140: Why Alzheimer’s May Be a Metabolic Disease with Dr. Ben Bikman

What if Alzheimer's disease is actually a metabolic disorder? For decades, scientists believed Alzheimer's was caused by amyloid plaques, sticky proteins that build up in the brain. The entire field focused on finding ways to remove those plaques. But there's a major problem with that idea. Some people have lots of plaques and no dementia, and many drugs designed to clear plaques have failed to improve cognition. So researchers have started asking a different question. What if the real problem isn't plaques, but energy metabolism in the brain? A growing body of evidence suggests Alzheimer's may be a form of brain-specific insulin resistance, sometimes called Type 3 diabetes. When insulin signaling fails in the brain, neurons struggle to use glucose for energy. The brain essentially begins to starve for fuel even when plenty of glucose is present. But interestingly, the Alzheimer's brain can still use ketones, an alternative fuel that doesn't require insulin. This is Lecture 140 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Today's mini lecture aims to teach you about the metabolism of Alzheimer's disease and why a growing body of evidence suggests this devastating condition may be at its root a metabolic disorder. Now, you might be thinking, Ben, isn't Alzheimer's all about plaques, about sticky proteins in the brain? That's exactly what most of us were taught, or at least what we've heard, and what most of the scientific community has believed and funded for decades. But I want to walk you through a fascinating, and if I'll be honest, somewhat troubling story about how a dominant scientific theory was built on questionable foundations, how the drugs it inspired have largely disappointed, and how a metabolic framework may offer the explanations that the plaque theory never could. But as usual, let's start from the beginning. It starts— the story starts in 1906 when a German psychiatrist and neuroanatomist, so a guy who would look at brains, named Alois Alzheimer described a 51-year-old woman with profound memory loss and disorientation, all of the cardinal signs that we would associate with Alzheimer's disease. When she died, he examined her brain under a microscope and found two striking abnormalities. Sticky plaques between the neurons and tangled fibers inside them. That was the birth of what we now call Alzheimer's disease. For most of the 20th century, research into these findings was slow, but in 1992, a landmark hypothesis emerged: the amyloid cascade hypothesis. The idea was nice. A protein called amyloid beta, or A-beta, accumulates between neurons and forms plaques. These plaques were proposed to trigger a cascade: neuroinflammation, something called a tau tangle— that was those tangles— the tau tangle formation, neuronal death, and ultimately dementia. The plaques were not just a marker of the disease, but as the theory went, the plaques are the disease. This became the dominant paradigm. In fact, I could say the only paradigm. Research funding poured in. By 2021, NIH funding for studies centered on amyloid or related pathologies with Alzheimer's disease reached nearly $300 million per year. The entire field oriented itself around this theory, and the goal became finding ways to clear or prevent those plaques. But there were problems almost from the beginning. Problem number 1: you can have lots of plaques and no cognitive decline whatsoever. Autopsy studies have found abundant amyloid deposits in people who were cognitively completely normal at the time of their death. Conversely, some people with clinical Alzheimer's disease had relatively modest plaque burden. As researchers put it in one particular published manuscript, the amounts and distribution of A-beta deposition are only weakly correlated with the clinical expression of the disease. That's the end of the quote. And by age 80, as many as 60% of cognitively normal elderly individuals have detectable amyloid in their brains. That is a fundamental problem. If plaques caused dementia, they should track with dementia. They often don't. Now, let me tell you a story that should shock you. It makes these things get even more troubling because it did shock the scientific community. In 2006, a neuroscience group at the University of Minnesota published a big paper, a landmark paper in a very big journal called Nature. The paper described a specific form of amyloid beta and appeared to show for the first time a direct cause-and-effect relationship between this protein and memory impairment. This was in animals. It was exactly what the field had been waiting for. It was the scientific smoking gun. The paper became one of the most cited Alzheimer's papers of the 21st century. It was cited and has been cited— well, it gets complicated, as I'll get to in a moment— thousands of times. It buoyed confidence in the amyloid hypothesis at a moment when it was facing a lot of skepticism after a lot of failed drug trials. More on that in a moment. It shaped research priorities and helped direct