NEW YORK ─ Quest Diagnostics' recent move to make its AD-Detect Alzheimer's disease test available as a consumer-initiated product has raised concerns among researchers and clinicians in the space.
In interviews with 360Dx, Alzheimer's experts questioned whether the test is backed by sufficient data and suggested that it could produce a significant number of false positives, which could lead to unnecessary patient anxiety and further burden memory clinics that are already struggling with backlogs.
The AD-Detect test uses mass spectrometry to measure the ratio of amyloid beta (Aβ) 42/40 in blood to assess the likelihood that an individual has brain amyloid pathology characteristic of Alzheimer's disease. Quest launched the test in May 2022 and began last month offering it as a consumer-initiated test that customers can order at its questhealth.com site for $399 plus a $13 physician service fee.
The test is one of a number of Alzheimer's blood tests that have either come to market or are approaching launch. While PET imaging and cerebrospinal fluid-based tests are the current gold standards for diagnosing Alzheimer's, many expect blood-based testing, which is less invasive and less expensive than PET and CSF testing, to play a major role in diagnosing and managing the disease.
Two developments have been key to accelerating interest in blood-based testing. Recent US Food and Drug Administration approvals of Biogen's Alzheimer's drug Aduhelm (aducanumab) and Eisai's Alzheimer's drug Leqembi (lecanemab) have raised the possibility that physicians will, in the near future, need Alzheimer's screening methods to identify patients who may benefit from these and/or future treatments.
Meanwhile, advances in biomarker discovery and measurement have made it possible to detect analytes linked to Alzheimer's in patient blood, raising the possibility of diagnostics that, unlike existing cerebrospinal fluid or PET imaging tests for the condition, can be run cheaply and at scale in large, potentially asymptomatic populations.
To date, no Alzheimer's blood test has received US Food and Drug Administration approval, but several companies including Quest, C2N Diagnostics, and Quanterix have launched laboratory-developed tests targeting the condition.
Like Quest's AD-Detect, C2N's PrecivityAD and PrecivityAD2 tests use mass spec to assess the likelihood that an individual has brain amyloid pathology. The PrecivityAD test includes in its model Aβ 42/40 ratio as well as apolipoprotein E proteoform measurements and patient age. The PrecivityAD2 test includes those factors as well as the ratio of phosphorylated-tau 217 to unphosphorylated-tau 217.
Quanterix's LucentAD LDT measures blood levels of p-tau 181 to assess brain amyloid pathology as a rule-out test for the disease.
Other companies including Roche, Sysmex, and Fujirebio are also working on blood-based Alzheimer's tests.
Aside from Quest, no companies have marketed their Alzheimer's blood tests as consumer-initiated products. Quest is also alone in having made its test available to asymptomatic patients, though it has since backtracked on that decision.
The test order page at questhealth.com requires that individuals click a box certifying that they have or are experiencing mild cognitive impairment or decline and at least one additional risk factor including a family history of the disease, past brain trauma or head injury, or excessive alcohol consumption. In an email, a Quest representative said the company is not marketing the test to asymptomatic individuals.
Michael Racke, medical director for neurology at Quest, told 360Dx shortly after the test launch that it is appropriate for some asymptomatic patients — a 55-year-old individual with no symptoms and no family history of Alzheimer's, for instance. Such a patient would receive the test if they ordered it, he said.
Asked about Racke's comments, Quest said that it has since changed the ordering criteria and that while upon launch of the test individuals were not required to certify that they were experiencing cognitive impairment or decline, "after careful consideration, we strengthened this to include that individuals must acknowledge that they have or are experiencing mild cognitive impairment [or] decline and at least one additional risk factor from a specified list."
The company also says the test "may not be appropriate" for individuals younger than 50 years old.
Racke said Quest believes that making AD-Detect more easily accessible to patients could make individuals more likely to get tested for Alzheimer's risk and perhaps see a specialist if needed.
"I've always been of the opinion that the more knowledge people have about their health, the better it is," Racke said. He added that while "it would certainly be better if you [undertook Alzheimer's testing] through your primary care [physician], because it is someone who knows you and is perhaps familiar with your circumstances … in this day and age there are a lot of people who are comfortable with using" a consumer-initiated test.
Racke noted that physicians are involved with the consumer-initiated testing, first to evaluate whether individuals meet the appropriate criteria to receive the test and then to explain the results and, in the event of a positive test, to help them to pursue the recommended follow-up.
Some Alzheimer's experts worry, however, that Quest's criteria for ordering the test are too lax and are likely to generate large numbers of false positives. These false positives, they said, will likely add to patient backlogs at already overburdened memory clinics.
