The Energy Equation in Alzheimer’s Disease: Glucose-Driven Degeneration and Ketone-Driven Protection

Introduction

Alzheimer’s Disease is best known for its impact on memory and cognition, but underneath the surface, it is also a disease of metabolism. While the buildup of amyloid-beta (Aβ) plaques and tau tangles defines the condition under a microscope, researchers are increasingly pointing to something more fundamental happening in the brain: a failure of the cells’ ability to use energy properly.

In recent years, Alzheimer’s Disease has been called “Type 3 Diabetes”, a nickname that reflects a striking pattern. Just like in Type 2 diabetes, where the body becomes resistant to insulin, people with Alzheimer’s Disease often show insulin resistance in the brain. This makes it harder for neurons to use glucose, their main fuel source. As glucose metabolism breaks down, a cascade of problems follows, cellular stress builds up, protective pathways falter, and the conditions for Aβ and tau accumulation begin to take shape.

We’ve previously written about how glucose and insulin signaling contribute to Alzheimer’s pathology. But what is especially compelling, and far less talked about, is what happens when the brain uses ketones instead.

Ketones are energy molecules made by the liver when glucose is in short supply, during fasting, exercise, or on a ketogenic diet. The two most important ones are beta-hydroxybutyrate (BHB) and acetoacetate (AcAc). Unlike glucose, ketones don’t depend on insulin to enter cells, and once inside, they follow a different metabolic route that appears to be cleaner, more efficient, and possibly even protective.

In fact, in many ways, ketones seem to do the opposite of what glucose does in the Alzheimer’s Disease brain. They reduce oxidative stress, improve mitochondrial function, and may help clear out misfolded proteins like Aβ and tau. They also act as signaling molecules, activating genes that protect against inflammation and cellular damage.

This research review explores the contrast between glucose and ketones as energy sources for the brain, and what this distinction reveals about the metabolic underpinnings of Alzheimer’s Disease. It also explores how ketone metabolism intersects with core pathological features of Alzheimer’s Disease, such as mitochondrial dysfunction, oxidative stress, and protein misfolding, and evaluates whether metabolic interventions could represent a viable strategy for modifying disease progression.

Background: Insulin Resistance and Alzheimer’s Disease

One of the earliest and most consistent clues in Alzheimer’s research doesn’t come from memory tests or behavioral changes—it comes from a scan. Even in people who are cognitively healthy but at higher risk of Alzheimer’s, imaging studies often reveal something troubling: key regions of the brain aren’t using glucose the way they should.

This “energy gap” creates a hidden vulnerability. Synapses (the connections between neurons) may still be structurally present, but no longer fire efficiently due to a lack of glucose as fuel. In healthy brains, insulin helps regulate glucose metabolism and keeps key cellular pathways in balance. But in Alzheimer’s Disease, insulin signaling is impaired, especially in neurons. As a result, glucose metabolism falters, and with it, the machinery that protects brain cells from stress and degeneration.

This breakdown in insulin signaling sends ripple effects throughout the brain. One of the most critical involves the protein tau, which normally helps stabilize microtubules—the internal scaffolding that gives neurons their shape and structure.

In a healthy brain, insulin activates a pathway known as PI3K/Akt. Among its many protective roles, this pathway keeps an enzyme called GSK-3β (glycogen synthase kinase-3 beta) in check. GSK-3β is responsible for attaching phosphate groups to proteins like tau—a process called phosphorylation. While some phosphorylation is necessary, an overactive GSK-3β adds too many phosphate groups, leading to what’s known as hyperphosphorylation.  [1]

When tau becomes hyperphosphorylated, it detaches from the structural scaffolding inside neurons (microtubules), starts misfolding, and eventually clumps into tangles. These neurofibrillary tangles are one of the two defining pathological features of Alzheimer’s Disease. [1]

This isn’t just a theoretical link. In studies of diabetic mice with severe insulin resistance, researchers have observed excessive tau phosphorylation and accompanying memory decline. In human brains affected by Alzheimer’s, the story repeats: neurons filled with tangled tau often show signs of impaired insulin signaling. A key protein called IRS-1 (insulin receptor substrate-1), which normally helps transmit insulin’s message inside cells, is frequently found in an inhibited, dysfunctional state—essentially silenced by its own misregulated phosphorylation. [1]

Taken together, these findings suggest that insulin resistance isn’t just a side effect of Alzheimer’s. It may be one of its driving forces—pushing tau toward dysfunction and starving the brain of the energy it needs to stay resilient.

