Biomarker Testing and its Role in an AD Diagnosis


An expert explains the role biomarker testing plays when diagnosing a patient with AD.

Alireza Atri, MD, PhD: We’ve come into a new and important era in detection and diagnosis of Alzheimer disease [AD]. We’ve gone from a model where we didn’t have direct evidence of these hallmarks of Alzheimer disease—the plaques and the tangles—until we had tissue, which was oftentimes death, to now where we have biomarkers that molecularly can show these proteins or the plaques and the tangles. That would be molecular biomarkers of actual amyloid or tau, the A part in this new classification that has been proposed for a biological definition of Alzheimer disease. The A stands for amyloid. We have markers for that now. The T stands for the abnormally hyperphosphorylated tangles. And then there is an N biomarker, which is neurodegeneration, which can be seen on MRIs or by FDG [fluorodeoxyglucose]-PET [positron emission tomography] with patterns of atrophy or cortical thinning. That’s another marker.

In practice, this is still evolving as part of a diagnostic workup after there’s been clear history that’s gone through the subjective complaints on multiple domains, with different domains of cognition taken into consideration and function. Those are instruments that are important. There are also standardized instruments that you can give to patients and families for them to list changes in their daily function, whether it’s high instrumental activities of daily living [IADL], complex activities, or even basic ones. Things like the functional assessment questionnaire or the Amsterdam IADL Scale are important. Looking at behavior is also important.

After you’ve done that, have gone through a review of medications, looked at other risk factors, and family history, etc, you’re going to come down a pathway where it’s important to do the brief cognitive assessment. At that point, you’re making a decision. Are these complaints and this performance consistent with normal aging or could there be something else going on? It’s important at that point to make the decision of whether you’re going to go down the pathway of both, excluding conditions that may be contributing. You can do that through laboratory work and getting 1 good imaging study, which oftentimes will involve the MRI of the brain, which can also look at patterns of atrophy, temporal atrophy, parietal atrophy, and other regions that tend to show the AD pattern.

How much is the burden of white matter disease, or leukoaraiosis? Are there microhemorrhages? This is going to be important in this new era of monoclonal antibody therapies. Are you going to use other biomarkers? Are you going to go down the pathway of getting an FDG-PET or ordering something like spinal fluid or PET scans to look at the amyloid or tau involvement? There are complexities because of coverage at this point, but in clinical practice, individuals who have atypical syndromes or early onset syndromes who want higher degrees of confidence regarding their diagnosis will end up going down the pathway of seeing specialists at that point to improve the level of confidence that their condition is actually caused by Alzheimer disease. In which case, then you have an option of spinal fluid analysis or the PET scans, which aren’t routinely covered by insurance companies. That’s the amyloid PET and the tau.

When I go down the pathway of ordering things like spinal fluid or an amyloid PET scan, which can be done at this moment using the new IDEA study, which is a CMS [Centers for Medicare & Medicaid Services] coverage with evidence development study for Medicare beneficiaries, you have to be 65 and older. In those cases, individuals and families want to have higher confidence that the underlying process neuropathological changes is Alzheimer disease.

As far as looking at the tenets of management, the first tenet is early timely detection, an early and accurate diagnosis, and appropriate disclosure. Second is a lot of psychoeducation about what’s going on and what to expect environmentally and behaviorally. That’s important. The third pillar is medication management, oftentimes taking away bad medications that may be cognitively deleterious and then adding stage-appropriate medications for Alzheimer disease in a very systematic fashion, which at this point are cholinesterase inhibitors for mild stages and beyond and memantine for moderate stages and beyond that. I don’t start individuals with the maximum doses of anything. I start them on a small dose and see how they tolerate it. I counsel them appropriately and have them come back. We test them with some of the cognitive and functional instruments that we talked about to assess whether they’re in a sweet spot. Are they where I’d expect them to be? If not, we increase the dose of the medicines.

When it comes to the biomarkers going all the way to an FDG-PET, I’m looking for a hallmark of Alzheimer disease, being temporal and parietal metabolism or percutaneous hypermetabolism. It wouldn’t show you the proteins, but it gives me higher confidence that the changes include Alzheimer disease. Today, the major driver of whether someone is going to get spinal fluid analysis for the AD pattern or get an amyloid PET scan would be if they’re considering treatment with aducanumab [Aduhelm], which is a newly approved monoclonal antibody. It was approved under accelerated approval for lowering amyloid plaques in the brain with reasonable likelihood that they may have clinical benefit downstream. This is an important concern regarding whether individuals want to start treatment. Because part of the considerations for that—we can get into that more—is what clinical stage they’re in and whether they have amyloid in the brain. The only way to show that is through either spinal fluid analysis or the amyloid PET scans.

This transcript has been edited for clarity.

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