Q&A: Increasing Metabolic Function to Promote Brain Health and Prevent Alzheimer's Disease


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, explained David Perlmutter, MD, FACN, ABIHM. But when it relates to the brain, specifically Alzheimer's, we don’t have the medicine to fix those problems.

Ahead of his upcoming presentation at the Integrative Healthcare Symposium this February, Dr. Perlmutter, board-certified neurologist and author of Grain Brain spoke on the Integrative Practitioner Podcast about the role of metabolic dysfunction in Alzheimer's disease, the subject of his session.

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: 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 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.

Avery St. Onge: I'm assuming you're just going to say someone should be healthy throughout their 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 mindful 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 positron emission tomography (PET) scans called fluorodeoxyglucose (FDG) 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 in 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 of this incredibly pervasive disease.

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: This brings us back to an interesting point about genetics. 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 mitochondria. We're going to discuss something called AMP-activated protein kinase (AMPK), 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.

There's no one-size-fits-all solution when it comes to dietary recommendations. It doesn't only depend on genetics but also other metrics. For example, where is the person in terms of waist-to-hip ratio, percentage of body fat, blood sugar, and 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. Achieving that 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 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.

About the Expert

Courtesy photoDavid 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 NeurologyNeurosurgery, 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.

Editor’s note: This interview was edited and condensed. To listen to the full podcast, click here.