SRQ Magazine | April 2017
Alzheimer’s disease is perhaps one of the most terrifying looming giants in the aging process, with the veritable unspooling of a life’s worth of memories. Fortunately, researchers and clinicians man the front lines in a bold campaign to combat the progression of the disease, both in the realm of reversing the effects of cognitive impairment and uncovering early markers to prevent the disease from the get-go. Here, SRQ was joined by clinical neuropsychologists, a neurologist and researchers to talk about the strides being made in clinical trials underway attempting to solve the Alzheimer’s conundrum.
SRQ: What causes Alzheimer’s disease and what happens in the brain? Dr. Edwin Bercaw (Neuropsychologist, Comprehensive MedPsych Systems): There’s no one particular cause. There are genetic risk factors and then, of course, age is one of the primary risk factors. Even level of education can modify risk. There’s an idea that cognitive reserve—people with higher intelligence or higher education—might be more protected. In terms of what causes it, that is still a subject of research. There are some genetic links—there are at least four as far as genes that have been identified. Dr. Andrew Keegan (Neurologist, Roskamp Institute): We are usually thinking more about the end result. We know there is a buildup of the proteins beta-amyloid and tau. But is that really the cause or just what you see in the pathology at the end? Bercaw: And beta-amyloid does exist in the brain normally to some extent, but there’s an overproduction that occurs with Alzheimer’s. Keegan: Doctors have always said the disease is caused by amyloid and tau but now I sound like a fool saying that—maybe that’s what’s there in the brain at the end, but that’s not what’s causing a lot of the late-onset Alzheimer’s disease. Bercaw: It makes a lot more sense now to talk about risk factors and things that increase your chances. Other than identifying some genetic links, I don’t think you can say there is one cause. We haven’t put our finger on anything like that yet. Dr. Michael Schoenberg (Neuropsychologist, USF Byrd Institute): In the brain of someone with Alzheimer’s, there is marked atrophy, predominately in the parietal lobe spreading to the frontal lobe—in particular, the inside edge of the temporal lobe gets very shrunken.
What are the different roles that neurologists and neuropsychologists play in the treatment and research of Alzheimer’s? Keegan: As a neurologist, we depend on neuropsychologists often, especially in some of the earlier cases where it’s hard to separate things out. Getting a good pattern of what’s happening helps us with what we are looking at in the imaging or what we’re thinking is happening. Schoenberg: I would say that neurologists are key healthcare providers in the treatment of memory disorders (not just Alzheimer’s disease) because the diagnostic workups for coming to a conclusion about probable or possible Alzheimer’s disease is an exclusion of other possibilities. There is no biometric test of Alzheimer’s disease. A neurologist needs to evaluate and rule out other potential causes of memory loss that can appear like Alzheimer’s disease, such as B12 deficiencies, thyroid-stimulating hormone (TSH), static encephalopathy, some kind of chronic infection or vascular dementia, among others. Keegan: And some of the things we lean on neuropsychologists for are figuring out if the symptoms are those of just normal aging or some subjective memory complaints that you don’t find on testing, or is this pseudo-dementia from depression. Neuropsychologists help point us to other issues—maybe it has to do with medications the patient is taking—to figure out if the pattern is something you would see in early Alzheimer’s. Bercaw: It’s not just about memory loss. That pattern also includes looking at the history—knowing the onset, the course and, from the testing, knowing if there really is a memory retention problem. With Alzheimer’s, I expect to see some deficits with learning and retention of new information. There could be some other frontal or executive impairment. Often as the disease starts to progress, you see things like loss of naming ability or other language disturbances, visual-spatial problems or constructional problems that indicate some involvement of the temporal and parietal areas of the brain.
