 I'm a doctoral candidate from the University of Illinois at Chicago, my name is Rand Akashay. I'm focusing on the link of Alzheimer's disease to diabetes. I'm dedicating this to my grandma who passed away last January and she had dementia. And I also think that diabetes is important because it's on the rise. I like to start with the basics. Alzheimer's disease, it's a degenerative disease of the brain's cerebral cortex. Its principal manifestation is dementia and loss of cognitive functions. And it's the most common form of dementia. It affects approximately five million Americans in the United States. And it's important to understand that regardless of the etiology, be it Alzheimer's or dementia, both of them are not a normal part of the aging process. So there's something that can be done about that. Patients rarely get symptomatic before 50. The disease may either be sporadic, meaning that it is late onset, it's senile, it's not related to a direct or a single cause. On the other hand, we have the familial Alzheimer's disease and this is the one that's related to clusters within families, single genetic mutations and this is the less common form, which occurs at early ages in midlife and tends to be more detrimental maybe. In the world, the prevalence also of Alzheimer's disease is high. We currently have like in 2015, as we see here, we have about 35 million cases and it's projected to increase to one or six million cases by 2050. And that's very high. So starting with the brain, the brain is anatomically and functionally divided into lobes and Alzheimer's actually starts within this part of the brain, which is the temporal lobe and it has the hippocampus and this is the part that's basically responsible of memory and learning and as the disease progresses, it spreads throughout the brain through other areas like planning and the ones responsible for planning and judgment, then speech and language and then the patient would reach a phase where they lack awareness of the outer world, they forget their names, they don't know anything, which is of course sad. And the macroscopic examination as the professor's address involves the atrophy of the cerebral cortex, this is what we see. These alterations usually become later in life, years after the related risk factors happen or occur and they may not be the best tools for early diagnosis. And then the molecular characteristics or the microscopic examination of the disease revealed two types of changes that occur in the brain and these are the plagues and the tangas. First we have the plagues and these are made of the beta-amyloid peptides, which are derived from the amyloid precursor protein and these exist between cells. They occur like patches here between the neuronal cells and with time they cause troubles. We also have the tangas that are made by the tau protein and these are alterations that occur to the tau protein inside the cells and eventually can lead to the death of these neurons. So that's how we start. And normally the amyloid precursor protein on the cell membrane, it gets cleaved by enzymes here like alpha secretase and gamma secretase generates a soluble fragment that the body can recycle and get rid of. On the other hand in Alzheimer's disease we have another enzyme and actually many others so it's much more complex than this graph including the beta secretase and the gamma secretase which lead to the formation of amyloid beta peptides which with other conditions like inflammation they aggregate and they further drive the progression of the disease. And then after the amyloid form they also cause problems inside the neurons. The tau protein is very important to stabilize the structure inside the neuron. It guides the passage of nutrients and neurotransmitter along the brain, the neuronal axons. But in Alzheimer's disease it gets chemically modified or hyperphosphorylated and this alters its function and causes it to form tangas. The hallmark of many neurodegenerative diseases is actually the formation of protein aggregates but here our protein of interest is the amyloid beta. So we are supposed to have a balance between the amount of protein that's being produced and the amount of protein that's being destroyed or recycled by our cell machineries. And it happens in many other diseases like for example in Parkinson's disease we have increased misfolding and aggregation of the protein alpha-synuclein and there are many other examples. For this reason pharmaceutical companies have put lots of effort and money in clinical trials to try to clear these amyloid peptides either through modulating the secretase enzymes that produce them or through direct immunotherapy that would target the amyloid beta and help us get rid of it. But as you can see many of them were discontinued some are still going but maybe it's better if we actually look at the reason that these amyloids are forming we need to address the cause again not just these that occur in later stages of the disease. What causes this imbalance in protein formation and recycling and this will help us find answers to how to prevent and treat Alzheimer's disease. This could be genetic, environmental or an interaction of both. And in a disease like Alzheimer's the familial form we have three identified genes which are the amyloid precursor protein Pracinellin one and Pracinellin two which are considered to be as direct causes of the disease when they exist because they lead to excessive either altered structure of these proteins therefore their recycling and their functions are altered or their over expression. On the other hand the other genetic genes that are related to Alzheimer's