Ketones as an Alternative Brain Fuel

Here’s the twist: while the Alzheimer’s Disease brain struggles to use glucose, it still knows how to use ketones.

Ketones, primarily β-hydroxybutyrate (BHB) and acetoacetate (AcAc), are produced in the liver during periods of fasting or carbohydrate restriction. These aren’t exotic backup fuels; they’re an evolutionarily conserved energy source, synthesized when glucose is scarce. Interestingly, the brain doesn’t have to wait for the liver alone—astrocytes, a type of glial cell, can also produce small amounts of ketones locally.

To power the brain, ketones must first cross the blood–brain barrier. They do so using specialized proteins called monocarboxylate transporters, which usher them into both neurons and glial cells. [3]

Once inside the brain, ketones bypass several of the steps that glucose requires to generate energy. Under normal conditions, glucose must go through a series of steps to yield usable energy. It enters cells with the help of insulin, then travels through glycolysis, forming pyruvate. From there, it depends on the enzyme pyruvate dehydrogenase (PDH) to convert pyruvate into acetyl-CoA, which fuels the tricarboxylic acid (TCA) cycle inside mitochondria. At several points, this process leans heavily on mitochondrial complex I, a key driver of ATP production.

In Alzheimer’s Disease, both PDH and complex I are frequently impaired, leading to a breakdown in energy metabolism. This creates a metabolic logjam—glucose enters the system but can’t efficiently generate energy. The result: neurons starved of fuel, unable to maintain their structure and function.

Ketones circumvent these roadblocks. They do not require insulin to enter cells. They don’t rely on glycolysis. And most critically, they can be converted directly into acetyl-CoA, feeding straight into the TCA cycle. This allows cells to continue producing energy even when the usual glucose-based pathways fail, providing an advantage in the metabolically compromised Alzheimer’s Disease brain. [3]

PET imaging studies have confirmed this in living patients: even in brain areas with poor glucose metabolism, ketone uptake and oxidation remain remarkably intact. In that sense, ketones act as an emergency backup generator for the brain, restoring energy production when glucose falters. This ability to bypass broken metabolic machinery is one reason researchers are excited about ketogenic strategies.

In mouse models of Alzheimer’s Disease, supplying ketones has been shown to restore mitochondrial complex I activity, even in the presence of toxic Aβ. Neurons treated with BHB or AcAc continue making ATP and avoid the energy crash that usually follows amyloid exposure. It is a rare case where the disease process is happening, but the cells are still able to function, thanks to a different fuel. [4]

Ketone Bodies’ Impact on Aβ

The metabolic story of Alzheimer’s doesn’t end with energy failure—it also involves biochemical fallout from chronically high glucose. In individuals with insulin resistance or diabetes, elevated blood sugar doesn’t just starve neurons of energy by impairing insulin signaling. It also initiates a chemical chain reaction that alters proteins in ways that promote inflammation, protein misfolding, and neuronal damage.

One of the major culprits is a group of molecules called advanced glycation end-products (AGEs). These form when excess glucose reacts with proteins in the body, essentially “sugar-coating” them in a non-enzymatic process. AGEs accumulate in tissues over time, and in the brain, they bind to a receptor called RAGE (the receptor for advanced glycation end-products), found on neurons and glial cells.

This AGE–RAGE interaction is like striking a biochemical match. It triggers inflammatory cascades and activates enzymes like cathepsin B—an enzyme that shifts how the brain processes amyloid precursor protein (APP). Normally, APP can be cleaved in ways that are relatively benign. But under the influence of inflammation and altered enzymatic activity, APP is increasingly routed down the beta-secretase pathway, a molecular shortcut that results in the formation of amyloid-beta. Worse yet, this pathway favors the production of Aβ₄₂, a particularly toxic form of the protein that aggregates into the sticky plaques seen in Alzheimer’s brains. [6] 