What is the goal of current research—to treat? To cure? To prevent? An amalgam of all three? Schoenberg: I would say it depends on who you ask. Hopefully all three. The ideal goal would be to prevent Alzheimer’s disease, although millions of dollars have been spent on trying to do that and have so far been unsuccessful. Another would be to reduce the rate of decline or alter the neuropathological course—a lot of money has also been spent on that with variable success. For example, donepezil (which has FDA approval) has some evidence that it alters the disease course slightly. Keegan: Early detection is one of the biggest areas of research—can we detect something before it’s symptomatic, and then, if you can, can you do something about it? Those things are kind of working together. That’s where some of the newer medications and ideas that have been tested in phase 2 or phase 3 are unfortunately not working out. The questions we’re asking are: is it still not early enough in the disease process? If you think amyloid is one of the causes, if you pull it out but you pull it out too late and there’s already been atrophy, there’s already been synaptic destruction, is it too late? How early do you have to start? Is the dose of medication not strong enough? Those are some of the things that are changing the research world right now because of all the amyloid failures. Bercaw: We’re finding that beta-amyloid isn’t the whole story.
How do you find the whole story? For example, you hear about scientists at MIT who are doing light therapy to reverse memory loss on rats, or the study at Washington University School of Medicine where researchers are giving rats injections of RNA to prevent or reverse the course of the disease. How do you decide which direction to take your research? Keegan: You have to remember, these tests were done on a mouse, and that mouse was genetically programmed to overproduce amyloid and that only represents 1 percent of the Alzheimer’s disease that we’re seeing. That treatment may work in that situation but it doesn’t explain all the other instances. You could talk about these things all day long, but you won’t know if they work until they are tested on humans in a big long study that has neuropsychologists assessing memory over time, neurologists making sure there aren’t complications—you spend two years following somebody. That becomes expensive and a long process. We want answers sooner but it’s not easy.
What is working now, or what has the potential to work? Schoenberg: There are more efforts now with the recent identification of the potential ideology with idiopathic Parkinson’s disease—researchers have found more of a prion protein component. There is ongoing interest in the cause of the onset of Alzheimer’s disease in your 50s and early 60s, which almost certainly has a genetic component. For late-onset Alzheimer’s disease, there is a real focus on trying to identify the disease much earlier with the idea of pre-mild cognitive impairment (pre-MCI), where you find the very earliest markers of the disease before really any cognitive changes or structural changes have occurred. Advances with looking at changes with the default mode network (DMN) of brain activity, which is an activity that occurs in the brain during sleep and inactivity that changes in various disease stages, may be a very early marker. There’s some research looking at blood markers that may be an indication of the onset of Alzheimer’s disease pathology. The challenge has been that in the early 2000s, there was a lot of interest in MCI as an early disease marker—amyloid-removing agents (which could be introduced either orally or injected) would prevent any amyloid buildup and would prevent the onset of Alzheimer’s disease. The animal models were pretty successful. But unfortunately, in humans, even though there was some initial success with removing amyloid, it doesn’t appear to change the disease pathology, which is why there’s been a readjustment in neuroscientists’ statements about what causes Alzheimer’s disease away from an amyloid or tauopothy. What folks can do now: worldwide, some of the studies have shown that the best ways to minimize developing mild cognitive impairment and reduce risk for dementia include things like getting regular aerobic exercise, controlling risks for vascular disease (making sure hypertension, high cholesterol, hyperlipidemia, diabetes are well controlled) treating any form of hepatitis and a regular good diet. Bercaw: You have to emphasize the modifiable risk factors. Diet and exercise, obesity—those are the things you really have control over. Getting back to things that are working for Alzheimer’s patients, while I don’t do research, my job is to identify if this is normal aging or is it one type of dementia versus another. What I have to work with is helping the person compensate for behavioral changes. A lot of this applies to the family as well—helping them plan for the future. With the patient, behavior changes might be things that they really don’t want to face—stopping driving, for example—and then compensatory strategies, things you can do for your memory in the early stages: learning how to write things down, being more organized, having reminders. I help educate the families and get them support they need emotionally. Keegan: We’re doing one clinical trial at Roskamp called the 7-11 Trial. We’re looking at people who have normal memory, or people who want to be followed because they may be in their 60s and have a family history—we draw blood at that visit and do a memory test at that visit and every year they come back. The goal is to see if there is something in that blood at that baseline that would predict them developing Alzheimer’s disease. We think of Alzheimer’s as kind of one homogeneous disease—that it is all the same no matter the person. But there may be 12 different paths that people developed Alzheimer’s with, maybe one is more of an inflammatory person, maybe genetics predispose them, maybe their lifestyle—that person would need an approach that is really anti-inflammatory. Another person may be more vascular—the longitudinal data is more of a vascular story. We have to come up with better ways of adjusting and managing vascular disease. Some of the drugs that are being tested are going after those different areas. We’re still working in the area of modulating amyloid on some of the phase 3 clinical trials, but we’re hoping some of the future phase 3 trials will be focusing on improving vascular health in a way that is more cerebrovascular. Just approaching this in different ways, not just going after amyloid, but hitting these other areas. Still, the best we can offer is helping people with early recognition and changing lifestyle, and if the family learns early on I think it makes a difference. It makes them handle the disease better to get plugged in and connected while the scientists are trying to find something that works. Bercaw: There are a lot of behavioral changes that go along with it that are really hard for the families. That’s an area where we can exert some positive influence while we can’t yet stop the disease. Keegan: You can see the stress levels of caregivers change after they’ve learned some appropriate techniques. It makes the home a little bit easier. Decreasing that stress feeds back, in a way, to reducing inflammation and probably has some biological impact as well that could affect the disease progress.