A core issue is that it is challenging to assess brain amyloid status using blood-based amyloid measurements alone. The difference in plasma Aβ 42/40 ratios between patients with and without brain amyloid pathology is typically only 10 to 15 percent, and drugs commonly used in older populations can significantly impact patient ratios. Some studies have indicated that this difference may be too small for tests to reliably detect and that the inclusion of other markers may be necessary to provide the required performance.
Research has shown that mass spec-based assays for Aβ 42/40 ratio have higher performance for identifying amyloid positive individuals than do immunoassays, but "you have to be very rigorous about" your measurements, said Suzanne Schindler, associate professor of neurology at the Washington University School of Medicine. Schindler's colleague in the Wash U neurology department, Randall Bateman, is a cofounder of C2N, but Schindler said she has no financial relationship to the company and has not received any payments from it.
"There's only about a 10 percent difference between positives and negatives, and so if you are off by a little bit or your assay drifts, then you can really misclassify a lot of people," she said, adding that Quest has released little data on the analytical and clinical performance of its test, making it difficult for outside clinicians and researchers to assess its quality.
"I don't know how rigorous Quest has been in dealing with these issues," she said.
Michelle Mielke, professor of epidemiology and prevention at Wake Forest School of Medicine and a member of the school's Sticht Center for Healthy Aging and Alzheimer’s Prevention, likewise raised concerns about the level of data Quest has made available about the test.
At the 2022 Alzheimer's Association International Conference, Quest presented a poster on AD-Detect, and the company said it aims to publish data on the test in a peer-reviewed publication.
Nevertheless, Mielke said that "with a lot of the other tests that are being developed, some of which are now available for clinical use, you've seen results at numerous conferences over multiple years. They have been peer-reviewed, they have been questioned."
"With this particular test, there is just very, very little information," she said. "So, one concern is the accuracy of the results. It's hard to guide patients on what the test really means."
Even assuming the AD-Detect test meets Quest's stated performance characteristics of 89 percent sensitivity and 71 percent specificity, it would be expected to generate large numbers of false positive results. Schindler said that in a typical dementia clinic population where the prevalence of brain amyloid pathology is around 60 percent, a test with those characteristics would have a false positive rate of around 20 percent.
For the general population under 60 years of age without clinically significant cognitive impairment, amyloid positivity rates are less than 20 percent, Schindler said, noting that at that prevalence level, the AD-Detect test would have a false positive rate of more than 50 percent.
She added that while Quest's AD-Detect ordering page requires customers to certify that they are experiencing mild cognitive impairment or cognitive decline to order the test, such individuals cannot be said to have a clinical diagnosis of mild cognitive impairment, which requires confirmation via cognitive testing, but rather have what is termed "subjective cognitive decline." She noted that research indicates that individuals with subjective cognitive decline have brain amyloid positivity rates similar to individuals who are cognitively normal.
Schindler said patients with false positive results seeking follow-up will likely worsen what are already lengthy wait times for specialist appointments.
An acute shortage of dementia specialists exists already, she said, noting that her clinic typically has a wait time of around six months for new patients. "This could create a lot more of a burden for us that we really can't manage very well."
In addition to such systemic challenges, false positives present potential issues for individual patients, Schindler said, including lengthy waits to get a confirmatory test, during which time they will live with uncertainty and anxiety about their Alzheimer's status.
She added that it was unclear whether memory clinics would even take on these patients for confirmatory testing.
"Should I order a confirmatory test on someone who I think is cognitively normal?" she asked. "Because I wouldn't normally do that."
Robert Friedland, professor of neurology at the University of Louisville School of Medicine, said his experience with individuals who had undergone direct-to-consumer genetic testing for Alzheimer's informed his concerns about the consumer-initiated Quest test.
He recalled receiving an email from an undergraduate at his university who was concerned because his mother had tested positive for an Alzheimer's-linked genetic mutation. When Friedland looked into the result for the student, he saw that it was not, as he had initially feared, an autosomal dominant mutation, which would put the student and his mother at high risk for early onset disease, but was an APOE allele.
"It wasn't an autosomal dominant [mutation], it was a risk factor," Friedland said. "But he didn't understand and she didn't understand. And this applies to this [AD-Detect] blood test. People won't understand what [the results] really mean. That even applies to physicians, but this is particularly horrible because it is being sold to the general public."
Mielke suggested that a larger challenge is that the field itself doesn't yet have a good understanding of what a positive amyloid blood test means.
"We know that pathology starts decades prior to clinical symptoms, and so it's possible that you will be positive and never develop dementia before you end up passing away," she said. "My concern is that people will think this is deterministic and that they are going to develop dementia in a couple of years and that will be it. And that's not necessarily the case."