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Psychiatrist, internist, and addiction medicine specialist Muhamad Aly Rifai discusses his article, “How insulin resistance may cause Alzheimer’s disease.” Muhamad introduces the paradigm-shifting concept of Alzheimer’s as “Type 3 diabetes,” arguing that insulin resistance in the brain is the root cause. He explains how this metabolic dysfunction starves neurons (especially in the memory-critical hippocampus), leading to the toxic beta-amyloid plaques and tau tangles associated with cognitive decline. Muhamad highlights the crucial link between diabetes and Alzheimer’s risk and discusses breakthrough diagnostic tools (like new blood tests) that can identify the disease before memory loss begins. Discover the practical lifestyle and medical interventions (from diet to new diabetes medications) that may prevent, manage, or even reverse cognitive decline by treating its metabolic underpinnings.

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Transcript

Kevin Pho: Hi. Welcome to the show. Subscribe at KevinMD.com/podcast. Today, we welcome back Muhamad Aly Rifai. He is a psychiatrist, internist, and addiction medicine specialist. Today’s KevinMD article is “How insulin resistance may cause Alzheimer’s disease.” Muhamad, welcome back to the show.

Muhamad Aly Rifai: Thank you very much for having me to talk about this timely topic with new discoveries and developments about the involvement of metabolic aspects, both in cognitive issues as well as mood issues and anxiety issues, and specifically talking about the metabolic component in Alzheimer’s disease.

Kevin Pho: All right. For those who didn’t get a chance to read this article, tell us what it is about.

Muhamad Aly Rifai: Alzheimer’s disease is part of the cognitive disorders that affect individuals as they age. It is a ruthless disease that robs us of the essence of our identities, the memories, the ability to process, executive functioning, and the ability to live an independent life. It was thought initially that genetics contributed significantly to the development of Alzheimer’s disease and cognitive disorders in general. However, research over the past 10 or 15 years really suggests that there may be a significant metabolic component to Alzheimer’s disease. We talk about Alzheimer’s as actually a metabolic disorder, and we call it even type 3 diabetes. These are very important concepts that are developing and that can help practicing clinicians out there to be able to modify some of the risk factors that a lot of our patients experience.

Kevin Pho: For those who may not be familiar with the data, those with metabolic syndrome or diabetes, in a ballpark range, how much would that increase their potential risk of Alzheimer’s?

Muhamad Aly Rifai: We are thinking more like three to five times.

Kevin Pho: Wow. So, it significantly, exponentially increases the risk.

Muhamad Aly Rifai: Basically, the whole concept goes back to the cellular components. As you know, insulin, which is the hormone that controls sugar and glucose metabolism, is more like a key that allows glucose to penetrate into the cell. We remember from our days of biochemistry, and we have actually gained significant understanding of that, that the insulin receptor in the cell is actually interconnected with both the dopamine receptors and the serotonin receptors.

Any disharmony or any difficulty in terms of metabolism affects this. If there is insulin resistance and it does not allow glucose to enter into the cells, the dopamine receptors and the serotonin receptors are also disrupted. Basically, in diabetes (which is a complex disease), there is some component of insulin resistance. This does not allow insulin as a hormone to affect the insulin receptor and allow glucose into the cell, starving cells in the brain as well as the rest of the body of glucose. This leads to the significant metabolic issue that happens in Alzheimer’s disease. It basically also affects both the dopamine receptors and the serotonin receptors. We see that significantly, and that accelerates the development of cognitive issues and specifically Alzheimer’s disease as well as other forms of cognitive issues such as vascular dementia and Lewy body dementia.

Kevin Pho: As far as you understand from the research, are these effects permanent? Are any of these potential risks reversible with better blood sugar control?

Muhamad Aly Rifai: Sure. Basically, in the case of Alzheimer’s, the main part of the brain that is affected is the hippocampus. This is basically the memory unit in our brain and is very densely populated with insulin receptors. It has also a lot of dopamine receptors and serotonin receptors. When the brain is starved, we lose our memories, we lose our ability to have executive functioning, and we lose our ability to process information.

We are finding that when we start to modify some of those risk factors that are there, there may be positive results. In the article, I talk about a hypothetical visit where a patient may visit their physician and they are found to have insulin resistance. They may have also high blood pressure or other things, and basically may have a genetic component that predisposes them to Alzheimer’s disease. I talk in the article also about some of this genomic testing.