What does the future hold for research into Alzheimer’s? Keegan: I still think eventually we’re going to have not just Alzheimer’s disease, but type 1, type 2, type 3, and people will know which direction their disease is taking so that there will be an intervention that is more customized. It’s called precision medicine—it’s based on kind of a panel with some genetics, some blood tests, which will give the right direction of treatment. Schoenberg: I would agree that perhaps what we are currently calling Alzheimer’s disease—there may be several different paths. Indeed it appears that cerebrovascular disease, and maybe that brain trauma, can develop some neurophysiological pathways that increase your risk for developing dementia. Not to say that everyone that has some white matter disease or a history of head injury will go on to develop dementia, but there may be some individuals that have an increased risk for that. Just recently, they’ve identified that it may be the biome of the gut that is involved in the onset of Parkinson’s disease, which would be really remarkable that it doesn’t originate in the brain at all. It makes one wonder whether or not that same integrated brain-body synching is some of the component in what presents as Alzheimer’s disease. For example, there’s an interior variant Alzheimer’s, there’s your classic Alzheimer’s and there’s posterior cortical atrophy Alzheimer’s—there’s already three sub-types that have been identified. I’m sure more will likely be found. I think the future is pretty bright. There is no shortage of researchers looking into both the diagnostic and the neuropathological process for the onset of Alzheimer’s disease. I think with each failure comes new advancements and understanding about the disease, so I wouldn’t want to give the perspective that it’s just been littered with failure—the research needed to be done to better understand the disease and how complicated it is, which has lead us to new places to better grasp the normal and abnormal aging processes.
About Our Participants
Dr. Edwin L. Bercaw, PhD is a board-certified clinical neuropsychologist with more than 10 years of clinical experience. He obtained his doctorate in Clinical Psychology from the University of Maryland – College Park and completed his post-doctoral fellowship in neuropsychology at the Rehabilitation Institute of Michigan at the Detroit Medical Center. Dr. Bercaw is currently a clinical psychologist at Comprehensive MedPsych Systems in Sarasota where he performs cognitive and psychological testing of traumatic brain injury, dementia and other neurological and psychiatric problems such as Alzheimer’s disease.
Dr. Andrew P. Keegan, MD, MS is a board-certified neurologist. He began his training at Rensselaer Polytechnic Institute in Troy, NY where he completed his BS in Biomedical Engineering. Dr. Keegan completed medical school at Tulane University in New Orleans, LA. He is currently the associate director of the Roskamp Institute Clinic in Sarasota, FL where he is the principal investigator of multiple clinical trials.
Dr. Michael R. Schoenberg, PhD, ABPP-CN is a board-certified clinical neuropsychologist at the Florida Alzheimer’s Disease Research Center at University of South Florida of South Florida’s Byrd Alzheimer’s Institute. As a scientist and a clinician, Dr. Schoenberg has published research in the areas of aging, measuring change in cognitive function over time and aspects of diagnosis among patients with known or suspected neurological illness.