David Perlmutter on the Role of Metabolic Dysfunction in Alzheimer’s Disease
David Perlmutter, MD, FACN, ABIHM, joins Integrative Practitioner Content Specialist, Avery St. Onge, to discuss using proactive lifestyle-centered measures to increase metabolic functioning, promote brain health, and significantly reduce the risk of Alzheimer's disease.
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About the Expert
David Perlmutter, MD, FACN, ABIHM, is a Board-Certified Neurologist and six-time New York Times bestselling author. He serves on the Board of Directors and is a Fellow of the American College of Nutrition. Perlmutter received his medical degree from the University of Miami School of Medicine, where he was awarded the Leonard G. Rowntree Research Award. He serves as a member of the Editorial Board for the Journal of Alzheimer's Disease and has published extensively in peer-reviewed scientific journals, including Archives of Neurology, Neurosurgery, and The Journal of Appl ied Nutrition. In addition, he is a frequent lecturer at symposia sponsored by institutions such as the World Bank and IMF, Columbia University, Scripps Institute, New York University, and Harvard University, and serves as an Associate Professor at the University of Miami Miller School of Medicine.
Avery St. Onge: Can you start by giving a brief overview of what you'll be discussing at the symposium?
David Perlmutter: I can. As many in the audience know, I am a neurologist, and I've been really involved in the notion of Preventive Medicine as it relates to the brain. Most neurologists, and I include myself here until about three decades ago, have been really involved in treating neurological conditions. And I think that's great. But I wanted to go upstream from that and ask, why are we getting these issues in the first place?
I'm going to focus on what makes a good brain go bad and what lifestyle interventions we can employ to help people really chart the brain's destiny for the better. We are taught to live our lives until a problem comes up, and then, once we develop a problem, modern medicine is there to solve our ills. When it relates to the brain, and specifically Alzheimer's, which will be a central theme of my presentation, we don't have anything. I mean, this past year has seen a lot of headlines, if you will, talking about new and exciting medicines to treat Alzheimer's disease. And as I will present, the data, in terms of what they're actually able to accomplish, shows that it's minimal. And it's at an incredibly high cost, not just in terms of money, but also in terms of risk for the individual patient—risks like bleeding in the brain and brain swelling. So, when we look at the risk-benefit ratio, the benefit is really low, the risk is significant, and the cost is pretty overwhelming. We can do better.
So, these whole new classes of medications are really centered on a single premise that carries forth through all of the development, and that is the cause of Alzheimer's disease is the accumulation in the brain of a particular misfolded protein called beta-amyloid. And leading researchers around the world are publishing information that isn't necessarily true.
One recent study appearing in the Journal of the American Medical Association described, first, that this amyloid hypothesis is on shaky ground, and second, that what really seems to be happening in the brain, leading to things like degeneration, loss of neurons, cognitive decline, and even amyloid accumulation, are metabolic threats to the brain. The brain's metabolism begins to decline—it's called the bioenergetic theory. And this was a headline in the Journal of the American Medical Association. Frankly, we've been talking about that for about two decades now.
So my purpose is to bring the audience up to speed, not only in terms of really defining what this bioenergetic theory is all about but much more importantly, to talk about how we can create an internal environment whereby the brain is nurtured, and therefore maintains good metabolism, and is able to resist the decline that we then ultimately call Alzheimer's disease—a disease affecting more than 50 million people globally. So it's really quite a devastating issue. And I'm going to do this in the context of the fact that we don't have any real meaningful pharmaceutical intervention as yet.
Avery St. Onge: Okay, and then taking a step back, what does make a good brand go bad? How do lifestyle choices influence brain health?
David Perlmutter: Fundamentally, what causes a good brain to decline are the changes that happen in brain metabolism. Primarily, this means how the brain is able to utilize fuel, primarily glucose. That begins to decline as the brain becomes resistant to the function of insulin. So, we're back to an area that the audience is really quite familiar with, and that is something called insulin sensitivity—or the loss of that—when the brain and the body become insulin resistant. And we allow that to happen based on the choices that we make each and every day. Do we exercise, or not? Do we eat a high-carbohydrate diet, or not? Are the fats that we consume highly modified? What are the levels and functionality of the various vitamins in the body? And how does that affect insulin functionality?
