NEW YORK – As the science around blood-based biomarkers for Alzheimer's disease continues to develop, new analytes have come to the fore, potentially displacing certain older markers and leaving some firms playing catch-up.
Specifically, plasma phosphorylated-tau 217 (p-tau 217) has emerged as a highly promising marker of the brain amyloid pathology characteristic of Alzheimer's and one that could lessen demand for plasma amyloid-beta 42/40 (Aβ42/Aβ40), the first blood-based marker for the disease to come to market.
While companies including Quanterix and C2N Diagnostics currently offer p-tau 217 for clinical use, other companies active in the Alzheimer's testing space, including Quest Diagnostics, Roche, and Fujirebio, do not, though there are indications that these firms are pursuing versions of assays using this biomarker.
In general, blood-based biomarkers for Alzheimer's have received significant academic and industry interest in recent years as researchers have demonstrated the feasibility of detecting markers linked to the disease in patient blood.
Blood-based tests for Alzheimer's are highly appealing because, unlike existing cerebrospinal fluid or PET imaging tests for the condition, they can be run inexpensively and at scale in large, potentially asymptomatic populations. Recent US Food and Drug Administration approvals — in particular of Eisai's Alzheimer's drug Leqembi (lecanemab) — have raised the possibility that physicians will in the near future need easily scalable Alzheimer's screening methods to identify patients who may benefit from these and/or future treatments.
At last year's Alzheimer's Association International Conference in Amsterdam, a working group brought together by the Alzheimer's Association and the US National Institutes of Health's National Institute on Aging (NIA), proposed that blood-based markers be included in clinical guidelines for Alzheimer's testing.
Plasma Aβ42/Aβ40 tests were the first blood-based Alzheimer's assays to come to the clinic. St. Louis-based C2N launched the first such test, its PrecivityAD product, in 2020. The mass spectrometry-based test measures levels of Aβ42 and Aβ40 (calculating the ratio of the two) and apolipoprotein E in patient blood, combining those measurements with the patient's age to generate a risk score predicting the likelihood the patient has the amyloid brain plaques associated with Alzheimer's.
In 2022, Quest launched its AD-Detect test, which likewise uses mass spectrometry to measure Aβ42/Aβ40 ratio in blood. Last year, the company released a consumer-initiated version of the test.
Plasma Aβ42/Aβ40 ratio is not an ideal marker for brain amyloid status, however. The difference in plasma Aβ 42/40 ratios between patients with and without brain amyloid pathology is typically only 10 to 15 percent, and drugs commonly used in older populations can significantly impact patient ratios. Some studies have indicated that this difference may be too small for tests to reliably detect and that the inclusion of other markers may be necessary to provide the required performance.
One player in the Alzheimer's diagnostics space, Roche, moved on from a prototype immunoassay for assessing plasma Aβ 42/40 ratio due to the small difference in levels between patients with and without amyloid pathology and the challenge of measuring that difference consistently. The company is now pursuing a plasma panel consisting of phosphorylated-tau 181 and apolipoprotein (APOE) E4.
In another indication of the challenges of using plasma Aβ 42/40 alone, Quest this month announced it has added plasma p-tau 181 to its AD-Detect test to boost its performance.
At the same time, p-tau 217 has emerged as a highly promising blood-based marker for assessing brain amyloid status and one that might prove sufficient as a standalone test for this purpose. Research has found p-tau 217 to be a higher performing marker than p-tau 181. Additionally, in its proposal, the NIA-Alzheimer's Association working group highlighted the superiority of plasma p-tau 217 to plasma Aβ 42/40 for detecting amyloid pathology and noted that plasma p-tau 217 has "accuracy that is equivalent to approved CSF assays."
Last month, a team led by scientists at the University of Gothenburg, published a study in JAMA Neurology looking at the effectiveness of p-tau 217 for detecting amyloid pathology and tracking changes longitudinally. Using a p-tau 217 test from diagnostics firm Alzpath, which runs on Quanterix's Simoa immunoassay platform, the researchers collected p-tau 217 measurements in 786 individuals (525 without cognitive impairment and 261 with cognitive impairment) and compared those results to the current gold standard measures — CSF Aβ42/40 and p-tau and PET. They found that plasma p-tau 217 identified amyloid pathology with an area under the curve of 0.92 to 0.96, comparable to CSF markers, and that it outperformed other plasma Alzheimer's markers including p-tau 181, p-tau 231, Aβ42/40, GFAP, and NfL. Roughly 20 percent of individuals tested returned an indeterminate p-tau 217 score.
