Dimitrios Kapogiannis, an internationally renowned behavioral neurologist and clinical scientist at the National Institute on Aging at NIH, and Adjunct Associate Professor of Neurology at Johns Hopkins University, offers us much reason for hope that he will be able to detect Alzheimer’s Disease years before its symptoms manifest themselves. With alarm bells sounding worldwide regarding the proportions that this disease is taking on, as well as its expected effects 20 years from now, the innovative research being conducted by Dr. Kapogiannis and his team on neuronal and astrocytic-enriched extracellular vesicles being harvested from blood, which seeks to discover biomarkers associated with this neurodegenerative disease, sounds like a miracle to all of us looking on as scientists conduct research to discover the heretofore invisible causes of Alzheimer’s Disease.

Although his evidence is still in the process of being validated, as a global expert, Dr. Kapogiannis has managed to spearhead research focusing on neuronal extracellular vesicles in the blood and see precisely what is inside of an Alzheimer’s patient’s brain cells, while the latter is still alive. There are a series of clinical interventional studies being conducted in his lab on treatments including antidiabetic drugs, 5-2 calorie restriction dieting, and oral ketone ester supplements targeting the brain’s metabolism to counter the pathogenic processes associated with Alzheimer’s Disease.

Dimitrios Kapogiannis hails from Messenia and was raised in Piraeus. He studied medicine at the University of Athens and completed his Neurology residency training at Massachusetts General Hospital, along with a Clinical Fellowship in Behavioral Neurology at the National Institute of Neurological Disorders and Stroke.

He has authored over 120 peer-reviewed publications and is an Associate Editor of the Journal of Extracellular Vesicles. He is also a member of the editorial boards of Ageing Research Reviews, npj

Aging and Mechanisms of Disease, Cells, and Biomedicines. Presently, the results of his studies are so encouraging that they are spurring immense hope for the early detection of this illness.

The National Herald: Why did you study Neurology and specialize in Alzheimer’s research?

Dimitrios Kapogiannis: I always considered our nervous system, which is responsible for higher-order cognitive function, to be the most interesting and fascinating organ in the human body. I was always fascinated with studying diseases that impact an organ as important as the brain. Specifically, I got involved in Alzheimer’s research because it is a disease that generates immense interest from a scientific standpoint, considering that, in actuality, we don’t know what causes it. In other words, it is veiled in mystery and complexity, and therefore, it poses a constant challenge for researchers, who must avoid adopting easy solutions and attempt to dig deeper until they can find  avenues of treatment. This is a motivation related to the cognitive and scientific approach to treating this illness. However, there is also the major motive of preventing human suffering that the disease causes not only to patients, but their families as well, which we doctors seek to ease.

The third motive for research has to do with the huge social and financial costs associated with the disease. Alzheimer’s is a disease that costs a lot of money both from a standpoint of out-of-pocket expenses, as well as from a human resources standpoint, because there are so many people needed to treat patients, who, often times, are unable to care for themselves. These costs will continually rise as people get older and their life expectancy increases thanks to medical advancements.

TNH: How do we distinguish between the decrease in cognitive ability caused by Alzheimer’s and the symptoms associated with the natural aging of the brain?

DK: On the one hand, the basic risk factor for the onset of Alzheimer’s is age. On the other hand, there is the natural aging of the brain that takes a certain toll on the memory, as it does to the human body’s other systems. However, the damage caused to the brain by Alzheimer’s is completely different. Not all elderly people will suffer from Alzheimer’s, but the older one gets the greater the chances are. At around the age of 85, fifty percent of people suffer from Alzheimer’s.

TNH: Your studies have focused on the preclinical diagnosis of this disease years before its onset. Tell us more.

DK: We are approaching this subject from different perspectives. As a researcher working in the lab, I deal with the development of certain diagnostic tests on blood samples that have the capability to diagnose the illness at the clinical stage, ensure its early detection, determine whether it will progress quickly or not, and most importantly, detect the illness in a pre-clinical stage, when the patient does not present any symptoms. These types of tests are based on the detection of biomarkers, which are substances that we identify in patients’ blood to determine whether or not they suffer from a particular illness.

TNH: What sets your research apart from other studies?

