This article was amended to correct the names of the assays from ALZpath and Janssen.
NEW YORK – The blood-based biomarker p-tau 217 showed the strongest relationship with other hallmarks of Alzheimer's disease, such as positron emission tomography (PET)-based detection of abnormal amyloid proteins, cortical thickness, and dementia severity, in a new analysis from a team of researchers at Washington University in St. Louis.
For patients to be eligible for new Alzheimer's therapies such as Eisai and Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab), doctors must confirm they have early-stage disease, when symptoms are mild. Doctors typically do this through neurological exams, cognitive function tests, and evaluations of certain biomarkers like beta-amyloid and tau via imaging or in cerebral spinal fluid.
Labs are now starting to market blood-based biomarker tests that they say will make it easier to diagnose patients, but the accuracy of these tests compared to standard methods in determining whether patients have Alzheimer's is uncertain.
A team of researchers led by WUSTL's Suzanne Schindler and supported by the Foundation for the National Institutes of Health evaluated the ability of six plasma biomarker tests — PrecivityAD2 (from Washington University spinout C2N Diagnostics), Lumipulse (Fujirebio Diagnostics), Simoa ALZpath p-Tau 217 Assay (ALZpath), NeuroToolKit (Roche Diagnostics), Neurology 4-Plex (Quanterix ), and the LucentAD p-Tau 217 assay (Lucent Diagnostics/Quanterix) — to detect amyloid and tau, compared to PET, and to gauge cortical thickness and dementia severity. The researchers particularly wanted to track how well these blood-based tests gauged the presence of amyloid, compared to PET.
The study, which has been accepted by the journal Alzheimer's and Dementia and is currently available as a preprint on MedRxiv, assayed plasma samples from 392 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) biorepository, collected within six months of an amyloid PET scan at three distinct time points.
Of the biomarkers the various tests assayed, the study showed p-tau 217 consistently had the strongest correlations with amyloid PET status, early tau PET, cortical thickness, and dementia severity. This biomarker also consistently outperformed Aβ42/Aβ40 in predicting amyloid status and other characteristics of Alzheimer's.
"The most interesting result of this study was that p-tau 217 was the best biomarker for all of these Alzheimer's disease outcomes," Schindler said.
This result meant that the best-performing assays were those incorporating p-tau 217. These included PrecivityAD2, Lumipulse, the ALZpath pTau217 assay, and LucentAD p-Tau 217. The top two performers across all measures were PrecivityAD2 and Lumipulse.
While neither Roche's NeuroToolKit nor Quanterix's Neurology 4-Plex include p-tau 217, Roche recently entered into a licensing agreement with ALZpath for the use of the ALZpath pTau217 antibody, which Roche plans to offer on its Elecsys platform.
P-tau 217, in fact, correlated so strongly with the measured Alzheimer's outcomes, Schindler said, that it performed equivalently to CSF tau tests currently approved by the US Food and Drug Administration for classifying amyloid PET status. Because of this, Schindler suggested that it might be reasonable to include p-tau 217 plasma tests in diagnostic evaluations for Alzheimer's disease.
"If [a] patient has a clinical syndrome typical of Alzheimer's disease and biomarker testing demonstrates the presence of amyloid pathology and the patient does not have other apparent causes of cognitive impairment, the patient would likely be diagnosed with cognitive impairment due to Alzheimer disease," she said.
Although PET imaging and CSF obtained via spinal tap are the primary methods for determining the presence of beta-amyloid, these methods are costly and not consistently covered by insurance. As such, researchers have been actively investigating plasma-based liquid biopsies as possible alternatives.
If a plasma-based measurement of p-tau 217 can consistently match the accuracy of those established methods, Schindler said that research studies and clinical trials might be able to "simplify things" by relying on it alone, or at least on a more limited number of blood analytes to measure signs of Alzheimer's disease.
"It's better to have a single high-performing analyte than a bunch of low-performing analytes," she said.
She cautioned, however, that the other Alzheimer's biomarkers evaluated in the study —neurofilament light chain (NfL), p-tau 181, and GFAP, in addition to Aβ42/Aβ40 — still provide information that is useful in other contexts.
Schindler suggested that those other biomarkers could be used within studies examining the effects of drugs on people with Alzheimer's who haven't yet started to experience cognitive problems or determining whether someone's cognitive issues stem from Alzheimer's or another condition. In her team's analysis, the differences in correlation to clinical outcomes between p-tau 217 and the other biomarkers, for example, narrowed considerably in cognitively unimpaired and amyloid PET-negative patient cohorts. Schindler said this likely occurred because this population has lower levels of amyloid pathology.
Schindler collaborated on a separate study, for instance, that found the ratio of phosphorylated to non-phosphorylated tau 217 in combination with Aβ42/Aβ40 provided high diagnostic accuracy in identifying which individuals with cognitive symptoms likely had Alzheimer's disease.
Nonetheless, Schindler said that the current findings caution against relying too heavily on Aβ42/Aβ40 itself in cognitively impaired individuals.
"Unfortunately," she said, "people really like the simplicity of Aβ42/Aβ40. That's the [typical] measure for amyloid PET, and that will misclassify a lot of people."
Schindler said that her findings also call the use of the amyloid tau neurodegeneration (ATN) biomarker framework into question. That framework relies on measurements of Aβ40, Aβ42, and the Aβ42/Aβ40 ratio as well as p-tau 181, NfL, and total tau and is used by some academic and commercial labs to quantify Alzheimer's pathology.
"This could create a lot of problems," Schindler said, explaining that the reliance on measures such as Aβ42/40 could result in false-negative findings.
Schindler's findings parallel those in a separate study led by researchers from Lund University, and with whom her group collaborated. That study, which is also posted as a preprint on MedRxiv, consisted of a head-to-head comparison of both plasma and CSF-based assays for p-tau 217 and included both commercially available and research-use-only kits.
In this analysis, the researchers compared Lilly Research Laboratories' Meso Scale Discovery immunoassay, Roche's Elecsys CSF, Fujirebio's Lumipulse G1200, Johnson & Johnson's LucentAD, ALZpath's pTau217 assay, and C2N's PrecivityAD2.
Similar to Schindler's study, the Swedish-led group determined that p-tau 217 –– measured by both mass spectrometry and immunoassays –– generally compared well to PET-based amyloid detection, with PrecivityAD2 again showing the best performance.
Schindler is now using the longitudinal information from the ADNI samples to follow up on her current findings. In one study, she and her team are investigating when in the course of a patient's disease, levels of Alzheimer's biomarkers such as p-tau 217 and Aβ42/Aβ40 change. Such longitudinal plasma biomarkers, she said, will help to build more accurate prediction models for Alzheimer's symptoms. And in a closely related line of research, she and her team are also evaluating how the rate of change in plasma biomarkers corresponds to changes in other Alzheimer's disease outcomes.
Finally, while the six tests included in Schindler's investigation need to be studied in more diverse datasets, as approximately 92 percent of the ADNI cohort is primarily of European ancestry, she doesn't expect the overall conclusion that p-tau 217 outperforms other measures of amyloid pathology to change significantly.
"This [study] really drives home that p-tau 217 is a much better marker of amyloid and that you should use that and not Aβ42/Aβ40," Schindler said.