Blood-Based Alzheimer’s Tests Are Here, but Not Ready for Widespread Use
While new FDA clearances of blood-based early detection tests for Alzheimer’s represent significant progress, limitations remain.
These are heady times for Alzheimer’s diagnostics, thanks to the emergence of blood-based tests that detect elevated levels of the tau protein and other biomarkers associated with early onset of the disease. Since May, the US FDA has cleared two different tau-based Alzheimer’s early detection tests. But for all of the excitement, an influential panel of experts served a reminder that blood biomarkers (BBMs) of early-stage Alzheimer’s are still not ready for widespread use in primary care.
Current Alzheimer’s Diagnostics
The National Institutes of Health and Mayo Clinic estimate that there are over six million people in the US suffering from Alzheimer’s-related dementia. The easiest way to spot Alzheimer’s is by identifying impaired thinking. But because a significant number of brain cells must be damaged before a person begins to experience impaired cognitive ability, once Alzheimer’s is identified, it is frequently too late to provide effective treatment.
Current methods of early detection are based on identifying the abnormally large amounts of amyloid proteins that Alzheimer’s patients generate. The buildup of amyloid plaques strangle neurons and sever neuronal connections. While positron emission tomography (PET) scans can detect amyloid plaques, PET scans are relatively expensive and only about 70 percent accurate.
New Blood-Based Alzheimer’s Tests Emerge
Recent studies suggesting that elevated levels of tau phosphorylated at threonine 217 (p-tau217) are an accurate biomarker for early onset of Alzheimer’s offer new hopes of developing a simpler and more accurate BBM test that can be performed in a physician’s office. Of note, one study published in JAMA Neurology in November 2020 found that blood tests for detecting abnormal tau metabolism in the brain were able to detect pathology earlier than PET scans in patients with preclinical Alzheimer’s disease.
Currently Available Types of Blood Biomarkers
Plasma phosphorylated tau (p-tau) includes assays for measuring the levels of p-tau181, p-tau217, and p-tau231, which are related to both the density of Aβ plaques and tau tangles. Levels of different p-tau variants can also differentiate between people with and without significant Alzheimer’s brain pathology. There are currently several high-performing plasma p-tau immunochemical assays with similar performance, which bodes well for successful clinical implementation, but there are also commonly used assays with lower performance in head-to-head comparisons.
Plasma NfL can be used in both CSF and plasma as a marker of neuroaxonal injury, with the highest NfL concentrations in CSF and blood found in amyotrophic lateral sclerosis, or ALS, frontotemporal disorders, atypical parkinsonian disorders, multiple sclerosis, and HIV-associated neurocognitive dysfunction. In people with Alzheimer’s, plasma NfL is moderately elevated compared to healthy age-matched controls. In sporadic Alzheimer’s, there are associations of increased plasma NfL concentration in people with Aβ plaques and tau tangles, as well as people with longitudinal neurodegeneration detected by MRI (magnetic resonance imaging); however, this is mainly visible at more advanced dementia stages.
Plasma GFAP assays for glial activation detect high levels of GFAP protein, which are reflective of Aβ accumulation in the brain. Plasma GFAP is more strongly associated with Aβ pathology than CSF GFAP. Studies have shown that plasma GFAP levels can predict subsequent cognitive change and Alzheimer’s dementia in patients with mild cognitive impairment (MCI) and cognitive decline in CU subjects. Clinical-grade assays for plasma GFAP exist but more studies are needed in a memory clinic context.
Combining blood biomarkers with each other or with other easily accessible tests can increase clinical performance. For example, p-tau can be combined with Aβ42/Aβ40 ratio to detect a range of amyloid levels and predict cognitive decline. However, because certain plasma Aβ assays and p-tau assays perform less optimally than others, users should note which assays were used to quantify each biomarker.
On May 4, the FDA granted its first clearance for a blood-based in vitro test for early-stage Alzheimer’s, awarding De Novo classification to Fujirebio Diagnostics’ Lumipulse G β-Amyloid Ratio (1-42/1-40) test for use in people 55 years and older with cognitive impairment who are being evaluated for Alzheimer's. The Lumipulse test detects the presence of amyloid plaques by measuring the ratio of β-amyloid 1-42 and β-amyloid 1-40 in patient cerebrospinal fluid (CSF). In the clinical study supporting the De Novo submission, researchers examined 292 CSF samples from the Alzheimer’s Disease Neuroimaging Initiative sample bank and found that 97 percent of individuals who tested positive for plaques also tested positive via PET scan, while 84 percent of individuals who tested negative were also negative for amyloid on their PET scan. Those results indicate that the test gives patients a potential faster and cheaper alternative to “time-consuming and expensive PET scans,” according to Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, in a statement.