DK: Let me begin by saying that there is a huge effort taking place around the world at this moment to detect biomarkers for Alzheimer’s Disease in the blood, and so, each research team focuses on different biomarkers. Within this general research framework, it appears that the Tau protein is the most widely studied one internationally. This is a protein that is found in all human beings, however its abnormal forms are related to – or according to others, are responsible for causing – Alzheimer’s Disease. My team has turned its attention to extracellular vesicles, which are extracellular sacs that are constantly being released by our cells, including the brain cells. These contain not only the Tau protein and the beta-amyloid protein, which is considered the other basic molecular factor associated with this illness, but other substances as well that reflect the state of the cell’s health. By isolating the extracellular vesicles, we can detect not just one substance that is related to the disease, but many substances at the same time. This leads us to believe that this will bring us closer to developing a more precise ‘scan’ that will help us to determine what is going on in a particular patient.

TNH: How can this knowledge help you?

DK: There is a global trend associated with the development of ‘precision medicine’, which means knowing whether a particular patient has a specific abnormality in their cells and the degree to which specific functions are affected, so that a more individualized treatment plan for the disease can be designed. In other words, there are instances when we would not prescribe a medicine that would work on most patients but may prove ineffective on a particular one. Instead, precision medicine focuses on finding a medicine that is individualized and focused on treating each patient’s specific pathophysiology. I believe that extracellular vesicles will bring us close to reaching this goal because they enable us to view many parameters of the disease concurrently.

TNH: The predominant view is that the beta-amyloid protein is the basic risk factor for Alzheimer’s. What do you have to say about this?

DK: We know for sure, by definition, that Alzheimer’s Disease would not exist without the presence of the beta-amyloid protein. The definition of this disease presupposes the accumulation of the beta-amyloid protein in the brain, but this does not mean that the amyloid is the qualitative or final cause – as Aristotle would say – of the disease. We believe that there is an anomaly cascade – a pathological process causes harmful consequences, and in turn, these consequences lead to many more. In other words, the disease produces a domino effect. Certainly, that which we do not know is whether, in the final analysis, the amyloid is primarily responsible for causing the disease. We do not know if there is yet another underlying cause that appears earlier. For example, there is a significant number of people who have a large amount of amyloid protein in their brain, yet in spite of this, they never develop Alzheimer’s. They retain their cognitive abilities until death. This is a very interesting direction that our study has taken recently.

TNH: What are the studies on biomarkers that you are carrying out based on?

DK: Methodologically speaking, our studies are retrospective in nature. In order to detect the disease in a pre-clinical stage, we analyze samples that have been collected from people who had normal brain function at some point, and subsequently developed Alzheimer’s Disease much later in life. These samples can be found in sample banks. What we do is analyze the blood samples of future Alzheimer’s patients and samples of people who never develop Alzheimer’s by isolating the extracellular vesicles, analyzing the various pathological proteins, and seeing if we can distinguish those participants who will end up developing the disease from those who will not. The studies are based on sample banks of patients who are considered to have been carefully characterized and who have participated in major prospective studies.

In Baltimore, there is a very famous prospective study called the Baltimore Longitudinal Study of Aging. The BLSA, as it is known, includes healthy individuals from all ages as participants who continuously provide us with samples after we have conducted a full investigation of their physical and cognitive functionality.

TNH: How does memory loss associated with natural aging differ from memory loss in elderly Alzheimer’s patients?

DK: Natural aging causes certain anomalies in the memory process, which, however, do not cause significant issues in people’s lives. They involve secondary issues – small everyday incidents like forgetting where we left our keys or glasses. This kind of memory loss never leads to amnesia regarding important life events that hold a certain emotional value, like meeting up with a good friend 20 days ago and not being able to recall it afterwards. At the same time, there is something of equal importance to memory – executive functions, which are related to our ability to plan our future activities and carry out complex processes to produce a result. This could be something simple, like preparing a meal by following a recipe, or something more complex, like managing our bank account and personal finances. Executive functions are directly related to our ability to live independently, and unfortunately, these are completely disturbed in Alzheimer’s patients. Therefore, many people are frightened over the loss of independence and the thought that they will have to depend on others.

TNH: Most people don’t remember anything from their childhood, although that certainly doesn’t mean they suffer from Alzheimer’s Disease. Memory and forgetfulness seem to be mutually related. What can you tell us about this?

