Two blood markers, phosphorylated tau 217 (p-tau217) and phosphorylated tau 181 (p-tau181), showed strong diagnostic performances for Alzheimer's disease and discriminated Alzheimer's from frontotemporal lobar denervation (FTLD) syndromes and normal cognition, a retrospective study showed.
Both plasma biomarkers distinguished Alzheimer's disease syndromes from non-Alzheimer's disease disorders with a receiver operating characteristic area under the curve (AUC) greater than 0.90, reported Adam Boxer, MD, PhD, of the University of California San Francisco (UCSF), and colleagues, in Lancet Neurology.
"This confirms and extends our and others' previous work showing the exquisite sensitivity and specificity of new blood tests for Alzheimer's disease as opposed to other dementias," Boxer told MedPage Today.
"A previous JAMA manuscript suggested that plasma p-tau217 was highly superior to plasma p-tau181, however that study used two different types of tests which may have confounded the results," Boxer said. "Here, we used specially designed blood tests that differed only in their ability to detect either p-tau181 or 217. With these new tests, we show that both tests are highly accurate for diagnosis of Alzheimer's disease, although p-tau217 had small but statistically significant numerical advantages, for example in how well it correlated with tau-sensitive PET scans."
In the past 5 years, much research has focused on blood as a new matrix for Alzheimer's biomarkers that already had been validated in cerebrospinal fluid, noted Lucilla Parnetti, MD, PhD, of the University of Perugia in Italy, and colleagues, in an accompanying editorial.
"This study contributes substantially to the research of blood biomarkers for the diagnostic work-up of neurodegenerative diseases leading to dementia, by confirming the potential of plasma p-tau181 and p-tau217 for differential diagnosis," the editorialists wrote.
Boxer and colleagues studied 593 people, including 443 patients from the UCSF Memory and Aging Center and 150 patients from the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium in the U.S. and Canada. Mean age of the group was 64 and 50% were women. Data were collected between July 1 and Nov. 30, 2020, and immunochemical properties of p-tau217 and p-tau181 assays were directly comparable.
The cohort included 75 people who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, posterior cortical atrophy), 99 people with mild cognitive impairment, 274 people with FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioral variant frontotemporal dementia, non-fluent variant primary progressive aphasia, and semantic variant primary progressive aphasia), 14 people with Lewy body dementia, 13 people with traumatic encephalopathy syndrome, and 118 cognitively unimpaired controls.
Plasma p-tau217 and p-tau181 were correlated (r 0.90, P<0.0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's syndromes compared with cognitively unimpaired controls, with plasma p-tau217 showing an AUC of 0.98 (95% CI 0.95–1.00) and p-tau181 an AUC of 0.97 (95% CI 0.94–0.99).
P-tau217 outperformed p-tau181 in differentiating people with Alzheimer's disease syndromes from people with FTLD syndromes; p-tau217 had an AUC of 0.93 (95% CI 0.91–0.96) and p-tau181 an AUC 0.91 (95% CI 0.88–0.94; Pdiff=0.01). Both p-tau species were increased in pathology-confirmed Alzheimer's disease compared with pathology-confirmed FTLD.
Plasma p-tau217 was a stronger indicator of amyloid-PET positivity (AUC 0.91) than p-tau181 (AUC 0.89). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181.
The study had several limitations, Boxer and colleagues acknowledged. In the FTLD group, p-tau217 and p-tau181 concentrations were very low, with 79 measurements below the lower limit of quantification for p-tau217. Because the study focused on differential diagnosis, a relatively small number of people with Alzheimer's disease syndromes were included in the study. The cohort was relatively young and provided little information about how plasma p-tau will perform in older age.
"The tests we used are still for research only but hopefully within a few years, some versions will be available clinically," Boxer said. "Our results show that a well-designed, clinical grade p-tau181 or 217 blood test is likely to be very useful in many research and clinical applications."
"We are living in an exciting era of biomarkers for neurodegenerative disorders and are close to being able to apply them in clinical routine," the editorialists noted. "Healthcare providers and policymakers should become aware of, and knowledgeable about, the importance of this matter to enable use of blood biomarkers for diagnosis of neurodegenerative diseases to become a clinical reality."
Disclosures
The study was funded by the NIH, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J. Fox Foundation, Association for Frontotemporal Degeneration, and Alzheimer's Association.
Researchers disclosed relationships with NIH, Rainwater Charitable Foundation, Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Alzheimer's Drug Discovery Foundation, Alzheimer's Association, Alector, AGTC, Arkuda, Arvinas, AZTherapies, GlaxoSmithKline, Oligomerix, Ono, Regeneron, Roche, Samumed, Stealth, Third Rock, Transposon, Wave, Biogen, Eisai, Denali, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, CogRx, Fujirebio, AlzeCure, Brain Biomarker Solutions, AVID Radiopharmaceuticals, GE Healthcare, Pfizer, AC Immune, AlzPathway, Cerveau, Abcam, Axon, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Siemens Healthineers, Simon Foundation, Cura Sen, Wave Neuroscience, Ionis Pharmaceuticals, Mangurian Foundation, Little Family Foundation, EIP Pharma, Life Molecular Imaging, and Johnson & Johnson. Two researchers were employees of Eli Lilly and Company, which is exploring commercial development opportunities for p-tau assays. Another researcher holds a patent related to reagents used in p-tau assays.
Parnetti and co-authors disclosed no relationships with industry.