disease are actually considered as risk factors and we don't like to call them mutations because they could be just normal variations within the human genome that makes them more susceptible to certain diseases. They are not considered as direct causes to the disease but rather something that makes this person susceptible to the condition. And here is ApoE4 which we've heard about today. The graph actually also tells us that you know these having any of these genes is not a death sentence. It means that there are lifestyle factors that play into the process. So what are these environmental risk factors? We have diabetes, melitis, midlife hypertension, midlife obesity, depression of course and stress, physical inactivity a very strong factor, smoking, low education and also combine that of course would increase the number of cases. For example here we have diabetes melitis. What the table says is that if we take out diabetes we can prevent about 826,000 cases of Alzheimer's disease which is pretty impressive. And this is from Lancet Neurology. They also point out something interesting that late life obesity was actually associated with reduced dementia risk whereas being underweight was associated with increased risk. I couldn't find a good explanation of why that is. Maybe later in life having a little bit of extra reserves maybe it's good, I don't know but. So I'm focusing the rest of the presentation on the link to diabetes. And this is because diabetes is a disease that's going on the rise. The rates are going up all over the world and in America most Americans actually and according to Inhaze data consume their energy or the most of their energy from cereals, breads, cakes, cookies, soda. This is by Inhaze data and this is a recipe for disaster. So what is it about diabetes that actually leads or contributes to Alzheimer's disease is actually hyperinsulinemia. So there are many metabolic risk factors that contribute to Alzheimer's disease and these as you have heard before are increased homocysteine, hypercholesterolemia, hyperinsulinemia, increased inflammatory cytokines because of infections or inflammatory diseases, vitamin D insufficiency, folate deficiency, vitamin B12 deficiency. Other than that, of course, heavy metal toxicity, head injuries and so on and so forth. There are many of those. So most of the studies that examined a correlation between diabetes and Alzheimer's disease found that diabetes increases the risk of Alzheimer's disease except for these two cross-sectional studies. And after a closer look into these studies they found that what differs in these studies is that the patients were not really hyperinsulinemic. So that gives us a hint that insulinemia or high insulin levels in diabetes may be the strongest mechanisms of how diabetes leads to Alzheimer's disease. How is that possible? Scientists found the answer in what we call the insulin-degrading enzyme. So this enzyme is expressed actually in many cells all over the body but it's strongly expressed in our brains and it's functioned that it degrades or it's responsible for the recycling of many proteins like amyloid beta and insulin. So what happens is that when in the brain there is the insulin-degrading enzyme, if we have too much insulin, then insulin which has a higher affinity to IDE than amyloid beta is gonna compete and take the IDE away from the amyloid beta. And this way you have debilitated the mechanism that helps your brain get rid of these amyloid proteins. On the other hand, we also have that certain IDE genetic variations leads to their altered functions and therefore they would lead to higher amyloid beta and high insulin levels in the brain. So it could go both way. It depends on the cause of IDE alteration. Before I go deeper into the mechanisms related to diabetes and Alzheimer's, I thought of giving just a brief about what happens inside the brain and how it deals with nutrients. First of all, lipids represent 50% of the dry mass of the brain which is only second after adipose tissue. And the main lipid is cholesterol. The human brain represents only 2% of the total body mass but contains 25% of the total body cholesterol. In addition to that, the cerebrospinal fluid glucose concentration is 50 to 80 milligrams per day-sea liter and this compares to 60 to 70% of the concentration in the blood. So maybe the brain needs a bit, it's glucose and cholesterol are very essential. Maybe it tells us that it likes glucose but maybe not so much, like not as concentrations compatible in the blood. And the brain consumes about 20 to 30% of the body's total energy needs. And these energy substrates come from glucose in the fed state, ketone bodies in the fasting state and gluconeogenesis could happen in fasting state to a lesser extent. And lactate, which is considered an emergency form of fuel because by itself it can be translocated to the mitochondria and generate ATP. It also has other important functions in the brain. And of course the medium chain fatty acids, the cholesterol, the lipids, all these have important and independent functions. So inside the brain we have the main cells which are the neurons. These are the ones that are mainly responsible of neurotransmissions and we have other supporting cells which are astrocytes and we have the oligodontrocytes and we have the microglia. What happens is that when we need glucose from the blood, it's gonna be transported through this carrier which is glucose one transported. It works independently from insulin and then after that this glucose goes to either the neurons, to astrocytes and enters through the glutathree transporter where it can be used to generate