Currently, or maybe in the very near future, the physician would say: “Listen, you have high risk for dementia with this genetic component. You have insulin resistance, and you have high blood pressure. We need to act now to be able to modify these risk factors.” This is especially true if the person is at age 40 or age 50. Instead of Alzheimer’s or cognitive issues developing at age 60 or 70, they are pushed further in life. They may even be averted altogether, but we have to start acting very early, at age 40 or 50, specifically for individuals who have risk factors with diabetes and genomic factors that predispose individuals to Alzheimer’s. Acting very early is very important.

Kevin Pho: In terms of potential management or treatment strategies, are they simply the traditional ways that we manage blood sugar control or treat diabetes? Is there anything specific as it relates to that connection between diabetes management and the risk of Alzheimer’s?

Muhamad Aly Rifai: The traditional management includes lifestyle interventions, exercise, remaining active, and remaining cognitively active. This can help with protecting neuronal integrity and can help us really push back the development of Alzheimer’s disease. It may actually improve insulin sensitivity and the ability of insulin to modify these things.

When there is insulin resistance and the cells are starved of glucose, those harmful amyloid plaques that we study about develop in the brain, in the hippocampus, as well as other parts of the brain. Those are basically manifested with memory loss and loss of executive functioning. So, lifestyle modification, modification of risk factors, diet, and exercise are the main things that we do that support this concept. We are modifying these factors very early. Remaining active is very important.

We see that actually, these simple factors have the highest impact in terms of delaying the progression of cognitive issues. It is not medications, and it is not these expensive vitamins or supplements that people take. It is actually those simple lifestyle modifications. Now there is a role for medications, and now these GLP-1s are being involved. They are thought to be something that would be employed and may actually push further the risk of developing cognitive issues to later in life, if not averting them completely.

Kevin Pho: Now, where does this leave traditional Alzheimer’s treatments like cholinesterase inhibitors? Given this potential connection with metabolic syndrome and Alzheimer’s, do they still have a role in potential management of Alzheimer’s?

Muhamad Aly Rifai: There is still some role to them. Their effect is modest. The cholinesterase inhibitors delay the progression of cognitive issues by a few months. I think donepezil, rivastigmine, and galantamine have some role once the issues are realized and spotted. They may delay the progression somewhat, but their effect is very modest.

The interventions with the most impact are lifestyle modification, diet modification, exercise, and remaining cognitively active. However, there may be in the future, as we do more research on these newer agents that are managing diabetes more effectively, we may find that some of these agents may have a little bit more impact than what we thought before. We may be able to deploy them a little bit more effectively to prevent development as well as progression of cognitive issues in Alzheimer’s and in memory issues.

Kevin Pho: In your article, you mentioned some newer blood tests that can potentially predict whether one may be struck with Alzheimer’s. Talk about some of these newer tests on the horizon.

Muhamad Aly Rifai: There are now a couple of tests that are FDA-approved and cleared that combine looking for different components of the amyloid proteins, the beta-amyloid proteins, in the blood. Basically, you can do a blood test and look at a ratio of these different proteins in the blood. The FDA approval has been granted because they have significant positivity in terms of being able to predict whether a person is at high risk for developing Alzheimer’s disease.

We have seen news about some actors and celebrities being tested and finding out that they actually are at high risk for developing cognitive issues and Alzheimer’s. They have actually decided to step back from their job or their acting career just to spend more time with family because they found out that they are actually at high risk for developing Alzheimer’s. These tests are really making an impact on a person’s decision about what to pursue in life and whether they are going to work hard on modifying some of the risk factors, such as diabetes, lifestyle modifications, vitamin deficiencies, as well as nutritional factors that are very important. We have seen that some of these tests that got approved in the last couple of years are making a valid impact on people’s decisions in terms of what they do in life and lifestyle modifications.

Kevin Pho: We are talking to Muhamad Aly Rifai, psychiatrist, internist, and addiction medicine specialist. Today’s KevinMD article is “How insulin resistance may cause Alzheimer’s disease.” Muhamad, let’s end with some take-home messages that you want to leave with the KevinMD audience.

Muhamad Aly Rifai: The message I think is clear and it is urgent. Alzheimer’s does not have to be inevitable. It can be prevented, it can be managed, and perhaps in the future, we may be able to reverse it by embracing its metabolic underpinning. Primary care doctors, psychiatrists, and neurologists can work with their patients to foster awareness, advocate for early screening, and prioritize the metabolic aspect of cognitive issues so we can reclaim our memories and continue with a better quality of life as we age.

Kevin Pho: Muhamad, thank you so much for sharing your perspective and insight. Thanks again for coming back on the show.

Muhamad Aly Rifai: My pleasure. Thank you.