Andreas Jeromin, Alzpath CSO and an author on the JAMA Neurology paper, said the performance of the marker suggests it can be used as a standalone confirmatory test for brain amyloid status.
"If someone is coming in the door, mildly cognitively impaired, early [Alzheimer's], a potential candidate for disease-modifying treatment, how do you identify with high likelihood that that person shows amyloid pathology in the brain?" he said. "That is where I see the immediate intended use of a p-tau 217 assay."
He suggested the assay could also find a place in primary care settings as a rule-out test used in annual screenings or to evaluate patients with memory complaints.
Alzpath currently offers a research-use p-tau 217 assay and plans by the end of February to launch a clinical assay as a laboratory-developed test through a lab partner it has yet to announce.
Quanterix, whose Simoa technology underpins the Alzpath assay, already offers its own p-tau 217 LDT, the LucentAD p-Tau 217 test, which uses p-tau 217 antibodies licensed from J&J Innovative Medicine. The company also offers blood- and CSF-based Aβ42/40 assays for research use.
Quanterix President and CEO Masoud Toloue said that he expects p-tau 217 will become the go-to blood marker for determining whether patients have brain amyloid pathology and are therefore candidates for anti-amyloid therapies.
"I would say that anything less than 217 is not going to be a marker for testing patients in blood," he said. "If you don't have a p-tau 217 test, you don't have a marker you should be using in blood to detect amyloid pathology."
Moves within the Alzheimer's testing space suggest others feel likewise. Last year, C2N launched its PrecivityAD2 test, which adds p-tau 217 (specifically the ratio of p-tau 217 to non-phosphorylated tau 217) to the components of the original PrecivityAD test.
During a conference call following the release of Quest's Q4 2023 results, President and CEO Jim Davis said the company plans to launch a plasma p-tau 217 assay later this year that will complete its blood-based Alzheimer's test offering.
Bruce Jordan, international business leader of personalized healthcare solutions at Roche, said that his company is also exploring plasma p-tau 217 as a marker. He noted that the marker could prove particularly useful as anti-amyloid therapies become more commonly used.
"We've investigated multiple potential candidate [assays] for p-tau 217, and we're pretty confident that we have narrowed it down to some good candidates, and we hope in the latter part of this year to be able to say more about that," he said. "We definitely think p-tau 217 is an extremely promising biomarker."
Fujirebio currently offers research-use-only plasma tests for Aβ 42/40 ratio and p-tau 181 and is also developing an assay for p-tau 217. The company did not reply to a request for comment.
"P-tau 217 is a well-behaved analyte in the proper assay," said Joel Braunstein, C2N's president and CEO. "It has a nice dynamic range. There is a significant difference [in p-tau 217 levels] between people who have amyloid pathology versus those who don't."
Braunstein said, however, that he still sees a role for Aβ42/Aβ40. He noted that one shortcoming of p-tau 217 is that its sensitivity appears to decline as you move earlier in disease development.
"That is where we see Aβ42/Aβ40 continuing to play an important role," he said. "It appears to be one of the earliest indicators of the [Alzheimer's] disease process."
He noted that while today much of the emphasis in Alzheimer's testing is on assessing whether symptomatic patients have brain amyloid pathology — a use for which p-tau 217 is well suited — as the field tries to start therapies earlier and earlier in the disease process, markers like Aβ42/Aβ40 that can potentially pick up Alzheimer's in its earliest stages could prove key.
Braunstein added that plasma Aβ42/Aβ40 could prove useful for assessing patient response to anti-amyloid Alzheimer's therapies.
Michael Racke, medical director for neurology at Quest, likewise said that plasma Aβ42/Aβ40 appears to pick up amyloid positivity earlier in the disease process than other analytes, including p-tau 217, and suggested that Aβ42/Aβ40 still has a potentially valuable role as an Alzheimer's marker.
He said that p-tau 217 outperforms p-tau 181 and Aβ42/Aβ40 for assessing whether or not patients close to the onset of cognitive impairment have amyloid pathology. However, he said that "from the perspective of trying to identify people at risk [in the earliest stages], there are people who are 42/40 positive who are negative for the other" markers.
"And I would say that the goal is still that the earlier you can identify who is really on the path to Alzheimer's disease … the more likely you can have a significant clinical benefit," Racke said.
Added Roche's Jordan, "I think we're really seeing that there will be a role for many of these biomarkers to play at various stages of this journey."