hundreds of millions of dollars in NIH funding. Then, just a few years ago, in 2022, an investigation identified more than 20 papers with data that appeared to have been digitally manipulated to fabricate or exaggerate results. The 2006 Nature paper was eventually retracted in 2024, nearly, you know, about 20 years after its publication. In fact, now it is the second most highly cited paper that has been ever retracted. Now, defenders of the amyloid hypothesis will argue that the hypothesis doesn't rest solely on this one paper. The Genetics of Familial Alzheimer's The connection with Down syndrome and other lines of evidence, they would say, support a role for amyloid. But the critical point is that this one paper propped up a very weakening hypothesis at a moment of crisis. It directed the funding, it shaped drug development strategies, and it really reinforced a tunnel vision, if you will, in a field that desperately needed to consider other explanations. And the broader pattern of fraud in Alzheimer's research didn't actually stop there. Subsequent investigation found that an astonishing 132 scientific papers published between 1997 and 2023 by a former director of the Division of Neuroscience at the NIH contained doctored data. So if the plaque theory were correct, if amyloid beta deposits were the primary cause of Alzheimer's, then removing them should help patients. But let's look at that track record. For nearly 2 decades, from 2003 to 2021, not a single new drug was approved for Alzheimer's disease. Trial after trial of anti-amyloid agents failed to meet the endpoints. These are going to be drugs with the suffix -umab, like Solenesumab, Genternerumumab, Krennesumab. And similar names. But if you hear the suffix umab, it's going to fit into this family of drug. None showed meaningful cognitive benefits. Billions of dollars, but zero new treatments. Then in 2021 came another one, the latest addition, aducanumab. It was approved by the FDA then, and it was approved by the FDA through a very controversial accelerated pathway Despite the fact that its own advisory committee concluded that efficacy had not been demonstrated. Two large Phase 3 trials gave conflicting results. One showed a modest slowing of decline at high doses. The other didn't show anything. And in fact, there were consequences like brain swelling and microbleeds in over a third of the people who were on the drugs., and it was eventually pulled from the market in 2024, just about 30 months or so after it was initially approved. It seems increasingly apparent that clearing plaques does not cure the disease. It doesn't even stop its progression. What does this tell us? It tells us that amyloid plaques may be a consequence or even a bystander in Alzheimer's disease, not the root cause. There is something deeper going on. With the plaque theory crumbling under its own weight, we do have an opportunity for a different framework to gain some momentum. And that's exactly what's been happening. I frankly find the alternative view much more compelling because it is anchored in mechanism. It is supported by extensive epidemiology and aligned with what we know about insulin's profound effects on the brain. The key idea: Alzheimer's disease may be a form of brain-specific insulin resistance. In 2005, Dr. Suzanne De La Monte of Brown University published a pivotal finding. In her laboratory, when she knocked out or removed the insulin receptor in the brain of rats, she induced a state that closely resembled Alzheimer's disease. There was an accumulation of the amyloid protein. There was the tau phosphorylation in the tangles, and there was most importantly the cognitive impairment. She later coined the term Type 3 diabetes to describe Alzheimer's, a form of diabetes that selectively involves the brain, sharing molecular and biochemical features with both Type 1 and Type 2 diabetes. And that would be the hyperglycemia and the targeted insulin resistance. De La Monte and her colleagues demonstrated that brain insulin and brain insulin-like growth factor, which has this kind of overlapping signaling. If you remove that or reduce that signaling, that you induced a resistance to the signal, it would progressively promote an increased severity of Alzheimer's disease. And then using postmortem brain tissue, they showed that the more advanced the Alzheimer's pathology, the worse the brain insulin signaling. This was demonstrated at the level of insulin gene expression, insulin receptor binding, so the degree to which insulin can lock onto its receptor, as well as the downstream signaling or the cascade of events that happens within the neurons when insulin binds to its receptor. Now, why does insulin matter so much to the brain? Well, insulin is not just a blood sugar or blood glucose regulator. In the brain, insulin does indeed help promote some glucose uptake in some brain cells through the GLUT4 or the glucose transporter 4, but it also supports neuronal survival and synaptic plasticity. It does regulate glucose metabolism, including the degree to which the neurons