DK: That is a very good question. Both of these things exist as natural functions in our brain. Within the context of its normal operation, the brain creates memory, but also programs forgetfulness, as you termed it. It is important to note this because our brain does not come with unlimited storage capacity that would allow it to retain even the slightest detail associated with daily events. If this was the case, we would have a very dysfunctional brain. Thus, just like there are disturbances to the memory, there are also disturbances to forgetfulness, as is the case with post-traumatic stress, where the brain cannot erase or lessen the memory of a traumatic experience, and constantly recalls it. With Alzheimer’s, however, we don’t have normal forgetfulness. Memories which normally should not be erased are completely lost over time.

TNH: How long do you expect until you have the final results of the study you are conducting together with your team?

DK: We have already produced results and managed to predict if someone from the samples we studied from the BLSA will develop Alzheimer’s in the future with a 90 percent accuracy rate. But you also need to consider that there is a global effort taking place regarding Alzheimer’s research. I am not sure if our study will be the first to end up being approved for general use, or if it will be some other study, or even many studies together. However, I have the sense that we are very close and that in two to three years’ time there will be some tests that have reached such a level of maturity that they will be ready for clinical use. Whether these come from us or another team, I believe that within the next three years there will be a blood test made available for diagnostic purposes and that it will be widely used. There is already one that measures the presence of amyloid protein in the blood and has been approved. It can be ordered by a physician, but for the moment, it is not covered by any insurance plans.

TNH: Are there many theories regarding the role people’s diet plays in preventing and treating this disease?

DK: The effects of one’s diet on their brain is an area that we are researching intensely. For most people, under normal circumstances their brain is nourished by glucose – blood sugar. In Alzheimer’s patients, the brain cannot effectively nourish itself from glucose. Some people suggest that if we provide an alternative form of nourishment to change the brain’s metabolism, it would have beneficial results and help prevent the disease, or perhaps even reverse its effects if these have already manifested themselves. In other words, the brain would be able to nourish itself and operate normally.

TNH: How do you conduct clinical studies to prove this theory?

DK: At the moment, we are conducting two clinical studies to test these theories at an early phase. One type of diet we are investigating involves radically changing the manner in which we eat and adhering to intermittent fasting. Specifically, we are studying a diet that is called 5-2 calorie restriction and essentially means that people can eat normally for five days of the week, but must dramatically reduce their caloric intake for the other two days, limiting themselves to just 500 calories per day, thus producing a large differential between the days when they eat normally and the days when they fast.

TNH: Exactly what happens when the body enters into a state of very limited caloric intake?

DK: Fat begins to be processed and produces a substance called ketones, which are able to nourish the brain even if it suffers from Alzheimer’s. This gives us hope that if we can change the brain’s metabolism using an intermittent fasting diet like 5-2 calorie restriction or something similar to it, we can aid the brain in restoring itself. At present, we have completed a clinical study on people over the age of 55 who are insulin resistant (something like a pre-diabetic condition) – a factor that raises the risk of Alzheimer’s. We are now analyzing the data from this study and waiting to see if the 5-2 calorie restriction diet improved the memory of this sample. If this succeeds, it paves the way for us to see if we can implement it on Alzheimer’s patients. We are also studying a dietary supplement called ketone ester that we give to elderly individuals with metabolic syndrome, which provides them with ketones from an external source. In other words, we are trying to either make the body burn fat and produce ketones, or, in the second instance, to provide a drink that contains ketones which can be ingested by volunteers, so we can see if this will end up improving their brain function. If we succeed, perhaps it will create a pathway toward trying out ketone ester on Alzheimer’s patients.

TNH: You have dedicated your life to studying Alzheimer’s Disease. How does it make you feel to be one of the many scientists who are trying to ease human suffering?

DK: As you said, I have dedicated my career to researching this disease, whose cause has yet to be discovered. Nevertheless, it does not matter if it will be my team or some other team that will discover the basic mechanism responsible for Alzheimer’s Disease and the way to treat it. At the moment, there is a large-scale effort aimed at researching Alzheimer’s and research centers are receiving major grants to conduct studies.

Scientists, neurologists, and researchers from all across the world are actively working toward identifying the causes and developing treatments for this disease. Hence, due to the unprecedented mobilization and grant availability, I am hopeful that we are getting somewhere. Scientific knowledge, which is our only tool for finding a treatment for Alzheimer’s Disease, is constantly developing and growing.

Information: NIH 3001 S. Hanover Street; Harbor Building, Room NM-531; Baltimore, MD 21225. Tel.: 410-350-3953. Email: [email protected].