CSF biomarkers in ‘a new era’ for Alzheimer’s

Another slowdown in the wider use of CSF biomarkers has been lack of standardization. Aβ42 has both a reference method and reference material, so when the tests become FDA approved, interpretation will be consistent across sites, says Dr. Algeciras-Schimnich. But P-tau is a work in progress.

That’s putting it mildly. With tau, there’s even more to untangle.

In multiple studies, researchers have reported lower CSF T-tau and P-tau concentrations in Black participants versus white participants. And there is a push for data. The long-term Alzheimer’s Disease Neuroimaging Initiative (currently ADNI3) is ongoing, but last year researchers were charged with recruiting underserved populations for the study’s final two years, says Dr. Shaw, who has been involved with ADNI since 2004. The work won’t stop there. “In ADNI4 the recruitment effort will be like nothing we’ve ever done in the ADNI study, to [ensure] that we achieve that goal,” he says. “Alz­heimer’s centers across the U.S. are recognizing that the population we are all studying has to be more representative of the [U.S.] population.”

“The whole art and science of reaching those folks requires a great deal of thought and effort,” Dr. Shaw continues. “You don’t just decide to do it and it happens. It’s not a piece of cake. There’s a lot of strategy and culture change at the level of the people doing the recruiting.”

It also requires—not to put too fine a point on it—money. “You have to spend money,” Dr. Shaw says. Lack of spending has inhibited efforts in the past, he concedes. But national efforts to advance Alzheimer’s disease research, coupled with “the national recognition of our failure with underserved minorities, means we are galvanized. More money will be spent.”

“We’ll get to the bottom of that fairly quickly, once we get the data together,” he adds. “We can get something meaningful done in the next few years. I think ADNI will be out there, sooner rather than later, with systematically collected biofluid, imaging, and data across a more diverse and representative population.”

Dr. Hu and his colleagues were the first to report lower tau levels in groups of Black patients compared with groups of white patients, findings that have since been replicated in people as young as in their 20s, he says.

The first thing to note, he says, is that these are differences in averages, with a great degree of overlap between patient groups. “We’re not saying the spinal fluid levels of tau and phosphorylated tau in Black Americans are completely separate from the levels [in] white Americans. We’re just saying the averages are lower.”

In terms of disparities, he’d like to see more research consider inclusivity—as he defines it, being “inclusive of people with Alzheimer’s disease without sacrificing the accuracy of the test. If we just lower the T-tau and P-tau levels, we will gain more true positives at the cost of more false-positives. We need to better understand why, at the group level, the levels of tau and P-tau are lower in Blacks, and that means not excluding Black research participants when their tau levels are lower.”

Dr. Hu eyes individual factors to explain the difference. “That’s what many of us are trying to study—whether there are genetic factors that modulate tau levels or phosphorylated tau levels. This is a very active area of investigation.” Other proteins apart from the two taus also appear to be different between groups. “These are scientific observations that need to be resolved if we want to use them responsibly in the clinical setting.”

How confident is he that this work will be carried out responsibly? “I don’t think any of us has found a protocol yet on how to do this,” he says.

Arguably he and colleagues took a step in that direction when they first noted the differences. They contacted the National Center for Bioethics at Tuskegee University “and invited them to start looking at our work when we first came up with the differences between Blacks and whites.” It was not a hard decision. “We don’t know how this information will be used in the future,” he says. “And I think any discovery can be misused.”

Dr. Hu adds, “I want to make sure that we are scrutinized in a prospective way, so that we are not looking back—if some information that we learn today is abused in the future—and saying, Oh, I wish we had thought more about those downstream implications.”

“I don’t personally believe we should stop looking just because of the potential for misuse in the future,” he continues. Study participants of African ancestry are eager to know this information because it affects their health, he says. “But we need, at the same time, to put safeguards in place.” This work has been the focus of studies as well as a recent conference hosted by the Alzheimer’s Association, he says. He also heads a working group to develop common nomenclature to describe observed differences. “It’s easy to say ‘race-based norm.’ But that’s not what we’re saying. We’re saying there are caveats and we need to resolve those caveats.”

As Dr. Hu notes, there are also white patients with Alzheimer’s who have equally low levels of tau. “It’s a matter of proportion. It’s the group mean that’s different, but the spread is still somewhat similar.”

He and others are trying to extend the work of looking at biomarkers in patients of East Asian and South Asian descent. “Some of the work coming out of those countries show very different genetic risk profiles for Alzheimer’s disease.”

But equity should be seen with an even wider lens than U.S. racial categories, Dr. Hu insists. “I think it’s important to remember that spinal fluid is the most available test for the rest of the world.” The United States may lead the world in PET scanner availability, “but from an equity and justice perspective, we feel we need to advance this [CSF] methodology to accommodate the 40 million people outside of this country.”

Another equity issue, he says, has to do with body habitus. “A number of my colleagues don’t do spinal fluid in people who are over a certain weight limit.” Patients still have the right to that information, Dr. Hu says. “Excluding people with a certain BMI because it is more technically difficult [to do an LP] is not equitable.”