are burning glucose for ATP. It inhibits tau hyperphosphorylation, which is the main driver of the neurofibrillary tangles. And it facilitates beta amyloid clearance via an enzyme called insulin degrading enzyme. And lastly, insulin modulates neurotransmitter systems, including acetylcholine. So when brain insulin signaling fails, you get energy starvation of neurons, you get a runaway of tau phosphorylation inducing the tangles, and you have impaired amyloid clearance. In other words, the full picture of Alzheimer's pathology could be explained as downstream consequences of impaired insulin signaling in the brain. Nothing more, nothing less. This is a profound reframing of the paradigm. Plaques may not be the cause. They may be the exhaust fumes from a brain that has lost the ability to use insulin properly. In other words, it's a consequence. Not a cause. Now let's step back and look at the population-level data. As much as I'm loath to ever rely on epidemiology, when the epidemiology is in sync with the mechanism, then you have a powerful data perspective. If insulin resistance drives Alzheimer's, then people with type 2 diabetes, who of course have insulin resistance, should be at elevated risk, and they are. The evidence here is striking. A major meta-analysis of 28 prospective observational studies found that individuals with diabetes have a pooled relative risk of 1.56, so 56% increase for developing Alzheimer's specifically, and 1.73 for any type of dementia. And this is a consistent signal across a lot of different populations. In fact, a more recent meta-analysis from 2024 covering over 10 million individuals with diabetes found a 59% increased risk of dementia. That's pretty consistent with earlier findings. And then another large study out of the Netherlands, one of the most respected epidemiological studies in the world, found that diabetes nearly doubled the risk of dementia. And it's not just the presence of diabetes, it's the metabolic severity that tracks with the risk. A 2025 Meta-analysis of over 7 million individuals with type 2 diabetes found that those with longer diabetes duration had substantially higher dementia risk. Higher hemoglobin A1C was associated with hazard ratios as high as 3.88 in the most extreme category. Diabetes diagnosed before age 50 was associated with a hazard ratio of threefold higher risk for Alzheimer's compared to age-matched controls. But here's an important nuance that I need to admit to. Not all people with type 2 diabetes develop Alzheimer's, and not all Alzheimer's patients have type 2 diabetes. The overall framework, again, initially posited by De La Monte's group, accounts for this by distinguishing between systemic insulin resistance, which can secondarily impair the brain, and primary brain insulin resistance, where you just have a more targeted insulin resistance of the brain, perhaps driven by a random genetic or familial susceptibility. The two can occur together and certainly can amplify each other, but either alone can move someone toward neurodegeneration. Now let's talk about one of the most important genetic risk factors in Alzheimer's disease, the APOE4 allele, or that variant of a gene. The apolipoprotein E gene comes in 3 main variants: E2, E3, and E4. Carrying 1 copy of ApoE4 increases your risk of late-onset Alzheimer's by 3 to 4-fold. Carrying 2 copies increases it up to 15-fold. So about 50% of Alzheimer's patients carry at least 1 ApoE4 allele. The traditional explanation for why ApoE4 is dangerous centers on the role in amyloid clearance. The E4 isoform is less efficient at helping clear amyloid beta from the brain. But here's the fascinating question that metabolic researchers have been pursuing: what if ApoE4's primary danger is that it directly impairs insulin signaling? In 2017, a study published in the journal Neuron provided a mechanistic answer. The researchers showed that in neurons, ApoE4 physically interacts with the insulin receptor and traps the insulin receptor inside the cell, the inside these little compartments called endosomes, which then prevents the receptor from reaching the cell surface where it would normally respond to insulin. The insulin receptor gets locked in or sequestered inside the neuron where it's essentially inaccessible. To the insulin that's waiting outside the cell. The result of this is obvious. You, of course, have impaired insulin signaling and all of the consequences that comes with it. So impaired glucose uptake, impaired glucose metabolism and producing ATP generation, impaired regulation of tau phosphorylation and all the other things I mentioned earlier. Even if blood insulin is fine and even if insulin is working well elsewhere, The effect they noticed was age-dependent, and it worsened with diet-induced obesity in a particular animal model. In aging ApoE4 mice, as ApoE4 protein aggregated and the function of the cell deteriorated, the inhibitory effects of insulin signaling became even more severe. Subsequent work has reinforced this. Studies in human ApoE-targeted replacement mice—so using a human