At the same time, the brain’s capacity to clean up amyloid-beta begins to falter. A key enzyme responsible for this job, insulin-degrading enzyme (IDE), also happens to break down insulin. In healthy metabolic states, IDE balances its duties. But when insulin levels are chronically high—such as in metabolic syndrome or Type 2 diabetes—IDE gets overwhelmed. Faced with a flood of insulin to clear, it becomes less efficient at breaking down Aβ. As a result, the protein begins to accumulate. [6]

This two-hit scenario, more production, less clearance, creates a perfect storm for Aβ accumulation. And we see the consequences: people with diabetes or metabolic syndrome often show faster cognitive decline and higher levels of Aβ on brain scans. Glucose metabolism, it turns out, isn’t just fueling the brain; it may also be feeding the disease. [6]

Flipping the script, ketones, especially beta-hydroxybutyrate (BHB) and acetoacetate (AcAc), appear to do the opposite of what glucose does in this context. Rather than promoting amyloid buildup, ketones seem to protect neurons from Aβ toxicity and may even help clear the plaques away. [1] 

In laboratory studies, BHB has been shown to shield neurons from the harmful effects of Aβ, preserving synaptic function and preventing cell death. One particularly striking study found that BHB could block Aβ from entering neurons, keeping the toxic protein outside the cell where it does less damage. This not only protected mitochondrial function but also helped restore markers of synaptic health. [1]

In animal models of Alzheimer’s, dietary or pharmacological interventions that raise ketone levels have led to lower amyloid plaque burden, improved mitochondrial efficiency, and better memory performance. These findings suggest that ketones don’t just compensate for lost energy; they actively counteract the processes driving the disease.  [1]

Mechanistically, ketones may enhance Aβ clearance, in part by upregulating enzymes and transporters that help remove amyloid from the brain. They also tamp down on inflammation, particularly through suppression of NF-κB, a key player in the inflammatory signaling network that can accelerate Aβ deposition. [1]

Ketones and Tau Pathology

The story with tau is still unfolding, but early data is encouraging. In animal models, particularly the widely used 3xTg-Alzheimer’s mice (which develop both Aβ plaques and tau tangles), ketogenic interventions have produced notable results. Mice given ketone esters or ketogenic diets show not only fewer amyloid plaques, but also a marked reduction in tau pathology—lower levels of hyperphosphorylated tau and fewer neurofibrillary tangles. While still in early stages, these findings raise the possibility that ketones could slow or modulate the second major protein pathology in Alzheimer’s. [1]

The mechanism appears to be at least partly indirect—but no less important. As we’ve seen, ketones can improve insulin signaling in the brain. That, in turn, reactivates the Akt pathway, which plays a central role in suppressing GSK-3β—the enzyme that hyperphosphorylates tau. By keeping GSK-3β in check, ketones may reduce the likelihood that tau detaches from microtubules, misfolds, and forms tangles [7]. In this sense, ketosis may help restore the intracellular signaling balance that Alzheimer’s disrupts. 

Another line of research adds a second layer to this protective effect. A recent proteomic study found that BHB enhances the brain’s capacity to clear misfolded proteins. Through upregulation of autophagy and other proteostasis pathways—the cellular housekeeping systems that identify and dispose of damaged proteins—BHB appeared to boost the brain’s ability to maintain protein quality control. While tau itself wasn’t explicitly analyzed in that study, the broader implications are clear: ketone signaling seems to support a cellular environment more capable of resisting toxic protein accumulation.  [7]

Oxidative Stress and Mitochondria in Alzheimer’s Disease

We’ve already seen how the Alzheimer’s brain struggles to use glucose efficiently. But what makes this dysfunction especially damaging is that glucose keeps arriving—flooding neurons with a fuel they can’t properly burn. Instead of providing energy, this metabolic mismatch pushes cells into oxidative overdrive, turning an essential nutrient into a source of stress.

