The search for a blood test to diagnose Alzheimer's disease has been a long one, and researchers moved closer this year than ever before. In May, 麻豆传媒 reported on an investigational blood assay for tau phosphorylated at threonine 181 (p-tau181). Here's a review of what's happened since then.
Plasma phosphorylated tau (p-tau) assays for Alzheimer's disease continued to take center stage with big breakthroughs this year, but it was an amyloid test that was first on the market.
In October, C2N Diagnostics, a company based on the work of Randall Bateman, MD, and David Holtzman, MD, of Washington University in St. Louis, the launch of PrecivityAD, the first widely available blood test to help clinicians diagnose Alzheimer's.
The test uses mass spectrometry to look at the ratio of two amyloid-beta isoforms -- Aβ42 and Aβ40 -- and the presence of apolipoprotein E (APOE)-specific peptides that reflect a patient's APOE genotype. The results form a score that indicates the probability of being amyloid-positive on PET imaging.
The score correctly identified amyloid status (determined by PET scans) in 86% of 686 older adults with cognitive impairment or dementia, with an area under the receiver operating curve (AUC) of 0.88, the company said.
PrecivityAD is not a stand-alone diagnostic tool. It was introduced as a laboratory developed test (LDT) regulated under the CMS Clinical Laboratory Improvement Amendments () program and received FDA breakthrough designation, but is not FDA-approved, though that's in the works, C2N CEO Joel Braunstein told 麻豆传媒. "It's important to recognize that the two pathways -- LDT through CLIA pathway vs FDA pathway -- are not mutually exclusive and instead can be seen as rather complementary," he said.
But its lack of FDA approval means groups like the Alzheimer's Association have not endorsed the test. "Without FDA review, health care providers lack the agency's guidance for how to use it when making decisions about a person's health or treatment," Alzheimer's Association chief science officer Maria Carrillo, PhD, told 麻豆传媒. "The FDA has had no say about what the test should measure, what are healthy and unhealthy levels, or how to ensure accuracy and predictability."
The test costs $1,250 and is not covered by private insurance providers, Medicare, or Medicaid, but patients who qualify based on income can pay between $25 and $400, Braunstein said. In contrast, amyloid PET scans, which also aren't covered by third-party payers, can cost about $4,000, though costs vary widely.
P-tau217: 'a real game changer'
In May, plasma p-tau181 was heralded as "an important advance that could transform the diagnosis of Alzheimer's disease," in an editorial by Mayo Clinic's Clifford Jack, Jr., MD. But in July, two papers presented at the Alzheimer's Association International Conference (AAIC) suggested another phosphorylated isoform might produce even better results.
Plasma p-tau217 discriminated Alzheimer's from other neurodegenerative diseases with significantly higher accuracy than plasma p-tau181, neurofilament light chain, or MRI biomarkers in several cohorts, said Oskar Hansson, MD, PhD, of Skåne University Hospital in Sweden, at the AAIC.
And while both p-tau217 and p-tau181 could predict the presence of amyloid plaques on PET scans, p-tau217 amyloid measures were superior, Bateman and Nicolas Barthélemy, PhD, also of Washington University, reported at the meeting. In a discovery cohort of 36 people, p-tau217 and p-tau181 were highly specific for amyloid plaque pathology (AUC 0.99 and 0.98, respectively). In a validation cohort of 92 people, p-tau217 was still specific to amyloid status (AUC 0.92), but p-tau181 measures were less specific (AUC 0.75).
A p-tau217 blood test could be "a real game changer," said Howard Fillit, MD, of the Alzheimer's Drug Discovery Foundation in New York City, who wasn't involved with either study. "It's almost like the first steps that blood tests for cholesterol in heart disease took back in the 1950s and '60s," he told 麻豆传媒.
Another analysis by Hansson's group, this one published in November, showed p-tau217 levels were increased in people who had abnormal amyloid-PET but normal tau-PET in the entorhinal cortex, an early region of neurofibrillary tangle formation.
"Our results are congruent with the idea that amyloid pathology increases phosphorylation and secretion of tau in neurons, which might be an important step in the development of widespread neurofibrillary tangle pathology in Alzheimer's disease," Hansson told 麻豆传媒.
The findings add to the growing evidence that plasma tau, especially p-tau217, may be used one day to detect and treat Alzheimer's disease, he noted.
"A blood-based biomarker like plasma p-tau217, detecting early Alzheimer's pathology, can be used to identify subjects suitable for clinical trials that evaluate disease-modifying therapies during the pre-symptomatic stages of the disease," Hansson said. "Such markers can also be used as pharmacodynamic markers, indicating whether a new treatment has an effect on Alzheimer's pathology in the brain."