This is familiar territory for our audience. But what may be a little bit unfamiliar is this discussion of insulin resistance in the context of brain health. The brain at rest, when the body is at rest, is consuming 20 to 25% of the body's calories, even though it weighs only about 5% of the total body weight. It is by far and away the most energy-hungry part of the body. So therefore, metabolic discussions and considerations are paramount as they relate to the brain.
We can predict which brain is going to decline—that is, who's going to get Alzheimer's—20 and 30 years ahead of time by simply looking at brain scans that reveal how the brain is metabolizing fuel. And again, what is so important, where the traction comes from, is the fact that our lifestyle choices are hugely influential in determining how the brain metabolizes fuel. So, we will chart our brain's destiny based upon the choices that we make each and every day.
And what I'll do in my discussion is reveal what those changes are, and certainly go through chapter and verse, what the scientific underpinnings are and what are our most well-respected, peer-reviewed studies demonstrating in terms of these lifestyle interventions that affect the brain.
Avery St. Onge: In your presentation, you're going to be specifically discussing Alzheimer's disease and how that relates to metabolic health. Can you tell me more about that connection and the metabolic risk factors for Alzheimer's disease?
David Perlmutter: Well, we've known for a couple of decades that being metabolically compromised is dramatically associated with Alzheimer's disease. More recently, we understand that becoming a type two diabetic, which is essentially a lifestyle choice, can increase your risk for this disease— a disease for which there is no mainstream pharmaceutical fix—by as much as fourfold. That's significant, especially considering that if you live to be age 85, your risk of becoming an Alzheimer's patient is 50/50. That's just the flip of a coin. One in three seniors will develop Alzheimer's or some other form of dementia, cognitive decline, or what we can call brain failure.
When we see strong correlations between well-defined metabolic parameters like hypertension and insulin resistance, and the development of Alzheimer's, we must take notice. We've known about these correlations from an epidemiological perspective for a long time. But now, we are understanding exactly how things like elevated uric acid, high blood sugar, increased insulin resistance, and hypertension are directly threatening the brain and its metabolism. Compromised brain metabolism means that the brain's energy-producing organelles within the neurons, called mitochondria, are starting to fail.
We recognize that the failure of these mitochondria, because they can't process fuel effectively, does two important things. First, it increases their production of damaging chemicals called free radicals. But another consequence of damaged mitochondria is that they trigger a specific suite of enzymes in a cascade called caspase, which instructs the brain cell, the neuron, to commit suicide, a process known as apoptosis.
This creates a powerful link between mitochondrial dysfunction brought on by metabolic dysfunction, which in turn is brought on by our lifestyle choices, and the death of brain cells. When we connect these dots, it becomes very real. The lifestyle choices we make every day—how much sleep we get, how restorative that sleep is, whether we stress our muscles, and whether we choose a diet that threatens our metabolism and ultimately leads to the loss of brain cells—compose a message that is not only powerful but also empowering. Indeed.
Avery St. Onge: Of course, type two diabetes isn't necessarily a choice, some people are at a higher genetic risk. What do you say to those people who are more susceptible to insulin resistance and no matter their lifestyle changes, they still have a level of insulin resistance? Do you treat those people differently from people that aren't as susceptible and don't already have preexisting insulin resistance?
David Perlmutter: Let's be clear. Type Two Diabetes is largely not a genetic condition. Are there some genes that increase the risk? Certainly, there are genes associated with a higher risk for insulin resistance. However, the majority of individuals who become type two diabetics are those making inappropriate lifestyle choices. If it were purely genetic, we wouldn't be witnessing the dramatic rise in the incidence of type two diabetes that we're currently seeing. If it were genetic, the numbers would have remained relatively stable.
Do environmental factors increase risk and interact with a genetic predisposition? They absolutely do. But does that mean we treat those individuals any differently? The answer is no. We recommend that doctors institute the same interventions for people at risk as those who may not have a genetic predisposition. This is based on their metrics, their levels of demonstrated insulin resistance, fasting insulin levels, readings from continuous glucose monitors, and glucose tolerance tests—these are the metrics we use to determine where an individual stands on the scale of insulin functionality, along with blood sugar levels.
The recommendations follow a cascade from not very aggressive to more aggressive and interventional pharmaceuticals. If an individual has made the necessary lifestyle modifications and still has elevated blood sugars, putting them at risk for brain health, then there is indeed a time and place for medication. Which medications? That can be discussed, but generally, we start with medications that have a low risk of threat. We're seeing a lot of benefits from what are called the GLP-1 agonists these days, and certainly from Metformin.
