NEW YORK – As drugs to treat Alzheimer's disease come to market, led by the US Food and Drug Administration approval of Biogen's Aduhelm (aducanumab) nearly a year ago, diagnostic tests to detect the disease are following suit.
Blood-based biomarker tests have gained particular prominence, as they're less invasive and cheaper than both PET imaging and cerebrospinal fluid (CSF) biomarker testing — two current standards of care for patients presenting with Alzheimer's symptoms. But the biomarkers those tests rely on may not have the same diagnostic impact in non-white patients, according to a recent study published in Neurology.
Suzanne Schindler, a clinician at Washington University's Knight Alzheimer Disease Research Center and an author of the study, said that PET scans run for about $6,000 and often aren't reimbursed by insurance, making them largely inaccessible to patients. While CSF tests like Fujirebio Diagnostics' Lumipulse G β-Amyloid Ratio (1-42/1-40) assay are reimbursed, many patients "really are not eager to get a spinal tap," so they're usually only used for patients where clinicians believe one of the options will make "a big difference in their diagnosis and clinical care," which comes out to about 5 percent of patients who present with memory and thinking problems.
Using blood is significantly more accessible, since clinicians already routinely order blood draws for general dementia evaluations, and it's "pretty easy to add on a tube of blood" for an additional test, she said. And, as more Alzheimer's drugs come to market, Schindler said biomarker tests may be required before they're prescribed, because the "bandwidth" isn't available in hospitals for every patient eligible to receive more time-consuming diagnostics like PET scans or CSF tests.
Some of those blood-based tests are actively being used as laboratory-developed tests, such as C2N Diagnostics' PrecivityAD, and others are under development and moving toward commercialization, like Diadem's AlzoSure Predict test, which received breakthrough device designation from the FDA in January. Major diagnostic players are also entering the space, including Quest Diagnostics, which offers its Quest AD-Detect Amyloid Beta 42/40 (Aβ42/Aβ40) Ratio test, and Roche, which is pursuing FDA clearances for two Elecsys Alzheimer's tests.
Michael Racke, medical director for neurology at Quest Diagnostics, said in an interview that plasma tests are beneficial because they can be used to screen patients who are "normal cognitively" and may be candidates for intervention before they decline. Although developing blood tests has been harder than CSF tests because there are significantly more proteins in the blood that can present a technical challenge, blood-based assays are "much more conducive to be able to screen lots of people … before they even have the disease," he said.
However, "nearly all of the biomarker development" so far has been done in research populations — populations that are about 95 percent white, highly educated, and "very healthy," Schindler said. While that research has "given us a lot of information," applying the biomarkers to clinical populations requires that clinicians "make sure that they work the same way and work consistently across all the different groups of patients that we see."
The concern is whether those biomarkers will work in more diverse patients, and that's what the recent Neurology study looked to address. Comparing samples from 76 African American patients with 76 white patients that were near the same age, shared the same genetic risk, and had the same cognitive status allowed the researchers to "match … the groups pretty closely with respect to major [demographic] variables that we know affect Alzheimer's disease risk," she said.
The study team looked at four biomarkers used in blood-based tests and their ability to predict Alzheimer's by measuring brain amyloidosis. To measure the biomarkers, the researchers used C2N Diagnostics' test for Aβ42/Aβ40, laboratory-developed tests from Sweden's University of Gothenburg for p-tau181 and p-tau231, and a Quanterix assay for neurofilament light. Of the four biomarkers, three — p-tau181, p-tau231, and neurofilament light — performed inconsistently between the races, while Aβ42/Aβ40 was consistent across both groups.
The same biomarker value in African American patients was associated with lower risk of Alzheimer's, suggesting that with some of the biomarkers, "you'd be misdiagnosing" African American patients with false-positive results, Schindler said.
She noted that genetic differences between the races may not be the only reason for differences in biomarker levels — some comorbidities, such as chronic kidney disease, can affect biomarker levels, because if the kidney isn't clearing proteins correctly, the concentrations of those proteins may be different.
