New clinical trials on memory loss interventions are currently enrolling healthy participants with key Alzhemier’s biomarkers as young as 55 years old. Tau and beta-amyloid blood test are helping determine who’s eligible.
A co-principal investigator of the AHEAD Study, Dr. Reisa Sperling has her work cut out for her.
AHEAD is currently enrolling upwards of 1,100 people across the U.S. and Canada in research to test the theory that removing beta-amyloid plaques in the brain can delay or prevent the onset of Alzheimer’s symptoms. This is no easy feat: In this study, researchers are seeking trial participants as young as 55 years old, who are at risk of developing symptoms of Alzheimer’s disease as they get older, but who do not have symptoms yet.
The more precise trial administrators can be about this historically lesser-studied target audience of young, asymptomatic people predisposed to Alzheimer’s, the more researchers stand to learn about when these drugs are most effective. But identifying a large number of participants at-risk of Alzheimer’s is costly and logistically challenging. To date, this is generally done with pricey and hard-to-access PET scans and invasive spinal taps.
Adding to that is the pressing challenge to improve enrollment diversity: It is estimated that nearly 40 percent of the more than eight million Americans living with Alzheimer’s and related dementias will be Black or Latino, yet they are less likely to be included in clinical studies.
Luckily, Sperling, director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital, and other AHEAD investigators have a new tool at their disposal: blood tests, which are increasingly being leveraged in clinical trial enrollment to help expedite research and speed the path to developing new treatments, in part by helping make eligibility determination faster, easier and more accessible.
Sperling calls blood-based screening “a giant leap forward” when it comes to detecting changes in the brain among people who do not yet show memory loss symptoms. “New blood test technology can help identify those more likely to have Alzheimer’s disease changes in their brains, which enables them to enroll in prevention or treatment trials as early as possible,” she said in a news release from this week’s the international Clinical Trials on Alzheimer’s Disease conference (CTAD) in Boston. “This is a remarkable achievement that may lead to detecting and treating Alzheimer’s much earlier, and hopefully one day, preventing the memory loss associated with this devastating disease.”
In AHEAD, up to 75 research centers across North America will use PrecivityAD™, developed by C₂N Diagnostics, to identify those most at-risk for changes in the brain from Alzheimer’s by testing for the presence of the key biomarker beta-amyloid.
AHEAD is studying participants’ response to drug lecanemab, a monoclonal antibody. Meanwhile, TRAILBLAZER-ALZ 3 is enrolling upwards of 3,000 people age 60 and up to test another “mab,” donanemab. Both drugs received the Food and Drug Administration’s breakthrough status this year in the wake of the controversy around Aduhelm (aducanumab), another drug in the same family.
These “mab” drugs are anti-amyloids, developed according to the amyloid hypothesis that reducing the amount of beta-amyloid protein in the brain should slow or stop Alzheimer’s disease. But particularly following the aducaumab efficacy debacle, many experts theorize that the anti-amyloid approach may not be effective in later stages of Alzheimer’s, pushing research toward people with earlier stages of the disease, hence the need for pre-symptomatic cohorts, and in turn, the importance of accessible diagnostic tools that can pinpoint disease pathology in the brain earlier.
C₂N’s PrecivityAD™ test was put on the fast-track to FDA approval this summer, and results presented at CTAD today indicate that the blood test identifies specific beta-amyloid proteins in blood plasma — a key precursor to the development of Alzheimer’s symptoms — and that detecting the presence and quantity of this biomarker is a promising way to test someone’s likelihood of having amyloid build-up in the brain.
“Interested participants will get a blood test first, as part of the screening process,” Sperling told Being Patient. “If the blood test indicates increased likelihood of elevated amyloid, they will proceed to the next stage in the screening process, which is an amyloid PET scan.”
This process will roll out in the U.S. in November, which, according to Sperling, may make it the first trial ever to use Ab 42/40 ratio plasma screening in a trial aiming to prevent symptoms of Alzheimer’s disease.
Sperling also believes this approach could also offer a much-needed boost to diversifying clinical trial enrollment: “We also hope that this new test will make it easier for people from diverse backgrounds, especially people of color, to learn if they might be right for the study by starting with this simple blood test,” she said.
What’s Next for C₂N?
Outside of trials, the C₂N test is designed for people 60 and older who are experiencing cognitive impairment, and who are accordingly seeking testing for Alzheimer’s. In late 2020, it became commercially available U.S. states and in Europe at $1,250 — less expensive that amyloid PET scans. (It joins an existing Quest Diagnostics blood test designed to identify Alzheimer’s biomarkers.) Neither diagnostic method is covered by insurance at this time, but if the FDA approves C₂N’s test, that could change.
The C₂N Diagnostics test measures proteins in the blood that indicate the probability of amyloid in the brain, assigning patients a score ranging from zero to 100 and putting them into a risk category based on their score range: A value between zero and 36 is “low,” a value between 37 and 57 is “intermediate,” and 58 and above is considered a higher risk for amyloid in the brain. Data from early trials shows it keeps up PET scans’ prediction of beta-amyloid levels with 81-percent accuracy.
C₂N Diagnostics’ CEO Dr. Joel Braunstein told Being Patient in a past interview that risk scores can give a person more information on how susceptible they may be to Alzheimer’s: “We think over time, that number’s meaning is going to become even more important, as we get data on repeat sampling in many patients over many years,” he said. Outside of trial research, test makers hope a higher score may serve as an incentive to adopt more aggressive lifestyle interventions, utilize available therapies or participate in a clinical trial in hopes of dropping that score over time.
“I believe Trailblazer 3 will start widespread screening [with a tau plasma test] in early 2022, and I suspect that many trials will start using screening plasma tests,” Sperling told Being Patient. “The data we’re presenting [at CTAD], which show an area under the curve of .87 to detect people with even intermediate levels of amyloid for the A3 trial part of the AHEAD Study, is very encouraging!”