On July 19, the agency granted breakthrough device designation for Roche’s Elecsys Amyloid Plasma Panel, which measures the amount of p-tau 181 and apolipoprotein e4 (ApoE4) in blood to help determine whether an individual’s cognitive decline is more likely linked to Alzheimer’s or another cause. According to the NIH, ApoE4 “is the strongest risk factor gene for Alzheimer's disease,” so its presence can rule out other causes of cognitive decline. The panel may not only speed up Alzheimer’s diagnosis but also avoid unnecessary invasive and expensive testing for people who do not have Alzheimer’s. Specifically, by quantifying the p-tau 181 and ApoE4 biomarkers, the Elecsys panel can pinpoint which individuals should undergo confirmatory testing for Alzheimer’s via amyloid PET scans or CSF assessment; those who test negative can be directed toward follow-up testing for other potential causes of cognitive decline.
There are many more BBM Alzheimer’s tests in the pipeline. On May 4, Quest Diagnostics also launched its AD-Detect Amyloid Beta 42/40 Ratio test for assessing a patient’s risk of Alzheimer's disease. Based on a CSF test that Quest developed in 2017, the assay evaluates amyloid beta peptides Aβ42 and Aβ40 and can be used to monitor changes over time to assess the potential risk of Alzheimer's disease progression. According to Quest, in addition to providing insights into the risk of Alzheimer's disease, AD-Detect may also help identify patients who are candidates for early antibody treatment.
BBM prognostic tests designed to predict the progression of Alzheimer’s disease are also making their way to the US market, including Diadem’s AlzoSure Predict test, which received breakthrough device designation from the FDA in January 2022.
Limitations of BBM Alzheimer’s Testing
While the new FDA clearances represent significant progress, there are several limitations to blood-based Alzheimer’s testing. Accordingly, both the Fujirebio and Roche tests are only designed to be used alongside other clinical evaluations. When announcing De Novo clearance of the Fujirebio assay, the FDA noted that the test carries the risk of generating false-positive and false-negative results.
At the recent Alzheimer’s Association International Conference (AAIC), an influential panel cautioned that while BBM tests can change and improve the diagnosis of Alzheimer’s disease, they are not yet ready for prime time. The panel, whose paper was also published in the Alzheimer’s Association’s Alzheimer’s & Dementia journal on July 31, acknowledged the need for better diagnostic tools, noting that 25–30 percent of people who receive a clinical diagnosis of Alzheimer's are misdiagnosed. Methods for measuring the progression of the disease are also lacking.
“BBMs show promise for improving the diagnostic work-up for Alzheimer's,” said panelist Oskar Hansson, MD, PhD, of Lund University in Malmö, Sweden, at AAIC 2022. “But additional data are needed before [BBMs] can be used as a stand-alone test for diagnosis, and before considering broad use in primary care settings."
The Panel’s Recommendations
In their paper, the panel emphasized that CSF and PET scans remain the current reference standards for identifying Alzheimer’s and stopped short of recommending BBM tests for population risk screening or as direct-to-consumer tests “at this time.” However, the panel did recommend limited use of plasma Aβ42/Aβ40, phospho-tau (p-tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and potential combinations of markers for prescreening in the following settings:
- In clinical trials to identify patients who may have Alzheimer’s-related brain pathology.
- In specialized memory clinics as part of the diagnostic work-up of patients already experiencing cognitive symptoms.
However, the panel added in the paper that, in each case, status should be confirmed with CSF or PET “whenever possible.”
Next Steps
According to the panel of experts, BBMs have the potential to revolutionize Alzheimer’s diagnostics and prognostics, remarking that things are moving “very, very fast,” and that they would revisit their recommendations in 12 months. In the meantime, the panel identified research needed to enable the wider use of BBMs, including the following:
- Prospective studies in primary care settings that also include representative and diverse populations with cognitive symptoms.
- Analyses to determine whether BBMs outperform what is already available in primary care.
- Analyses to determine whether BBMs improve diagnosis and management.
- A better understanding of biological and disease-associated variability and the potential effects of medical comorbidities and concomitant medications on dementia.
- An assessment of whether BBM algorithms can be used alone to support an Alzheimer's diagnosis or whether additional CSF and PET studies are needed.
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