The Future in Managing Alzheimer Disease

Ronald C. Petersen, MD, PhD: If we are going to have a public health impact on this disease, and if this disease involves 5-and-a-half-million people in this country at this point and it’s going to triple over the next several decades, we have to deal with this earlier in the process. We cannot wait for people to develop symptoms and then treat them. It’s like, “I’ll worry about your heart disease when you have a heart attack.”

No, no, no. We have to worry about your heart disease, your risk for heart disease, when your cholesterol’s up, when your blood sugar’s up, when your hypertension is present. That’s when we’re going to be concerned about your risk of developing heart disease.

Well, the same thing is true in Alzheimer disease. As we design these risk profiles of people, there may be some genetic features, maybe some other biomarkers, and right now we’ve been focusing on imaging biomarkers, cerebrospinal fluid biomarkers, lumbar puncture. We may actually be able to detect these risks in the blood.

So, where the field is going is actually looking at these risk profiles in the blood. Can we develop blood tests to say whether you’re going to have elevated amyloid, elevated tau, or other biochemical features that may influence inflammatory processes in the brain?

I think it’s quite possible that we will develop a panel of predictors of your risk for developing Alzheimer disease based on some genetic features and perhaps some of these blood biomarkers that may give us a profile, with regard to the underlying proteins that you’re likely to develop later in life.

The advantage of that profile, of course, is that hopefully, we’ll be able to develop individual therapies for those proteins. So if you have an elevated amyloid profile, we’ll give you an amyloid drug. If you have an elevated tau protein, we’ll give you a tau drug. But it could be TDP-43, it could be alpha-synuclein, it could be a vascular disease, or a whole variety of contributors to your clinical picture. As we develop this profile, we design combination therapy for you.

Alireza Atri, MD, PhD: The other key piece of research is really on the diagnostic pathway because we do want to tailor and personalize the treatments in the future. One of the ways to do that is to have a timely diagnosis of where these proteins are going wrong and what they are causing. Again, we understand that for a given amount of disease in the brain, whether it’s amyloid and tau combined, symptoms can be different. An individual can have a head full of amyloid and tau but not have neurodegeneration, for example, and not have symptoms. Another individual who is relatively of the same age, etcetera, may have the same amount of amyloid and tau and have neurodegeneration of a mild-to-moderate amount and not have symptoms still. So there are, again, these components of both cognitive reserve and brain reserve and vulnerability that we need to understand better.

One of the things that’s very exciting, along with the PET [positron emission tomography] scans, that are now available clinically, although insurance coverage is an issue, is the amyloid PET scan, for example. Just recently, a very important paper came out in JAMA. This was 18,000 individuals who were studied in the dementia subspecialty care setting, who were age 65 and older. It was Medicare coverage with evidence development. One of the aims of the study, which was really an effectiveness study in clinical practice, was to see, in individuals who have symptoms who had some aspects of a work-up, including some neuroimaging and some testing, when a dementia specialist is unsure about the etiology or cause, whether having these amyloid scans help change diagnosis and management. And the answer to that was overwhelmingly yes, actually, and this dovetails with a study in the Netherlands related to knowing the etiology, the cause, which is important.

So the next part of the study is whether this is going to save money and how for the health care system, at least in the short term and over 12 months. But again, it goes back to having biomarkers, whether they’re imaging studies, or spinal fluid, or hopefully from the blood. I think over the next 5 to 7 years, we will have some biomarkers that are blood-related with some sort of propensity scores that allow us to have a broader ability to detect, sensitively, people, and then move them on to getting the more expensive and complicated biomarkers—let’s say spinal fluid or PET scans. But to do that, we still need involvement from clinicians, from society to go into these studies because we have to have the correlation between, let’s say, the blood, and the spinal fluid, and the PET scans, and even autopsy studies, eventually. So people are actually donating, in some cases, their brains and bodies for these. So that’s a very important pathway.

The other pathway I think is prevention. There’s this study that came out in 2017. I urge everybody to go read that. It talks about both pathways of resilience and cognitive reserve and how potentially somewhere between 30% and 35% of global dementia risk is potentially modifiable through the life course. Again, what is it that makes some individuals more resilient than others to damage in the brain? We know early education, for example, certainly IQ, learning throughout one’s life, mitigating cerebrovascular risk factors, including blood pressure, cholesterol, diabetes, metabolic syndrome…all of those things are very important in midlife, and even late in life. Things like physical activity, exercise, social engagement, mental engagement, and decreasing hearing loss are very important in actually delaying the dementia symptoms. As part of that, there are a number of studies, both in Europe and now in the United States, including what’s called the U.S. POINTER study. But there are others that suggest that we should be looking at multifactorial approaches—nutrition, physical activity and exercise, mitigating cerebrovascular risk factors, and again, social and mental engagement—and bundling them together to see how that could actually affect the course of cognitive decline and dementia risk prevention. So those are going to be very important factors in the future.