CLN - Feature
There has long been a need for a better way of diagnosing Alzheimer’s disease. The traditional route to diagnosis typically involves a pen-and-paper memory test and interviews with people close to the individual, which is not exactly misdiagnosis-proof.
Only a small minority of patients receive objective clinical tests that confirm the disease: PET scans of the brain that reveal amyloid plaques and spinal taps that measure amyloid proteins in cerebrospinal fluid. However, the former is costly, while the latter is an invasive procedure.
A new type of testing looks increasingly promising: blood testing. These tests work by measuring the presence of certain proteins in the blood associated with Alzheimer’s disease. The advantages include a lower cost than brain scans and a less invasive approach than spinal taps. With new advancements come new challenges, though, and clinical labs need to be ready to help healthcare providers understand the capabilities and limitations of these tests.
Researchers have been working on blood tests for Alzheimer’s for a long time, “but it hasn't been until somewhat recently that there have been some successes analytically to make that happen,” said Mari DeMarco, PhD, a clinical associate professor at the University of British Columbia’s department of pathology and laboratory medicine and a clinical chemist at Providence Health Care. “So all of a sudden, it’s become an opportunity.”
So far, research is promising. The results of a 2024 study suggested that a blood test could detect Alzheimer’s disease as accurately as standard spinal taps.
Aside from the gap in the market for cheaper, more accessible forms of testing, the need for a new approach to testing was also accelerated by the recent landmark development and approval of new drugs that treat the disease. These drugs work by targeting amyloid-beta (Aβ) pathology and have been shown to slow — though not halt — disease progression.
With the introduction of treatments for Alzheimer’s, the number of patients who need to be tested for it has skyrocketed. A blood test could enable many more people to get a faster diagnosis and initiate treatment at the right time, which is crucial because the drugs work best at slowing the progression of the disease when it is still in its early stages and symptoms are mild. That’s where the current gold standard methods for diagnosing the disease fall short — many patients may receive a diagnosis at a point in their disease progression when the treatments are no longer helpful.
“I think the whole idea of maybe moving treatment of amyloid early also spurred the development of having a blood-based test that can detect amyloid early in asymptomatic patients,” said Danni Li, PhD, an investigator in the Advanced Research and Diagnostic Laboratory at the University of Minnesota.
Another reason the new treatments spur on the need for blood-based testing is the safety concerns associated with the drugs. During the clinical trials, a handful of patients died as a result of side effects, particularly brain swelling and hemorrhage. “Having a biomarker that's predictive of that would be very helpful for monitoring patients on therapy,” DeMarco said. At the moment, patients are monitored using MRIs, which is “quite costly and cumbersome to the patient to have to go into repeat imaging,” she added.
A blood test could also monitor how well new treatments work. And another major boon of accurate blood tests is that they could help to drive clinical research forward. A simpler, cheaper mode of testing makes it easier to sign participants up for a clinical trial, DeMarco said. “These types of discussions need to happen with patients as part of pre-test counseling.”
The surge in biomarker research has led to calls to update the diagnostic criteria for the disease, and the Alzheimer’s Association is working on doing just that. The association’s draft guidelines promote the hypothesis that Alzheimer’s disease should be defined as a biological disease rather than based on a clinical syndrome. The idea is that someone could receive a diagnosis based on a positive test for amyloid — picked up by, say, a blood test — as opposed to the onset of cognitive decline.
Already, a handful of blood tests have made their way into the clinic, with many more following behind. However, despite the excitement over the advancements in blood-based testing, quality between tests tends to vary. Different tests look for different biomarkers, with some bolstered by more robust data than others. With such a big target population — more than 6 million people in the United States have Alzheimer’s disease — it’s important to ensure they are not used inappropriately.
Currently, the most promising blood-based biomarker is p-tau217, according to Alicia Algeciras-Schimnich, PhD, professor of laboratory medicine and pathology and co-director of the Clinical Immunoassay Laboratory at Mayo Clinic. It's a surrogate measure of Aβ accumulation in the brain and is the biomarker measured by the Mayo Clinic Laboratories test. While no blood-based tests have received Food and Drug Administration (FDA) approval — currently, all are available as laboratory developed tests — p-tau217 assays from Roche Diagnostics and Quanterix have received breakthrough status from the FDA, which expedites agency review of the assays.
Other tests, such as C2N Diagnostics, measure the Aβ42/40 ratio, which can be used to assess whether amyloid plaques have begun accumulating in the brain. This test also has received breakthrough status. Another company, Labcorp, has launched a test that measures three blood biomarkers: amyloid plaques, tau tangles, and neurodegeneration.
But while some biomarkers have a strong evidence base behind them, not all assays perform the same. “That's something that is probably not apparent to a clinician ordering the test,” Algeciras-Schimnich said. “We need increased transparency on diagnostic performance data from the clinical laboratories offering the test. This data needs to be based on the assay they offered and the intended use population.”
Right now, it is recommended that the tests only be used in specialized dementia clinics. However, if the goal is to eventually use these tests for early diagnosis, these products need to be evaluated in broader patient populations, DeMarco said. “We know they have different performance metrics if you move from a high prevalence population to a lower prevalence population.” There’s also a concern that these tests could be used in patient populations for which the accuracy has not been evaluated, such as young, healthy adults. One day, if the data support it, these tests could be used for these patients to predict whether someone with no symptoms will eventually develop Alzheimer’s. But the research is not there yet.
Li, however, is confident that these tests will be used in the correct context with education. “I think we need to educate providers so that those blood-based tests will be appropriately used in the context of asymptomatic individuals,” she said.
There’s a concern that because blood tests are so simple to administer, they will be used without due diligence. “You can imagine the ease of access [means] it tends to shift from appropriate utilization to what would now be considered inappropriate utilization,” DeMarco said. For instance, an asymptomatic individual in a primary care setting receiving a blood test as opposed to a symptomatic individual in a specialist setting. There are questions about what a positive test could mean for employment and insurance, too.
The rise of blood tests also brings up some ethical quandaries. There’s the question of whether clinicians should test asymptomatic individuals at all. For a diagnosis as devastating as Alzheimer’s disease — a condition with no cure — for some, more information is not always better. Say you get a positive result for a blood-based biomarker test. “What’s the follow up?” DeMarco said. “These types of discussions need to happen with patients as part of pre-test counseling.”
The need for blood tests for Alzheimer’s disease is clearly there. But it’s crucial that these tests are validated and used in the appropriate setting. “I’m enthusiastic, but also cognizant of some of these things we need to work out before we have more widespread usage,” DeMarco said.
To learn more about this topic, come to the ADLM 2024 session “Alzheimer’s disease and the new therapeutic age” in Chicago on Wednesday, July 31. This session will cover the rapidly shifting therapeutic landscape for this condition and the rise of biomarker testing.
Grace Browne is a freelance journalist who lives in London. She currently has a fellowship funded by the International Center for Journalists through the Health Innovation call. +Email: [email protected]