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UK Evaluating Utility of Blood-Based Markers for Alzheimer's Disease


NEW YORK – UK researchers have launched a pair of clinical studies exploring the utility of blood-based biomarkers for diagnosing Alzheimer's disease and other neurological conditions.

One study, called READ-OUT (REAl world Dementia OUTcomes) and led by researchers at Oxford University, will investigate a number of blood-based biomarkers that could be useful for diagnosing and distinguishing between various forms of dementia. The other study, called ADAPT team (Alzheimer’s disease Diagnosis And Plasma pTau217) and led by researchers at University College London, will focus specifically on the Alzheimer's blood marker phosphorylated tau-217 (p-tau 217).

The studies aim to explore whether blood-based biomarkers can hasten the speed with which patients are diagnosed, lower the costs associated with diagnosis and treatment, and improve patient quality of life and care.

Blood-based Alzheimer's biomarkers have gained prominence in recent years as potentially less costly and more accessible alternatives to existing diagnostic tools like cerebrospinal fluid testing and PET scans. According to Vanessa Raymont, senior clinical researcher at the University of Oxford and a leader on the READ-OUT study, only around 2 percent of patients in the UK access either CSF testing or PET as a part of work-ups to evaluate suspected Alzheimer's disease.

The UK's Medicines and Healthcare Products Regulatory Agency (MHRA) is also considering approving Eisai's Alzheimer's drug Leqembi (lecanemab) and Eli Lilly's drug donanemab. Blood-based markers could prove useful for the quicker identification of patients who are candidates for these therapies. In a draft diagnostic pathway for Alzheimer's published in February by the National Health Service (NHS) England in anticipation of future Alzheimer's drug approvals, blood-based testing played a prominent role as a screening tool for ruling out individuals who don't have Alzheimer's.

The READ-OUT study will enroll around 4,000 patients and be conducted in two stages over five years. In the first stage, the researchers will collect a variety of blood biomarkers from roughly 3,000 participants and investigate over the course of three years whether individual or a combination of markers, or combinations of markers and clinical data improve the diagnosis of Alzheimer's and other dementias. All participants will be symptomatic with most recruited from memory clinics and around 10 percent recruited from primary care offices. The study also aims for roughly 30 percent of participants to come from underrepresented ethnic groups, Raymont said.

The researchers have not yet finalized the set of markers they plan to look at, Raymont noted, but they will divide them into three tiers based on the level of current evidence supporting their utility. Tier 1 will include more established markers like p-tau 217, neurofilament light chain, and APOE4. Tier 2 will include markers like glial fibrillary acidic protein (GFAP) and possibly polygenic risk scores that have support in the literature but are not commonly used in the clinic. The third tier includes possible proteomic and genomic markers, Raymont said, adding that while the researchers will be collecting blood samples from participants for genomic and proteomic work, discovery and validation of those markers lies outside the scope of the current effort.

In the first stage, the researchers will also do longitudinal testing of a subsample of the study population. Additionally, they plan to explore the feasibility and scalability of remote testing using blood-prick samples, Raymont said. For this latter project, the team is working with Nicholas Ashton, a researcher at King's College London and the University of Gothenburg, who has been running a similar study in Sweden.

The READ-OUT study's second stage will be a two-year, 880-subject randomized controlled trial looking at the utility of sharing blood-based biomarker data with patients and their physicians with the primary outcome measure being improvement in the quality of life. Raymont said that outcome was chosen in part because data on it will be required by the NHS in order to add blood-based Alzheimer's testing to its list of covered services. The researchers will also look at qualitative assessments around "acceptability to the participants and family members" and "whether there is an impact on cognition and activities of daily living," she said.

The second stage will also model the health economics of blood-based Alzheimer's testing.

Raymont said she and her colleagues are considering a variety of platforms and test manufacturers for use in the study but noted that one factor they are particularly interested in is how easily a test can scale for use at multiple sites across the UK. Currently, she said, almost all of the country's biofluid-based Alzheimer's testing is done out of University College London (UCL).

UCL researchers are leading the ADAPT study, which is looking specifically at plasma p-tau 217, which is among the more promising blood biomarkers for Alzheimer's. Ashvini Keshavan, senior clinical research fellow at UCL and a leader of the study, said it will comprise three stages.

In the first stage, Keshavan and her colleagues will evaluate different p-tau 217 tests to determine which to use in later portions of the study, assessing factors like their pre-analytic variability and how well they can deal with samples transported from remote parts of the UK. In the second stage, the researchers will measure p-tau 217 in samples collected prospectively over a period of three years from patients undergoing PET scans at Imperial College London with the aim of ensuring that the cut points they establish for their p-tau 217 measurements don't drift over time.

The final stage of the study consists of a 1,100-subject randomized controlled trial investigating whether use of p-tau 217 testing increases the rate of Alzheimer's diagnoses.

"We know that in the UK at the moment, it is likely that people overall are being underdiagnosed with AD," Keshavan said, adding that the primary endpoint of the trial is a 10 percent increase in the rate of Alzheimer's diagnosis in the arm with access to p-tau 217 testing compared to the arm that does not.

Keshavan said that she and her colleagues have not yet nailed down which p-tau 217 tests they will evaluate for use in the study but that they would likely look at Alzpath's Alzpath Dx p-tau 217 test, which uses Quanterix's Simoa immunoassay technology, and Fujirebio's Lumipulse assay. Laboratory Corporation of America uses the Fujirebio assay for its plasma p-tau 217 test, which the company released in March.