pyruvate and then ATP and lactate. In addition to that in astrocytes, you see that they are capable of storing some glycogen so they can provide some glucose when the neurons are fasting or lacking in glucose. The oligodontrocytes uses the glucose for lipid or lipogenesis and this is important for the myelination of axons. We also have the microglia which also has important metabolic and immune functions inside the brain. In addition to that, the way that the brain deals with cholesterol, we have cholesterol that gets formed inside the astrocytes. It could be from glucose and then it gets packed in these lipid particles which carry on them the ApoE protein. And this is exocytost and then because ApoE4, ApoE has the ability to bind to receptors on the neurons, this will help neurons uptake the cholesterol and then use it for various metabolic functions related to axonal growth, neurogenesis and other important maintenance functions. But when actually the ApoE4 is here, this binding is not as great and that's why cholesterol uptake by the cell does not happen as efficiently. So going back to Alzheimer's disease and diabetes, we know that insulin resistance and type 2 diabetes and the metabolic syndrome all raise the risk of developing Alzheimer's disease and this is providing more evidence that it is in fact a metabolic disorder. Deregulated metabolism occur in the brain. Basically we have glucose hypometabolism and reduced uptake for different reasons. We have brain deficiency and resistance to insulin and insulin-like growth factor. So glucose and insulin, no doubt, very important but sometimes the brain cannot deal with them or is incapable of dealing with them. In addition to that, we have a cerebral metabolic rate of glucose that is 20 to 25% lower in Alzheimer's disease patients. And this earliest reduction of the hypometabolism in the brain was actually detected in the hippocampus and this later occurs in other parts of the brain including the temporal parietal and frontal. And just a reminder, Alzheimer's disease in general starts in the hippocampus and the temporal lobes which are responsible for memory. And this brain glucose hypometabolism is likely a cause and an effect in Alzheimer's disease. So the brain glucose hypometabolism occurs 30 or more years before the onset of Alzheimer's disease or the appearance of any symptoms, especially in individuals with ApoE for genotype and also those with maternal family history of the disease. Neural degeneration, on the other hand, and reduced cortical mass in the brain by itself leads to reduced overall glucose consumption. So when the brain size with the disease progression goes down, of course it's gonna start consuming less glucose. And it's very important to note that the brain metabolic dysregulation in Alzheimer's disease was found to be specific to the glucose metabolism while keto metabolism remains unaltered. To speak more about mechanisms, the brain glucose hypometabolism can be related to different causes. For example, reduced glucose uptake to reduce Gluta 1 and Gluta 3 expression. That could be because of excessive exposure of the neurons to glucose. For example, by itself it can downregulate Gluta 3 or it can be genetic, like people who have Gluta 1 deficiency and who cannot survive if they do not follow the ketogenic diet. We also have reduced glycolysis and acetyl-CoA synthesis from pyruvate that occurs, mitochondrial dysfunction, also as important factor in Alzheimer's disease. And it may explain the higher incidence of maternal family history, especially that we get the mitochondria only from our mothers and not from our fathers. So the lower glucose metabolism induces tau hyperphosphorylation eventually in addition to inducing inflammation, of course, and impairs neurotransmission and causes cognitive decline. And scientists also has named Alzheimer's disease as type 3 diabetes. And that is because brain insulin resistance can occur without obesity, without type 2 diabetes and without peripheral insulin resistance. And insulin levels were also found to be lower in the brains of post-mortem AD patients. Is type 3 diabetes an independent disease from type 2 and type 1? This is what scientists think because it's confined to the brain. But any type of diabetes can actually increase the risk of Alzheimer's disease because hyperglycemia, for example, or increased glucose can form what we call advanced glycation end products which make proteins dysfunctional and induce inflammation and drive the disease in the brain. Also, even people with type 1 diabetes who have their blood glucose controlled, if they are taking lots of insulin injections, this by itself is a risk factor to insulin. So the more these people with diabetes have insulin, the more they are at risk of Alzheimer's disease regardless of which type of Alzheimer's it is or which type of diabetes it is. So we go to the question, can ketones replace glucose in Alzheimer's disease? Ketones can actually provide 60% of the brain's energy demands. So ketones by themselves are a major source of energy to the brain. However, glucose is still essential, especially to provide lactate for various functions. According to studies achieving safe mild ketonemia and as Dr. Redsen pointed, through a low-carb, high-fat diet or flexible ketogenic diet or through ketone supplementation contributes to about 5% to 10% of the brain energy deficits caused by glucose, hypermetabolism and individuals at risk of Alzheimer's disease. So ketones can be an important energy fuel to compensate for glucose loss. But I want to point that normalizing blood glucose and insulin is still important and should