form of ApoE4 in the mice— They found that ApoE4 expression was linked to lower brain insulin signaling, lower brain glucose content, and higher overall outside-of-the-brain insulin levels, or in the brain blood but not in the brain cells. Crucially, when researchers attempted to boost cognition by inserting insulin through a separate mechanism, the ApoE4 carriers showed little to no benefit. Their neurons couldn't respond even to supplemental insulin because the receptor was trapped. Postmortem human brain studies by De La Monte and colleagues found that homozygous ApoE4 carriers— so people who had both copies from their mom and their dad— they showed earlier stage reductions in brain insulin expression. The brain was running low on insulin before the Alzheimer's pathology even reached advanced or noticeable stages. This suggests ApoE4 sets the stage for metabolic failure of the brain long before clinical symptoms appear. Think about what this means. ApoE4 isn't just a problem because it fails to clear amyloid. ApoE4 may be fundamentally and directly impairing the brain's insulin signaling system, creating a condition of brain-specific insulin resistance with a very clear genetic origin. The brain starves for energy, and of course, at the same time, tau goes haywire, inducing all the neurofibrillary tangles. Neurons are dying, and yes, amyloid accumulates because the clearance machinery that depends on insulin signaling has broken. Now, as much as the story I've been telling has maybe been a bit discouraging, let's take a more helpful turn. Um, because there is some fascinating science here that can leave someone quite optimistic. Because while the brain insulin resistance progressively shuts down the ability of neurons to use glucose, there is another fuel that the brain can use, one that doesn't require insulin signaling at all. That fuel is ketones. Let me explain why this matters so much. Glucose enters the brain and gets taken up by neurons through glucose transporters, one of which the brain has several— requires insulin. When insulin signaling is broken, as we now know it is in the Alzheimer's brain, glucose uptake falters and metabolic flux through the glycolytic or glucose-burning pathway kind of slows to a crawl. Brain imaging confirms this vividly. PET or PET scans using FDG, which is— which stands for fluorodeoxyglucose, which is a radioactive glucose that you can use for imaging. So you can get a a picture of this type of glucose with a PET scan. So PET and FDG, you can couple them together. It has been used to map the brain energy metabolism for decades. It's a, it's a well-established technology. In Alzheimer's disease, FDG PET scans show striking regional reductions in glucose uptake, and crucially, these deficits are detectable years before clinical symptoms of any kind of cognitive decline start to emerge. The brain is starving for energy long before the person knows anything is wrong. But the brain is a metabolic hybrid. Yes, it uses glucose as a fuel when it can, but it also uses ketones whenever they are available. To make that very clear, the brain is opportunistic. It's going to use whichever of the two fuels is available, and if both are equally available, prefers ketones. This is very clear. We've had decades of evidence showing this from as far back as Dr. Cahill's work. C-A-H-I-L-L. I invite anyone to look at his work on brain metabolism. But here's the critical question: does the same thing happen with glucose metabolism, or that happens to glucose metabolism, does it also happen to ketones? Ketones, primarily beta-hydroxybutyrate, and the other one, acetoacetate, but BHB, beta-hydroxybutyrate, is the main fuel. These are transported into the brain through monocarboxylate transporters, appropriately named MCTs. This is an entirely separate uptake pathway from glucose, and importantly, it is— it can work completely independently of insulin signaling. And once inside neurons, ketones like BHB are burned and they rapidly generate ATP. Again, all without needing to pass through insulin-dependent machinery or signaling that is impaired in Alzheimer's. Ketones literally bypass the broken steps. Research from Stephen Cunnane's group has been particularly illuminating. Using a specialized PET tracer for ketones, his group has directly imaged brain ketone metabolism in Alzheimer's patients alongside glucose PET scans. What they found was striking. In mild to moderate Alzheimer's disease, brain glucose uptake was up to 32% lower in key regions involved in cognition compared to healthy controls, but ketone uptake and metabolism was completely normal. I don't mean even modestly preserved, but totally normal. 