By Claire Jarvis

Pictured: Close-up of an arm receiving a blood draw/iStock, montiannoowong

Prior to the approval of effective therapies for Alzheimer’s disease, there was little need for biomarker tests. Now, with Eisai and Biogen’s anti-amyloid drug Leqembi on the market and approval of Eli Lilly’s donanemab expected to follow soon, the pipeline of Alzheimer’s drugs is expanding and the development of tests to detect the disease is accelerating.
With Leqembi’s full approval, the Centers for Medicare and Medicaid Services (CMS) has instituted broader coverage of the drug—with stipulations. To ensure reimbursement, physicians must participate in a qualified registry and patients must be diagnosed with mild cognitive impairment or mild Alzheimer’s disease dementia with evidence of beta-amyloid deposits. To help facilitate this, CMS proposed in July 2023 to increase its coverage of PET scans to detect these amyloid plaques—however, cheaper and faster diagnostic methods are still being developed.
The past decade has seen the development of biomarker tests to detect Alzheimer’s disease. In June, for example, the FDA cleared two tests from Roche that measure the concentration of beta-amyloid and tau proteins in cerebrospinal fluid (CSF). And at the end of July, Quest Diagnostics launched what it claims is the first direct-to-consumer blood-based biomarker test for Alzheimer’s.
“It’s an exciting time for Alzheimer’s disease biomarker research,” Ted Wilson, an investigator with the Alzheimer’s Disease Research Center Biomarker Core at Stanford University, told BioSpace. While these tests have yet to be accepted as diagnostic replacements for PET scans, researchers are hopeful that could be the way of the future.
Diagnostic Challenges
An estimated 6.7 million Americans have Alzheimer’s disease, with its prevalence predicted to rise. In 2023, it is estimated that dementias on the whole will cost America $345 billion. But despite their ubiquity, experts told BioSpace that obtaining an accurate diagnosis is difficult.
Part of the diagnostic challenge stems from the different types of dementia and neurological diseases that produce overlapping symptoms of cognitive impairment, Amanda Heslegrave, a research fellow at the UK Dementia Research Institute Biomarker Factory, told BioSpace. Alzheimer’s disease makes up 60–80% of dementia diagnoses, but other types include frontotemporal and vascular dementia, and a patient may suffer from multiple types of dementia simultaneously.
“The complete picture of what’s going on pathologically can often only be found at post-mortem,” Wilson said.
As a result, the diagnosis of Alzheimer’s disease is largely one of exclusion, or ruling out non-Alzheimer’s causes of symptoms, explained M. Laura Parnas, disease area network lead in cardiometabolism and neurology at Roche Diagnostics. “Obtaining an accurate diagnosis can take years,” she told BioSpace in an email.
Parsing out an accurate diagnosis is critical for making appropriate treatment decisions, experts say. For instance, frontotemporal dementia does not usually involve the buildup of amyloid plaques, and therefore anti-amyloid therapies such as Leqembi would not be an effective treatment.
To aid the diagnostic process, many researchers have set their sights on biomarker tests. These typically focus on two proteins that aggregate in the brain of dementia patients—amyloid and tau. Another biomarker for Alzheimer’s is neurofilament light chain (NfL), a marker of neurodegeneration. High levels of neurofilament indicate rapid neurodegeneration and disease progression, though a commercial diagnostic test using this biomarker has yet to be developed.
The tests approved so far examine one of two types of bodily fluids, CSF and blood. CSF samples require a lumbar puncture to retrieve and are unpopular with patients. Blood tests are often seen as the next step in Alzheimer’s diagnostics. Such noninvasive biomarker tests could reduce costs for patients and providers, Parnas said.
However, low concentration of Alzheimer’s biomarkers and the presence of other proteins in the plasma that might interfere with a potential assay have challenged this endeavor, Wilson. “Initially it was thought there were insurmountable problems using plasma as the matrix to detect these proteins.”
Currently Available Alzheimer’s Tests
Roche Diagnostics was one of the first companies to bring an Alzheimer’s diagnostic test to the market, with its Elecsys CSF beta-amyloid and phosphorylated-tau assays receiving approval in 2022. Then this June, the company received clearance from the FDA for its Elecsys CSF beta-amyloid and total tau assays.
In both cases, the pair of tests is used in tandem to measure the ratio of beta-amyloid to tau (either phosphorylated or total). High levels of amyloid and tau in the brain—and reflected in the CSF—indicate a patient is likely suffering from Alzheimer’s disease, Heslegrave said, while a high concentration of tau alone indicates other types of dementia are the cause of cognitive impairment.
In addition to the approved Roche Diagnostic panels, another CSF test from Fujirebio Diagnostics measuring beta-amyloid received marketing authorization from the FDA in 2022. CSF tests have comparable accuracy to PET scans when diagnosing Alzheimer’s disease.
For now, though, the Alzheimer’s Association still recommends that these tests be used in conjunction with PET scans to confirm the presence of amyloid plaques in the brain and officially diagnose a patient with Alzheimer’s disease, thereby qualifying them for treatment with Leqembi. However, CMS does not state how the disease must be verified, and it’s uncertain what diagnostic tests will be needed to qualify for CMS coverage. Currently, the most common use of biomarker assays is in clinical trials to screen patients and monitor drug effects, or as part of a broader diagnostic assessment alongside neuropsychological evaluation and clinical presentation, Wilson said.
Blood-based biomarker tests are further behind in clinical development. Quest Diagnostics’ blood-based test authorized at the end of July, for example, has not been officially validated as a test for Alzheimer’s and is not endorsed by Quest as a diagnostic tool, though it can reflect Alzheimer’s disease risk.
C2N Diagnostics is also developing a blood-based Alzheimer’s test that measures plasma-tau and amyloid concentrations, and the company recently reported that the second-generation version of the test, PrecivityAD2, had comparable diagnostic accuracy to CSF tests and PET scans.
Eventually, Parnas wrote in an email to BioSpace, these tests could be used as an official Alzheimer’s diagnostic, “providing a lower cost alternative to traditional imaging techniques” such as PET scans.