Currently, Alzheimer’s disease is not diagnosed until patients already have evidence of plaques and tangles in their brain.
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Blood tests can’t diagnose Alzheimer’s disease yet, but one is already approved and more are on the way.
Long before the telltale signs of dementia emerge in a patient with Alzheimer’s disease (AD), early signals could be lurking within their blood. The opportunity to identify these markers and diagnose someone much earlier with a simple blood test could significantly advance the field, allowing clinical trials to enroll patients and develop treatments that could one day prevent or even reverse the course of disease.
Today, the gold standard for diagnosing AD requires imaging with expensive and radioactive positron emission tomography (PET) scans or invasive spinal taps to gather cerebrospinal fluid (CSF), along with cognitive testing.
A noninvasive option
The reality of a basic blood test to diagnose AD may not be too far away. In May, the FDA approved the first blood test called Lumipulse from Fujirebio Diagnostics to detect proteins in the blood indicative of amyloid plaques in the brain in adults aged 55 and over. Specifically, the test looks for pTau217 (phosphorylated tau 217) and beta (ß)-amyloid 1-42 as indications of the buildup of amyloid plaques between neurons in the brain.
However, experts say this test and others like it can’t provide a diagnosis yet. “These blood tests are sensors that reflect ß-amyloid pathology — a necessary but insufficient ‘diagnostic,’” said Sally Frautschy, a neuroscientist studying AD at the University of California, Los Angeles (UCLA). “The tests are a game changer in some respects, such as in lowering costs for and streamlining clinical trials, and excluding AD as a cause of dementia, but do not provide insight into the regional distribution of AD in the brain or mixed pathologies needed for a definitive or differential diagnosis.”
The FDA agreed, stating in their news release: “Importantly, the Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio is not intended as a screening or stand-alone diagnostic test and other clinical evaluations or additional tests should be used for determining treatment options.” Yet, as a measure of amyloid pathology on its own, the FDA cleared Lumipulse for marketing based on the results of a clinical study of 499 patients showing that 91.7 percent of samples with a positive result also had the presence of amyloid plaques confirmed by a PET scan or CSF test, and 97.3 percent with a negative result showed negative PET or CSF results.
The Lumipulse blood test could be used in place of the more expensive and invasive options to identify amyloid plaques — and new guidelines suggest doing exactly that. In July, the Alzheimer’s Association released its first recommendations for blood-based biomarker (BBM) tests, put forward by a panel of 11 clinicians. Although Fujirebio’s assay is the first to be approved, many more are in development, and the panel decided not to endorse specific tests. Instead, their new guidelines say that in patients with cognitive impairments being evaluated at specialty care clinics, tests with greater than 90 percent sensitivity and 75 percent specificity can be used to rule out AD pathology, and tests with both sensitivity and specificity above 90 percent can be used in place of PET amyloid imaging or CSF testing. In a summary document, the Alzheimer’s Association stated, “As ‘living guidelines,’ these recommendations will evolve with new evidence on BBM performance, diverse populations, and advanced analytical approaches.”
Future diagnostic blood tests
As more companies design and evolve their own blood-based assays, more research is needed to determine what the best biomarker is to measure in the first place. As an example, while Fujirebio’s assay measures pTau217 relative to ß-amyloid 1-42, another assay developed by Roche in partnership with Eli Lilly measures pTau181 relative to ß-amyloid 1-42 as an indicator of amyloid pathology. Their test just received a CE mark from the European Union with a sensitivity of 83.6 percent and specificity of 93.8 percent.
Frautschy explained that although both assays are similar in predicting ß-amyloid accumulation in the brain, the type of tau antibody used in the pTau217 Fujirebio assay has been shown to be the most sensitive to the earliest stages of ß-amyloid accumulation. In contrast, the Roche-Lilly pTau181 assay may detect slightly later stages, but still early disease.
She emphasized that the current readouts — ratios of tau to ß-amyloid 1-42 — only reflect amyloid burden, which does not directly correlate with memory loss. These assays also do not necessarily reflect the later stage of tau tangle pathology that is known to drive rapid memory deterioration. Thus, Frautschy said that additional ratios incorporating other proteins will likely be necessary for more informative diagnostics that can track and detect the causes of memory loss. Fortunately, she noted that markers that directly reflect the brain pathology responsible for memory decline are currently in development.
In the future, Frautschy emphasized that “the ideal biomarker panel would distinguish between tauopathy alone and AD, which requires both tau and amyloid pathology.”