drive the treatment plan because they can actually inhibit the formation of ketone bodies inside our cells. How is that? What happens is that when you are fasting or starving, your cells are gonna start breaking down the lipids into fatty acids and these fatty acids get oxidized and they form the ketone bodies. They can be all these, acetoacetate, beta hydroxy, butyrate or acetone. And what we know about insulin is that it is anabolic hormone. It is lipogenic. It prevents dyslipolysis, the breakdown of lipids and it also prevents the formation of ketones. And if somebody is diabetic and have hyperinsulinemia, like for example in type 2 diabetes, they may still have the hyperinsulinemia through the night. So even at night, they're not getting this ketone body synthesis. So my main take-home message is that insulin acutely improves brain function. It is very important for the brain, but long-term and excessive exposure to insulin reduces its glucose utilization. It inhibits lipolysis and ketone production, which leads to reduced availability of ketone to compensate for reduced glucose metabolism. So a high-fat, low-carb diet or again the flexible ketogenic diet may not necessarily induce ketosis if hyperinsulinemia is not normalized. So we can no longer just tell everybody follow this diet and expect it to work and that's why we have variations. And ketogenic diet by itself can induce a form of insulin resistance because normally your cells are gonna try to keep the glucose in the blood for those cells that really need them. So it's an important survival mechanism, but we want to make sure that things don't go out of control and this is how we do that. We have to check on insulin and glucose consistently when people are on a ketogenic diet. So ketogenic diet and ketone supplements may improve the decline in cognitive function which occurs in hypoglycemia, in childhood epilepsy, in brain ischemia, in people with glutawand deficiency, they do not have the main transporter that can send glucose from the blood to the brain and also people with pyruvate dehydrogenase deficiency. All these people seem to be working well on ketogenic diet and for Alzheimer's disease, short-term improvement was found in patients, but if we're speaking clinical trials and the gold standard of scientific evidence, we want to test it for the long-term. Further studies are needed to clarify also whether early screening and targeting of glucose metabolism or hypometabolism may be a useful prevention strategy in Alzheimer's disease. So we need to address that. And to speak a little bit about other dietary factors or patterns, energy restriction in epidemiologic studies was associated with lower incidence of many neurodegenerative disorders, including Alzheimer's disease. And the benefits comes in decreases in metabolic stress, decreases in reactive oxygen species, also increases in neurotrophic factors like BDNF inhibition of apoptosis and inflammation and promotion of mitochondrial biogenesis. So you have more mitochondria or more capable of burning fuel, and therefore you have more ATP for the brain to survive. On the other hand, overnutrition is very detrimental. It leads to activation of a major inflammatory pathway inside our cells. This is the nuclear factor, Kappa B pathway. And this is what goes to your genome and tells your genes to produce the proteins that cause so much inflammation inside our cells. In addition to that, we have, this would lead to defective autophagy because your cells cannot keep up with too much food, too much nutrients that are running around. And this would lead also to endoplasmic reticular and mitochondrial stress. All together, this would need to neuroinflammation and this will need to impair intracellular signallings inside the neuron. It would need to reduce neurogenesis. It impairs the neural stem cells which are in our brain and also neural apoptosis occurs. So overnutrition is bad. It drives, it can contribute to Alzheimer's disease or neurodegenerative disorders and many diseases. And this by itself can drive more metabolic illnesses and other disorders. And this is just a table that summarizes the effect of caloric restriction and ketogenic diet and ketone body supplementation. Just to emphasize that caloric restriction is not exactly the same as ketogenic diet and it may be a useful strategy when people cannot follow very high-fat diets, cannot tolerate it for any reason. Fasting is really the way to go in this case and also there are more studies and we understand what happens in caloric restriction more than in ketogenic diet. We also know more about its long-term effect. So what are the clinical implications for diabetes related to Alzheimer's disease? First of all, fasting insulin, glucose and ketone levels should guide the prevention and treatment plan. We live in an exciting time in medicine where we can use these biomarkers to tailor our treatments and prevention strategies to every patient according to their needs. And also we need to follow strategies to improve insulin sensitivity because insulin is still, again, it is important. It is essential. It's not by itself a devil, but too much is not too good. So we need to improve systemic insulin sensitivity, follow the strategies that we all know which are exercise, stress reduction, sleep, spices like turmeric, cinnamon, herbs and eating whole foods. In addition to that, fast. I still hear practitioners, including nutritionists who say, oh, eat five or six meals a day. Why you don't have to? Give yourself a break. Give your brain a break from all these nutrients. It doesn't need all that stress. You only need so much to be able