3 separate studies from this group confirms these findings. The Alzheimer's brain, despite being in an energy crisis from glucose failure, retains its full capacity to take up and use ketones. Think about what this means. The metabolism of the brain is not uniformly disrupted. The specific problem is in glucose uptake and utilization, the insulin-dependent pathway. The ketone pathway remains intact. The brain is starving in a sea of glucose it can't use while the alternative rescue fuel sits waiting to be available. If only it is available. Even in my own lab, we've made some modest contributions in this space. In a paper we published in the journal Alzheimer's and Dementia, which is a good journal, we published in 2021. My team here at BYU set out to go beyond the PET imaging and ask what is happening at the level of gene expression. We analyzed RNA sequencing data from over 240 postmortem Alzheimer's and control brains. We analyzed gene expression across 4 distinct cell types of the brain, and we looked at genes governing 2 metabolic pathways: glycolysis, glucose burning, and ketolysis, or ketone burning. Across every cell type examined, genes governing glycolysis were significantly downregulated in Alzheimer's brains. The molecular machinery for burning glucose was broadly impaired across every neural cell type that we examined. That confirmed a lot of what others had shown, but at a more mechanistic level. But the ketolytic story was different and much more hopeful. In neurons, astrocytes, and microglia, ketolytic gene expression was not significantly altered. It was almost totally normal. There were some modest changes here and there, but overall the pathways of ketolysis were functioning normal. And that brings me to what I consider to be one of the most underappreciated metabolic realities of modern life. Ketones are produced when insulin levels are low. Primarily, of course, that means during fasting or carbohydrate restriction. When insulin is chronically elevated, as it is in most people eating a high-carb diet that is refined, high in refined starches and sugars, ketone production is essentially zero. The liver does not release meaningful ketones whenever insulin is high. So here's the tragedy in plain language: the Alzheimer's brain is progressively losing its ability to use glucose, but it retains the molecular machinery to use ketones. But because of the way most people eat, ketone levels are near zero essentially all the time. The brain is stranded. Now, of course, this is one reason why you would make the case for exogenous ketones in the form of GoBHB or any form of straight BHB. Clinical trials reinforce this therapeutic potential, whether it's exogenous ketones whether it's MCT-based supplements or straight MCT oil, which is highly ketogenic, it can improve the disease outcomes. There is a study finding that at 90 days with patients taking an MCT-based ketogenic compound, patients, patients who achieved ketosis showed significant improvements on cognitive assessments, with the most pronounced effects coming in those who did not have ApoE4, but still they found benefits in those individuals. There are multiple studies being published essentially at this point every year with exogenous ketones gaining more and more attention, particularly BHB. I am very optimistic that we're going to have a lot of good hopeful findings in the near future. So what does all this mean practically for you, for your family, for the people you may care about? First, the metabolic underpinnings of Alzheimer's are likely being established decades before symptoms appear. One of Dr. Stephen Cunnane's findings, in fact, was that in young women in their 20s, they could already detect this lowered brain glucose uptake and metabolism in these young women with PCOS, which, as you know, being as informed as you are, is in fact another symptom of insulin resistance. Second, anything that improves insulin sensitivity, like going on a low-carb diet, uh, by reducing your carbs, exercising better, etc., may represent the most meaningful Alzheimer's prevention strategy available. We don't yet have a drug that stops Alzheimer's, but we may have lifestyle strategies that substantially reduce the risk of ever developing it. Third, the ApoE4 story reminds us that genetics isn't destiny, but it does require attention. If you carry the APOE4 gene, your brain is more susceptible to impaired insulin signaling. That makes metabolic health even more critical and may make certain dietary strategies like carbohydrate restriction particularly relevant, since ketones can serve as an alternative brain fuel that bypasses that potentially disrupted insulin signaling pathway. Ultimately, science is a process. It advances when old paradigms give way to new evidence and when honest researchers are willing to follow the data wherever it leads, even when it may be uncomfortable. The story of Alzheimer's research over the past few decades is a cautionary tale about what can happen when a field becomes too invested in a single theory. The metabolic theory of Alzheimer's does something the plaque theory struggled to do. It really tells a complete mechanistic story from cell biology through epidemiology. It connects all the dots. And because of this, it opens the door for what I think will be much more meaningful findings and interventions in the future. Thanks for joining me in the Metabolic Classroom. 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