But first and foremost, it's crucial to emphasize lifestyle change before a patient becomes insulin resistant, before they are well down that path. It's vitally important that we focus on preventing individuals from becoming metabolically compromised, especially if we want to prevent brain decline as part of the metabolic issue.
Avery St. Onge: I'm assuming that you're just going to say someone should be healthy throughout their whole life. Obviously, that's ideal, but at what age group do you find that metabolic health really begins to be impacted by lifestyle choices? At what age group should people be particularly cognizant of this?
David Perlmutter: I've been asked that question many times. Studies show that changes in the brain's utilization of glucose, as demonstrated on specific types of PET scans called fluorodeoxyglucose PET scans, appear to set the stage for Alzheimer's. These changes occur 20 and 30 years prior to the onset of clinical symptoms like impaired judgment and memory. It's at this point that people seek help or are brought for medical guidance when their brain function is noticeably deteriorating. What I'm saying is that these brain changes begin to take place decades earlier, in our 30s or even earlier. But more specifically, metabolic issues start even before that, in adolescence, in childhood.
Therefore, we need to start making lifestyle changes very early on, like in grade school. We're seeing rising rates of obesity among children and what we used to call adult-onset diabetes, now soaring among the young. It's not called adult-onset diabetes anymore because of that; it's now type two diabetes, as children, who are not adults, are developing this condition.
This early intervention is critical. When we ask, "When does it begin?"—changes may actually start at birth, influenced by how a child is born. The differences in the microbiome between a child born vaginally versus by cesarean section can have significant effects. Regulating our metabolism involves a multitude of factors, and all these inputs should be considered when creating a scenario for better metabolism, and hopefully, optimal metabolism, to reduce the risk for this incredibly pervasive disease.
Avery St. Onge: You touched on this earlier, but can you tell me more about the role of nitric oxide in metabolic health and disease and how that then impacts the brain?
David Perlmutter: Now, we are beginning to understand a class of chemicals in the body called gasotransmitters. These are gases that affect various pathways in the body, such as hydrogen sulfide and, as you mentioned, nitric oxide. Nitric oxide is particularly important as it regulates the blood supply and insulin functionality—two critical factors for the brain. Therefore, we can draw a significant connection between nitric oxide levels and functionality to overall brain health. This is a very new area of research that unveils many intriguing correlations.
For instance, why is the risk of Alzheimer's greater in people with high uric acid levels? Interestingly, uric acid inhibits nitric oxide. And why is there an increased risk of Alzheimer's in people with changes in their oral microbiome, those who have poor dental health or significant changes in their oral microbiome? It turns out, the connection to Alzheimer's is through the mechanism of nitric oxide. About 50% of the nitric oxide functionality and availability in the human body relies on specific bacteria on the dorsum of the tongue. These bacteria assist in converting dietary nitrate into nitrite, which is the precursor for creating nitric oxide. This is profoundly important.
Blood supply to the brain is fundamental and is one of the primary mechanisms, in addition to free radical mediated stress and inflammation, that is involved in the deterioration of a healthy brain. This burgeoning area of research is exciting. The Nobel Prize was awarded in the late 1980s to researchers who discovered nitric oxide's significant role in regulating blood vessel tone. Now we know it does much more—it's involved in insulin functionality and even in regulating inflammation.
Avery St. Onge: For those who are trying to prevent Alzheimer's, what are the main lifestyle interventions that you suggest? And specifically in terms of diet, what kind of diet would you suggest?
David Perlmutter: Well, this brings us back to an interesting point about genetics that you mentioned earlier. I believe that no single diet works for everyone. The right diet for an individual is one that keeps blood sugar under control and maintains insulin sensitivity. This is crucial for the health of the mitochondria. We're going to discuss something called AMP kinase, which is activated by a diet that keeps blood sugar in check. This activation helps our bodies reduce blood sugar production, metabolize fat more effectively, and importantly, trigger the increase of mitochondria production, known as mitochondrial biogenesis.
These effects are achieved when a diet is tailored to the patient—this is what we call personalized medicine—by considering their genetics, among other factors, to create a recommendation that promotes good metabolism. So there's definitely not a one-size-fits-all solution when it comes to dietary recommendations. It doesn't only depend on genetics, but also on other metrics. For example, where is the person in terms of waist-to-hip ratio, percentage body fat, blood sugar, insulin functionality? What does the glucose tolerance test show? And what are the continuous glucose monitor readings?
