a reason not to start a patient on lecanemab given the reported risks of brain edema and bleeding.
He said an MRI also would provide information on whether a vascular disease separate from the amyloid might have caused the patient's cognitive symptoms.
“In cases with significant evidence of vascular disease, that might prompt a discussion about the degree to which vascular disease is driving symptoms versus AD pathology, which may also impact the relative benefits of the medicine,” Dr. Wolk said.
Suzanne E. Schindler, MD, PhD, associate professor of neurology at Washington University School of Medicine in St. Louis, who oversees the lumbar puncture program for patients at the center's memory clinic, said she has started to handle more requests for CSF testing.
“Five years ago, we would do three to five lumbar punctures a month, and now we are doing 15 a month,” she said. Still, only about 10 percent of their AD patients get AD biomarker testing, which, outside of research studies, has not been viewed as essential for AD care given there were no specific treatments available.
With lecanemab likely heading to market, Dr. Schindler said her center is gearing up to test more patients who will want to know if they are candidates for the anti-amyloid drug. Dr. Schindler said some patients shy away from getting a lumbar puncture because they view it as risky and invasive. But she said it can provide a wealth of information useful for the clinical evaluation of dementia, especially if the dementia presents atypically or at a young age. A CSF test also might reveal alternative diagnoses, such as infections or inflammatory and neoplastic conditions.
Dr. Schindler said CSF tests are less costly than PET scans and are more likely to be covered by insurance. She said the two FDA-approved CSF tests for AD currently on the market are comparable to PET scans in confirming amyloid pathology.
“There have been major improvements in the blood tests, and in the very near future, they are likely to agree as closely with PET scans as CSF tests do,” she said.
Washington University in St. Louis is a site for the AHEAD 3-45 study of whether lecanemab can slow down progression to clinical symptoms in patients who have amyloid pathology but no cognitive signs of AD.
Better Access Needed
Adam L. Boxer, MD, PhD, endowed professor in memory at University of California San Francisco, said he worries that lecanemab will be difficult to access by “people from historically underserved populations, such as Black and Latinx individuals, who often have trouble getting access to health care.”
Because the drug requires testing for AD pathology and making a diagnosis early in the disease course, people not connected with regular care may not be identified until it's too late to benefit, he said.
Dr. Boxer said the AD research community is excited about the potential of blood-based biomarkers because “they are easier to use logistically, and eventually, when more widely available, they will be much less expensive” than PET scans or CSF biomarker testing.
“Using blood biomarkers to evaluate younger people with possible early signs of dementia could improve their ability to access new treatments such as lecanemab at stages of disease when they might benefit the most.”—DR. ADAM L. BOXER
“Assuming people meet the basic criteria, a lot of the discussion will come down to the goal of an individual's care. The medication has to be given every other week in an infusion center, which will take one to two hours of their time, and it will require fairly regular MRIs of the brain.”—DR. IAN M. GRANT
He is co-leading a new NIH-funded study called BEYONDD (Biomarker Evaluation in Young Onset Dementia from Diverse Populations) to see whether a community-engaged approach using new AD blood biomarkers and home-based digital assessments could be used to evaluate people under 65 years old with signs of early-onset dementia.
“Early-onset dementia is particularly devastating because it affects people in the prime of their working years and often when they have young children at home, but little is known about the causes of early-onset dementia in diverse populations,” Dr. Boxer said.
“Using blood biomarkers to evaluate younger people with possible early signs of dementia could improve their ability to access new treatments such as lecanemab at stages of disease when they might benefit the most.”
Dr. Wolk has received fees for consulting from Eli Lilly, Qynapse, and GE Healthcare. He also is a member of the data safety monitoring board for functional neuromodulation. Dr. Boxer has received consulting fees from Alector, Arvinas, Arkuda, AGTC, Boehringer Ingelheim, GSK, LifeEdit, Merck, Oscotec, Roche, Transposon, and Wave. Drs. Grant and Schindler had no disclosures.