Jeffrey L. Cummings, MD, ScD: Very good. I want to stick with you a little bit longer, Elaine. You told us earlier about your approach to genetic screening and genetic testing. Are there other biomarkers, particularly blood-based biomarkers, that you see evolving or useful now or useful in the future? How do you see the blood-based testing landscape evolving?
Elaine R. Peskind, MD: Well, I think as you know, there has been for a long time now an accurate and very sensitive and specific spinal fluid biomarker, either amyloid beta-42 or the toxic form of amyloid in and of itself, which is reduced in Alzheimer disease. And actually, reductions in the spinal fluid amyloid predate changes on PET [positron emission tomography] amyloid and tau, which is increased in Alzheimer disease. Phosphorylated tau particularly is increased in Alzheimer disease in spinal fluid. But now there appears to be an increasingly usable blood test for measuring the ratio between the toxic form of amyloid, Abeta-42, and more normal amyloid, Abeta-40. This ratio is decreased in Alzheimer disease.
Interestingly, the levels of Abeta-42 and 40 in the blood do not correlate with the levels in spinal fluid, but they seem to be a very good initial test for screening for Alzheimer disease. They have high sensitivity. They have relatively poor specificity, so there will be a lot of false positives. And the idea is to use them as an initial screening test followed by a more definitive screening test, or using it as broad scale screening followed by a work-up for whether this person has a cognitive deficit. So, first the blood test. Maybe the second test is either the spinal fluid test or amyloid PET imaging. But it is now looking like this actually may be a useful test and may be able to be CLIA [Clinical Laboratory Improvement Amendments] certified and used as a broad scale screening test.
Jeffrey L. Cummings, MD, ScD: That’s great. Do you have a timeframe in mind for when the person watching NeurologyLive might be able to offer this to their patients?
Elaine R. Peskind, MD: I think there is still going to be some work that needs to be done to make this a reproducible screening test that can be done in a hospital laboratory. It’s going to be a while yet.
Jeffrey L. Cummings, MD, ScD: Are there other blood tests that people are thinking about that appear to be emerging and possibly informative? I’m thinking, for example, about Neurolite as something that’s garnering a lot of attention these days and appears to be an indicator of nerve cell death and is measureable in the plasma, and therefore might be used in conjunction with the Abeta-40 to 42 ratio and give us an indication not only of the presence of amyloid but its impact on nerve survival. So I think there are reasons for optimism in terms of real input from blood biomarkers, which is something that we have wanted for so long.
Alireza Atri, MD, PhD: In the next 2 to 4 years I think they’ll be coming into clinical practice more. Certainly, in the research realm, as you know, they’re going to be very helpful.
Jeffrey L. Cummings, MD, ScD: Can you tell us a little bit more about protofibrils and how they relate to other forms of Abeta? Are they measurable? How do you think about the protofibril issue?
Alireza Atri, MD, PhD: I think Alzheimer disease is by definition the amyloid plaques and the neurofibrillary tangles. That’s how the disease is defined. And after several decades of research, we understand that amyloid is probably something like toxic kindling. It’s something that tips off a cascade of issues that interact with other things, with the tangles, with brain inflammation, with vascular changes in the brain. But when you have the different flavors of amyloid, it comes off and it’s processed and snipped in certain ways. You get the 40 fragment and the 42 fragment, and these can go along as monomers and sometimes even oligomers and be toxic synapses. So they’re toxic kindling.
And then as you progress from the oligomers, they start to arrange themselves in certain ways. You can get protofibrils and then you get fibrils and plaques, which now are insoluble. Protofibrils are sort of in the middle. They seem to be a link between, in some ways, the other soluble forms and the plaque forms. The question of whether affecting this later in the disease is something that needs to be addressed, and there are clinical trials at this moment that are ongoing. Some of the initial data suggest that you can actually remove this from a brain, and it has effects on plaque.
In a correlated way, a phase 2 study has shown that there could be dramatic reductions in plaque load that are actually also correlating with slowing down of cognitive decline. So I think that’s very promising, taking some of this toxic kindling out, and potentially the question is if you even go earlier, whether you can actually start the fire that starts in the brain with neuroinflammation and maybe the tangles that spread like fire through the brain.