Additionally, does the individual have a high homocysteine level? If so, methylated B vitamins may be the go-to remedy. This issue can arise not just from diet but also from genetics that lead to higher levels of homocysteine, which is brain-threatening. So the one-size-fits-all approach we're looking for is a diet that regulates metabolism. How to achieve that really depends on the individual patient's evaluations and metrics.
Avery St. Onge: How do lifestyle factors like exercise and stress management impact brain health?
David Perlmutter: Well, let's parse those apart. Exercise will constitute a significant portion of this presentation because we're going to delve into the concept that muscles act as an endocrine gland. When muscles are stressed through exercise, they secrete various chemicals. Some of these, like increased lactate production and ketones, may be familiar, while others, such as cathepsin B and irisin, might be less known. Chemicals like interleukin-6 directly connect muscle activity to the activation of AMP kinase.
Viewing muscles as an endocrine gland, akin to the thyroid or pituitary—secreting substances that have effects elsewhere in the body—is a novel perspective that we're going to unpack. Understanding that these muscle-secreted chemicals are beneficial for the brain can make us more confident in recommending resistance-focused, weight-bearing exercise. There's a sweet spot, of course, a bell-shaped curve—excess can be as detrimental as deficiency, and I admit to sometimes overdoing it myself.
The connection between brain health and muscular activity is undervalued but extremely important. We'll delve into this further. For instance, a British study published in the Journal of the American Medical Association examined 78,430 adults over 6.9 years. They discovered a direct correlation between daily step count and reduced dementia risk, dose-dependent at that. The optimal number of steps was just under 10,000 per day. Notably, there was no minimum threshold beneath which benefits were not observed, meaning any increase in activity is beneficial.
This tells us that the time to start is now, regardless of the step count you begin with. This form of exercise is a powerful medicine, far more potent than anything available on a prescription pad. It involves activating the muscle-brain connection, prompting this 'endocrine gland'—the muscles—to send beneficial chemicals to the brain, fostering happiness, safety, and resistance to Alzheimer's disease, for which there is no significant pharmaceutical treatment.
Avery St. Onge: When recommending exercise to patients, especially in terms of metabolic health and brain health, how much do you stress the importance of resistance training inn comparison to cardio? Do you feel like resistance training is just as important?
David Perlmutter: Yes, I think it's essential to engage in both weightlifting and aerobics. Personally, I alternate between lifting weights one day and doing aerobic exercises the next. Lately, I find myself doing aerobics every day because I understand its importance. The benefits of aerobic exercise have been well-documented for about 18 years, with studies contrasting it with mere stretching, like the one from the University of Pittsburgh around 18 years ago.
It's crucial for people to participate in both forms of exercise. While walking is beneficial, as I've shown, the value of resistance exercise, which involves actively stressing the muscles, is becoming clearer, especially in terms of understanding the mechanisms at play. This type of exercise leads to the production of brain-responsive chemicals, including brain-derived neurotrophic factor (BDNF). BDNF stimulates the growth of new brain cells and the formation of synapses, or connections between brain cells, which is fundamental to brain health. Dr. Dale Bredesen has emphasized the importance of synaptic connectivity and the balance between synaptic plasticity, the creation of synapses, and synaptoplastic activity, the breaking down of synapses.
Exercise is a powerful lifestyle intervention that can prevent synaptic loss, and there's no medicine for this. It's something that isn't widely discussed in mainstream medicine. Despite the excitement in 2022 about new drugs for Alzheimer's, the cognitive decline in patients around 18 months shows we need to do better—and we can. Exercise is one way to achieve this improvement.
Avery St. Onge: Well, I won't make you go through your entire presentation. But, before I let you go, do you have anything else that you'd like to add?
David Perlmutter: I'll probably use this quote in my talk, but Desmond Tutu famously said— and I'll paraphrase here—while it's important to drag people out of the river, it's equally important, if not more so, to ask and find out why they are falling in in the first place. If we can target why people are falling into the river in terms of declining brain health, we're significantly ahead in doing the right thing for people, both from a cost and an efficacy perspective. When we consider metabolism in relation to the brain, that's the pathway we need to pursue to keep people healthy, particularly in preserving cognitive function.
Editor's note: This interview was transcribed and edited using artificial intelligence