Biomarker Assessments and Diagnosing AD


Jeffrey L. Cummings, MD, ScD, delves into the biomarker assessments that establish a diagnosis of Alzheimer’s disease and their use in clinical practice.

Jeffrey L. Cummings, MD, ScD: The emergence of new biomarkers for Alzheimer’s disease is such an exciting area of research. Most of our biomarkers have been imaging. That’s a type of biomarker where we can see the biology from the outside. Of course, MRI scans are a type of biomarker where we see cerebral atrophy, amyloid imaging is a type of biomarker where we can see the amyloid plaque in the brain, and tau imaging is a type of biomarker where we can see the distribution and presence of neurofibrillary tangles in the brain. Those are all types of biomarkers.

In addition, I should mention FDG [fluorodeoxyglucose] PET [positron emission tomography], which is a measure of cerebral metabolism. It’s much more available than amyloid imaging or tau imaging. And there’s a characteristic—though not quite pathognomonic pattern—of reduced metabolism in the brain of patients with Alzheimer’s disease. FDG PET can provide substantial supportive information without quite being diagnostically specific.

In the spinal fluid, we can assay the amyloid beta 42 and the 42/40 ratio. And experimentally, we can now also measure phospho-tau, or p-tau, which is an indication of the presence of amyloid on one hand, but its stimulation of the neurofibrillary tangle, and therefore the presence of tau pathology in the brain as marked by phospho-tau. There are several of these that are emerging in the laboratories at this point. One is phospho-tau 181. That’s the epitope that’s being measured. Phospho-tau 217 has a different epitope, and phospho-tau 231 has a third epitope. Those are so exciting because you can actually begin to see the pathology in the spinal fluid.

In addition, neurofilament light [NfL] is measurable in the spinal fluid and is a reflection of neurodegeneration. If we think of Alzheimer’s disease as ATN—amyloid, tau, and neurodegeneration—we now have in the spinal fluid amyloid measures, p-tau measures, and neurofilament light, which is an N measure. We can measure the entire ATN complex in the spinal fluid. And here’s what’s really exciting: We’re able to do that now in the plasma. We have a 42/40 ratio that’s measurable in the plasma. We have p-tau measures in the plasma. And you can measure neurofilament light in the plasma. We have the whole ATN repertoire now measurable in the plasma. Only the amyloid beta measure is approved and marketed at this point. The other biomarkers are coming fast, and they’re going to allow us to reform clinical practice to identify patients with Alzheimer’s disease early in the course accurately and with great feasibility, which has been lacking until now.

Amyloid imaging is very important in terms of identifying patients who are candidates for treatment with aducanumab [Aduhelm]. Patients who are candidates must have early Alzheimer’s disease, which is MCI [mild cognitive impairment] or early Alzheimer’s disease dementia. They must have a positive amyloid PET scan or positive spinal fluid study for Alzheimer’s disease pathology. And they must have an MRI scan, which lacks specific types of pathology that we wouldn’t want to include in patients who are treated with aducanumab. Multiple microhemorrhages or multiple places of hemosiderosis would exclude a patient from treatment with aducanumab. There are 2 types of biomarkers that are important for aducanumab. One is measures of amyloid. That might be the PET or CSF [cerebrospinal fluid]. The other is MRI to both show that the patient can safely have aducanumab initiated and to follow the patient for the possible emergence of ARIA, or amyloid-related imaging abnormalities, that sometimes occur in the course of treatment with aducanumab.

This transcript has been edited for clarity.

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