Biomarkers and Challenges to the Use of Biomarkers in Alzheimer’s Disease

Drs Atri and Cohen discuss biomarkers for Alzheimer’s disease and the challenges in their use in routine practice.

Marwan Sabbagh, MD: That brings us to our next question, Dr Atri. Biomarkers are being developed, and this is based on the understanding that we can measure things now. What biomarkers are available for Alzheimer disease [AD]? How widespread are they? Comment on histopathologic, genetic, blood-based CSF [cerebrospinal fluid].

Alireza Atri, MD, PhD: It’s an exciting time for Alzheimer disease and for neurogenic diseases because we’re in a new era of biomarkers that allow us to measure these components more precisely while people are alive. The notion that we can’t diagnose Alzheimer disease until someone’s death, until we have neuropathology, is no longer correct. We can have an accurate diagnosis of inclusion when people are alive. The framework we’ve been talking about, ATN [amyloid, tau, neurodegeneration], conceptualizes that the disease stage is different from the clinical stage. That link between disease and symptoms is very complex. It involves not just misfolding the proteins, including inciting events that are necessary but not necessarily sufficient with forms of soluble amyloid that are toxic.

Ultimately, they become aggregated and clump into plaques: starting cascades of issues with hypophosphorylation of tau, spreading of misfolded proteins in almost a prion-like state for different parts of the brain, dysregulating intercellular metabolism, breaking down the clearing of other abnormal proteins. Neuroinflammation is important—in some cases it’s protected, in other cases it becomes its own issue, and so is vascular dysfunction. We understand that there are particular resilience factors. Some people have vulnerabilities that ultimately end up causing the expression of the disease being different in different people.

How is it that some people could withstand for longer a handful of amyloid or toxic amyloid and others may not? Fluid biomarkers, like spinal fluid, are available. Blood-based biomarkers are coming to clinic, even though some are available. There’s mostly a consensus—a number of us are part of those consensus groups—that there needs to be more work done on the blood-based biomarkers because we need to understand it in more diverse populations, and in individuals with comorbidities, to understand what the cutoffs may be. That’s going to revolutionize clinical care in many ways, diagnostically and potentially therapeutically, as we come to stages that have targeted therapies for particular aspects of the disease, like amyloid removal.

Spinal fluid is still something that happens. In Europe, it happens more often than in the United States. It has good reliability. For particular populations, it’s covered better than neuroimaging. PET [positron emission tomography] scans, for example, are approved to look at amyloid plaques. There are a number of those. There’s also an approved PET ligand to look at tangles. The issue with that becomes coverage. Outside the VA [Veterans Affairs hospital], they’re not covered, at least not in the United States.

Other types of biomarkers that we use to look at neurodegeneration include glucose PET scans, FDG-PET scans, patterns of atrophy on MRIs. That allows us to come up with a diagnosis of inclusion, not just exclusion for Alzheimer disease. This comes with the caveat that as the machinery breaks down, the norm isn’t pure Alzheimer neuropathological changes in individuals in their 80s. But you can have Alzheimer changes with a smattering of Lewy body dementia or TDP-43 vascular changes. These are all the different components that we’re going to target with combination therapies. It’s an exciting time. I focus on clinical care, but for research the biomarkers are opening doors in advancing our therapies. That’s another game changer that’s occurring and that we’ve heard about in these conferences.

Marwan Sabbagh, MD: Dr Cohen, we’re moving from a diagnosis of exclusion to a diagnosis of inclusion. What are the challenges for the use of these biomarkers in routine practice?

Sharon Cohen, MD, FRCPC: There are considerable challenges, and in clinical practice we tend to rule out strokes, tumors, and bilateral subdural with a structural brain image—CT or, even better, MRI. That’s important. We’ll continue to need to do this. But this doesn’t rule in Alzheimer disease. As Dr Atri mentioned, cost is a factor. Even though we have approved PET ligands in many countries, not just the United States but in Canada, cost is not covered. Most people will not have access to a PET amyloid scan. With CSF, there’s variable uptake. Even though this is a good way to get a fluid biomarker to rule in Alzheimer disease and get a readout on not only amyloid levels but also phosphorylated tau and total tau. There’s a lot of information in 1 CSF sample.

But there’s been a cultural barrier to going back to LPs [lumbar punctures]. Even though we were ruling out neurosyphilis many years ago, of course you’d do that. It’s a more scalable procedure, and it probably should be done more. Most of the time in the clinic, we’re ruling out structural abnormalities. That won’t be sufficient when we have disease modifiers, which we need to make sure we’re right clinically about the diagnosis. We don’t want to treat someone with an anti-amyloid agent if they don’t have amyloid pathology. We can be wrong 30% of the time, at least when we diagnose someone with probable Alzheimer disease dementia—maybe 50% of the time or more we’re wrong if we say it’s MCI [mild cognitive impairment] due to AD. The clinical criteria are a start. The syndromic diagnosis is a start, but that’s by no means a confirmation of underlying biology.

Marwan Sabbagh, MD: We’re going to spend more time on this because that’s where the field has to move. We’re not going to give these new treatments if we don’t have a definitive biomarker confirmation. We’re going to come back to that as we go through our discussion.

Transcript edited for clarity

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