Knowing the potential issues with these biomarkers is only part of the battle, however. There's a "growing awareness" in the field that there's a need to diversify research participants, but "right now we just don't have the research cohorts we need," said Schindler. It can be hard to recruit diverse populations, since marginalized groups have been abused in the past and there's a lot of mistrust surrounding medical research. Diverse groups are also much less likely to participate in studies if there are any risks, such as those inherent in spinal taps, she said.
Even with its broader sample population, Thomas Karikari, a researcher in the department of psychiatry and neurochemistry at the University of Gothenburg and another author on the paper, said in an interview that the Neurology study only looked at two populations in one region. More work would need to be done to see if those same differences appeared in other communities and how comorbidities, such as diabetes and hypertension, can affect or accelerate a patient's cognitive decline, he added. If comorbidities do accelerate a patient's decline, the impact could have less to do with specific racial differences, or a "race effect," and more to do with health disparities that disproportionately affect marginalized people, he said.
To that end, Karikari is working to put together a global consortium to validate markers across diverse populations and show whether vascular comorbidities have an impact on the differences in the biomarkers. The consortium is using samples from cohorts across six continents, including three to four in the US from multiple states with all major racial groups represented, and is expected to launch early next year with more than 15,000 patients. Most of the cohorts included already have biomarker and imaging data, so one goal is to aggregate that data to see if "medical conditions that seem to be more prevalent in specific groups of people" might "affect different groupings differently," Karikari said.
Italian diagnostic firm Diadem, which is moving its AlzoSure Predict test toward commercialization, is broadening its validation across more populations as well. Its test was originally validated with a largely white Australian cohort, but the company is currently using more varied samples from the US to validate it further, with results reporting out in the next few months, CEO Paul Kinnon said. He said that the hardest part of clinical trials and studies is patient recruitment and retention, since it's "a big ask" for patients to do a prolonged study, particularly if a person isn't sure if they have Alzheimer's.
Another key component of validating Alzheimer's diagnostic tests more broadly is seeing how the assays perform in a patient over time, Quest's Racke said. "If somebody's Aβ42/Aβ40 ratio is positive but their PET scan is negative and they're normal, how long does it take until … their PET scan becomes abnormal and they become cognitively abnormal?" Furthermore, "how much time do we then have to try to intervene when we've identified someone we think is at risk for Alzheimer's disease, but before they’ve already had so much damage that treatment intervention doesn't work?"
Not everyone in the field has seen such significant differences in Alzheimer's biomarkers across races, however. Adam Brickman, a professor of neuropsychology at Columbia University, said that in his research with a subset of participants from the Washington Heights/Inwood Columbia Aging Project (WHICAP), a cohort study of over 6,000 white, African American, and Hispanic patients, the biomarkers "work pretty well in these different populations in discriminating those with and without cognitive impairment or dementia."
In a study of 300 participants from WHICAP published in March in Annals of Clinical and Translational Neurology, Brickman's team looked at Aβ42/Aβ40, p-tau181, p-tau217, and neurofilament light concentrations and "didn't see group differences across the race and ethnicity groups in the concentration of these biomarkers," he said in an interview. "We didn't see any differential associations of these blood-based biomarkers with outcomes whether they were clinical or pathological across the different race and ethnicity groups."
He noted that the Neurology study asked a "quite distinct" question, focused on amyloid positivity as "the meaningful outcome" when predicting Alzheimer's, while his study didn't focus on amyloid presence in the brain as the most primary or meaningful outcome and instead emphasized how the biomarker concentrations related to significant clinical and pathological outcomes.
He emphasized that while there is little reason to believe that the fundamental biological processes would be distinct across race or ethnicity groups, "it could be that across different cultural, racial, or ethnic groups, the combination of the biological and the social determinants of health could differ in predicting certain outcomes."
Regardless of those differences, more studies drawing from diverse populations are "important because they highlight the need for inclusive research," Brickman said. "The populations that are the most affected by Alzheimer's disease are the ones that are least studied in human-based research."
Researchers and test developers "need to be testing these assays in individuals with a variety of different medical comorbidities, who represent different social and economic groups," Washington University's Schindler said. "If we don't, what's likely to happen is that we will disproportionately misdiagnose individuals that are from diverse groups."