Glial fibrillary acidic protein, or GFAP, a marker of neuroinflammation, has also drawn interest. “We’re starting to get really good GFAP assays,” says Dr. Frykman, who calls the Lumipulse GFAP assay “superb.” It’s possible, he says, that GFAP, p-tau217, NfL, BD-tau (blood-based brain-derived tau), TDP-43, and potentially other blood biomarkers could eventually become part of a testing panel. And Dr. Shaw identifies markers of late-tau pathology as a “red-hot area of research.”
As with the currently approved blood-based biomarkers, each will have its own strengths and weaknesses, not only from a diagnostic potential but also in terms of test performance and sample processing. As the current work migrates from research discoveries to the clinical setting, Dr. Tran asks, “Does a research discovery translate well into pragmatic clinical operations?” Collecting samples as part of a study can be more precise than taking samples during routine patient care—a sticky protein such as amyloid-β, for example, may become more unruly in the latter instance. “This is the real world, and we’re starting to see some of the noise that comes up.”
As with the approved biomarkers, newer ones will also face competition, so to speak, from other diseases. As Roger Kahn wrote in his baseball classic The Boys of Summer, the bright moments of every spring training also reveal “the dead sunlight of a forgotten spring.” Not every player, no matter how “trim, graceful and effortless,” will ascend to greatness or a World Series ring. Promising biomarkers, take note.
NfL can be elevated with multiple sclerosis, for example, or with a CNS infection. It also increases with age, which makes it likely that age-specific cutoffs—even within the aging population of Alzheimer’s patients—could come into play if this biomarker becomes approved and widely adopted, Dr. Tran says. “As we test more, we realize there are more subgroups that we’re going to worry about. And we’re going to have to educate for that.”
There’s also the matter of when the tests are used and by whom.
Would baseline p-tau measurements be useful at some point? “That’s the dream for a lot of our tests. It’s more personalized,” Dr. Tran says. But cost-benefit considerations also come into play, including biological variability. “As we age the numbers may jump around, become more variable perhaps,” he says. And there is assay variability as well. “The assay jumps around because of statistics, not disease.”
Even more important might be the societal impact. “We quickly get excited” by new markers, says Dr. Tran. “A new toy! New technology that’s going to help us do X, Y, and Z. But over the years, I’ve seen that the real struggle is to leverage these tests in the right way so that everyone has access to care.” A blood test may be more accessible and affordable, and certainly this should be the case for these Alzheimer’s biomarkers. “But can patients afford the next steps?” Dr. Tran asks, such as a neurology appointment, a PET scan, and the therapeutic agents. Do they even have access? He sees echoes from the pandemic, when labs excelled at bringing up new tests quickly but they weren’t necessarily widely available “to all walks of life.” Remember, he says, “Alzheimer’s isn’t only a wealthy person’s disease.”
It’s possible, says Dr. Frykman, that eventually the field could shift even beyond these critical issues.
Though PET scans are used now to confirm certain positive blood-based biomarkers, Dr. Frykman predicts use of these imaging studies will decrease in the next five years. “The blood tests are going to be so good, they might be even better than the PET scans. So I would say that clinical chemistry is going to become the most important,” he says. “The blood tests are going to take a leading role within diagnosing Alzheimer’s, but also other neurodegenerative diseases in a way that is perhaps not fully understood today. But I look at the future with quite a bit of enthusiasm and excitement.”
He continues: “It’s obviously awful to get many diseases—cancer and heart disease and what-not. But when a person gets Alzheimer’s, there’s something very sad about it. My mom passed from that, and it was terrible to watch her go through it. The torture that this disease is is gruesome.”
He’s well aware of the setbacks that will occur along the way. But he gives free rein to his enthusiasm. If physicians can detect high-risk patients early enough, he says, therapeutic and lifestyle interventions might be able to help them circumvent the disease, possibly forever. “I see that happening in the next 20 years. I think, when we look back on this, it’s going to be a big step forward for humans.”
Karen Titus is CAP TODAY contributing editor and co-managing editor.