Nor is ignoring women. Research suggests tau levels tend to be higher in women than in men; it also appears women are at higher risk for Alz­heimer’s disease than men, he says.

Putting all these observations together in a succinct story is going to be a challenge, Dr. Hu acknowledges. “But it’s a challenge that many of us are working on.” That includes looking at perimenopause in terms of whether changes in that phase can influence the trajectory of amyloid and tau.

“I even think sleep is going to be a big part of this,” he suggests. Data show that even acute sleep disruption can change spinal fluid protein levels. “Spinal fluid is not a static fluid,” Dr. Hu says. “It is a dynamic flow system that can be regulated and dysregulated.”

When it became clear that promising Alzheimer’s drugs were on their way, Dr. Shaw and research colleagues wrote a 2018 paper (Shaw LM, et al. Alzheimers Dement. 2018;14[11]:1505–1521) on appropriate use of lumbar puncture and CSF biomarkers, to help clinicians prepare for expanded use, including when to make referrals for more specialized testing. The authors finalized 14 indications, rating six appropriate and eight inappropriate. The criteria were designed partly with GPs in mind, Dr. Shaw says, though for now the general recommendation might be to send patients to a memory disorders clinic for testing. “They have the armamentarium and experience in the subtleties and variables and variations,” he says.

That same year, he says, the NIA and Alzheimer’s Association produced a paper that defined AD based on biomarkers, “recognizing that clinical diagnosis is only 80 percent reliable at best” (Jack CR Jr, et al. Alzheimers Dement. 2018;14[4]:535–562). That’s especially important earlier in the disease continuum, Dr. Shaw continues, with plaque buildup (and ultimately tau pathology) occurring in people who are cognitively unimpaired.

Based on this work, it’s now common to describe an ATN approach to characterizing the disease pathology: Aβ pathology, tau pathology, and neurodegeneration or neuronal injury, all of which can be measured reliably with CSF as well as imaging.

Amyloid PET imaging has three FDA-approved ligands; tau PET is a newer method. MRI has been around for years and is often the first step at memory disorders clinics to rule out a tumor or other space-occupying lesions, says Dr. Shaw. It’s also valuable for measuring brain volume shrinkage and particularly hippocampal volume.

Blood, primarily plasma-based biomarkers, will doubtless be important too. Much of the work is emerging from the aforementioned ADNI, a study of the natural history of the disease from a biomarker perspective, involving several thousand individuals. Dr. Shaw, who is currently helping to write the competitive renewal grant for ADNI4, says that from a biofluid biomarker perspective, efforts will continue for CSF. “But there will be major increased interest in plasma-based biomarkers in ADNI4. There are some outstanding ones—I could talk for hours.”

Indeed, interest in them has diverted attention from CSF at times. “CSF in certain ways is almost passé,” Dr. Shaw says with a laugh—not in terms of its value but in terms of patient/family preference for a blood stick rather than an LP. (Though he’s quick to add: “The LP should not be shortchanged.”)

Dr. Hu also likes spinal fluid because it can be used for multiple applications (it works especially well for ALS and other TDP-43–related disorders, he notes), while with PET, a separate session is needed for each ligand.

Apart from the core proteins found in spinal fluid, Dr. Hu says, “We are learning a lot about neuroinflammation.” Researchers have been examining how protein levels vary between individuals with the same diagnosis as well as between diagnoses. “We’re analyzing the increasingly complex data set.”

The other advance involves looking at cells. Traditionally, it’s been thought that spinal fluid is acellular. “And it can be, when you look at only 100 microliters under the microscope,” he says. But cells abound in larger volumes of spinal fluid. “I think there will be exciting findings in the next two to three years.”

All biomarkers have been moving forward with the scientific community’s recognition that the most reliable detection method is based on biomarkers, says Dr. Shaw, along with the recognition that Alzheimer’s is indeed a disease and not an undodgeable aspect of aging.

Given his many years in the field, it shouldn’t be surprising that Dr. Shaw is also taking a long, wide view of the decision to approve aducanumab.

“From a purely scientific standpoint, it has its downsides,” he says. “There’s no way around that.” He has colleagues who say they plan to prescribe it to patients who request it and feel they can afford it. But they would like to see a further phase three trial.

When Dr. Shaw thinks about how cancer drugs have developed, he sees a helpful comparison, recalling the approval of early drugs that extended patients’ lives by several months. Repeated such approvals “kept the field going,” he says, offering hope against an equally challenging disease. “Look where we’re at now with breast cancer,” he says, which has moved into the curable stage. “And you can take other cancers now and start to say the same thing.”

Many hold a similar vision for Alzheimer’s disease, he says.

Aducanumab does knock out amyloid plaque burden to a significant degree, Dr. Shaw says, though the clinical impact is unclear. “But there is a measurable effect of removing one of the major pathologic things going on in the brain, despite all the controversy, despite all the questions—and there are plenty of them. It still looks like there is enough positive, pending experience—and that’s always going to be the bottom line—as clinicians begin prescribing this drug.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.