to carry your functions as long as you're meeting your fibers and micronutrients intake, then you're good. So skipping meals is okay. Yeah, I just want to thank my mentor, Professor Jamila Fentuzzi at UIC for her constant guidance and knowledge and also my friend Chris Alicia from Midwestern University, Medical School, who revised my abstract and also the H.S. Organizing Committee for accepting my abstract. Thank you. Hi, question. Thanks for your talk, this is very comprehensive. Thank you. Do you, what is the, you mentioned that you guys check insulin levels to assure that people are like, I guess in the better fat burning or ketone producing zone. What is the insulin level you look for? Okay, so first of all, I'm right now, I'm a researcher, not a clinician, but the normal fasting insulin levels. Yeah, I want to emphasize that it has to be the fasting levels because this is, during the time of fasting is when you want the ketosis to occur. You measure it in the morning when the patient is still fasting and somewhere around less than 25 units per liter is good. Do you know how they came to that number? Like did they measure, were there more ketones or was there like lower levels of glucose? This 25 is pretty high. I actually, if we're talking about, I guess it depends on the unit. But it can go a lot higher. I think they do it in how it goes in what is normal and what is how people are healthy in general. Like when the concentrations where most people are healthy and not having problems. So the reference range is probably is what they're looking at. Yes, yes. They don't come up with their own number. Maybe other studies would show lower is better. But even if you get it down to 10, eight, that's also good. Yeah. Below five. Okay. Yeah. Okay. Okay. The clinicians know. Okay. Good. Rand, thank you. That was a fabulous talk and it's wonderful to see the way all the information's coming together, giving a consistent story. I've got two questions. Where do you get the level of point four to point five ketone bodies for bridging the gap from? And the second question is if somebody is still insulin resistant on high fat, low carb and fasting isn't working, you'd add exercise maybe? Yes. Yes. So those two questions. Okay. So the ketone, the ketone one point four to point five, I got it from one of the paper that says clinical trials for that. I can send you the link. I can't recall. Is it out? Yes. I can talk to you about that. And the second is exercise. Exercise is known to sensitize ourselves to insulin through promoting the translocation of glutathor to the cell membrane and it has many other functions also. It maintains muscle mass. It maintains, which makes it more capable of metabolizing glucose. It stimulates mitochondrial biogenesis. So certainly exercise is important and speaking about Alzheimer's disease, it also improves the blood brain to everywhere, including the brain. So it is a great approach and physical activity in activity is a very strong risk factor for Alzheimer's disease. Thank you, Rand. You mentioned ketone supplementation as one of the options. Is there a particular type or method of that that was used in the researcher that is known to be more effective? I don't know much about that. I know that they can give acetate or beta hydroxybutyrate and it looks like they see some improvement in brain functions. But I favor, because we're talking about metabolic stress, if you are taking ketones and still you're not giving yourself a break, you're not fasting, you're always eating, there's so much glucose running around, that's still toxic to your neurons. So it's not the best. It can help when there's nothing else can be done, but the ketogenic diet or high-fat low-carb, anything that normalizes insulin and other metabolic risk factors would be better. So it's not something to rely on to supplementation? Not by itself, you certainly have to address all the risk factors, not just insulin, as Dr. Redson said, there are many metabolic risk factors. Okay, thank you. It appears that you think to drug companies that are trying to attack the plaque directly are kind of misguided? No. I just think that prevention is very important. It makes sense that we know that this protein is, maybe by itself it has important functions in the brain like the amyloid precursor proteins, but if it occurs later in the disease, then maybe it's important to catch the disease before all these problems occur. And let's say that somebody is in late-stage Alzheimer's disease, if this drug can help them a little bit, then why not? But we're spending millions of dollars on these drugs and immune modulators which have side effects and many of them have failed when we know that the risk factors are related to eating too much, not moving, all these smoking, all these lifestyle factors that can actually be addressed before we think of drugs. And again, these drugs would help clear the amyloids, but are we actually helping stopping their formation? Are we stopping the inflammation? Are we stopping the metabolic stress? No. So you can't isolate better amyloids from everything that happens and pretend like it's the only devil inside the brain. So then you think those drugs are good for advanced patients who have- I'm not a physician, so I can, I don't recommend drugs. I am a nutritionist, so I think it's a physician's job to decide when to prescribe drugs, but I think it is something to keep for late-stage of disease and even in late stages, we can still modify the lifestyle and you get much better results. This is something I'm sure of. As far as the drugs, I mean- Okay, thanks. Uh-huh, thank you. Thank you. Thank you.