In insulin-resistant or hyperglycemic conditions, neurons are flooded with fuel they can't efficiently use. This metabolic overload places a heavy burden on the mitochondria, the cell’s power plants, leading to what researchers call oxidative stress. In this state, unstable ROS molecules damage lipids, proteins, and DNA, particularly in brain regions already vulnerable to Alzheimer’s pathology. [9]

Glucose itself exacerbates the problem. In high concentrations, it can undergo auto-oxidation, forming toxic byproducts like ketoaldehydes and hydrogen peroxide. In the presence of metal ions such as iron or copper, these compounds fuel the production of hydroxyl radicals—among the most reactive and damaging molecules in biology. Amyloid-beta (Aβ) makes matters worse by binding to these metal ions and acting as a catalyst, accelerating ROS formation. What begins as a metabolic surplus quickly spirals into a self-perpetuating cycle of oxidative damage. [9] 

As ROS levels climb, mitochondrial function begins to unravel. Superoxide radicals destabilize the mitochondrial membrane, impair ATP production, and inhibit key components of the electron transport chain (ETC)—especially complex III. Aβ oligomers, meanwhile, directly target complex I, further disrupting oxidative phosphorylation. These effects are compounded by damage to mitochondrial DNA and dysfunction of critical enzymes like pyruvate dehydrogenase (PDH), the gatekeeper of glucose-derived energy. Deprived of usable fuel and burdened by oxidative stress, neurons falter in their ability to meet energy demands. [9] 

The consequences of oxidative stress extend far beyond mitochondrial damage. When ROS levels rise, glucose is increasingly funneled into alternative metabolic routes—such as the polyol and hexosamine pathways. These detours generate toxic intermediates that accumulate inside neurons, compounding the burden. Meanwhile, critical enzymes in the main energy-generating pathway—such as GAPDH, a key player in glycolysis—become impaired. The result is an even deeper energy crisis. As oxidative damage mounts, the brain's ability to generate ATP continues to erode, widening the metabolic gulf at the heart of Alzheimer’s pathology. [9] 

And the problem doesn’t stop at energy failure. Oxidative stress and inflammation form a tightly linked feedback loop—each fueling the other. In brains affected by Alzheimer’s, glial cells are frequently found in a state of chronic activation, releasing inflammatory molecules like cytokines. These immune signals, meant to be protective in the short term, become harmful when sustained. ROS activate intracellular immune complexes known as inflammasomes, including NLRP3, which in turn amplify the production of pro-inflammatory enzymes and additional free radicals. [9] 

In this way, oxidative stress and inflammation become co-conspirators. Each reinforces the other in a molecular echo chamber that accelerates neuronal damage and loss. The result is a biochemical landscape primed for degeneration—one in which energy failure, protein misfolding, and immune overactivation collide in a self-perpetuating cycle.

Ketosis: A Metabolic Reset Button

When the brain shifts from burning glucose to metabolizing ketones—a transition that can occur during fasting, ketogenic diets, or through ketone supplementation—it doesn’t just find an alternative energy source. It finds a cleaner, more efficient one. Compared to glucose, ketones generate fewer reactive oxygen species (ROS) per unit of ATP produced. That makes a substantial difference in a disease like Alzheimer’s, where oxidative stress is one of the primary engines of neuronal damage. [5]

Beyond reducing oxidative damage, ketones help restore the brain’s energy systems. One of the key ketones, beta-hydroxybutyrate (BHB), appears to actively repair and revitalize the brain’s metabolic machinery. It increases the NAD⁺/NADH ratio, a fundamental marker of cellular redox balance. This ratio reflects the availability of NAD⁺, a coenzyme essential for mitochondrial function. Higher NAD⁺ levels facilitate more efficient electron flow through the mitochondrial respiratory chain, reducing electron leakage and ROS production. In essence, BHB helps optimize the inner workings of the mitochondria, allowing them to generate energy more cleanly and reliably. [5]

This redox shift has broad implications. As NAD⁺ levels rise, so does the activity of enzymes that depend on it—such as sirtuins, which regulate mitochondrial biogenesis, DNA repair, and stress resistance. Alongside this, BHB boosts levels of glutathione, the brain’s master antioxidant, further reinforcing the cell’s defenses against oxidative injury. [5]

BHB also functions as a signaling molecule, turning on genes involved in detoxification and mitochondrial maintenance. In rodent studies, BHB has been shown to trigger mitochondrial biogenesis—the process by which cells produce new mitochondria—and to enhance the activity of the mitochondrial respiratory chain. In Alzheimer’s mouse models, ketogenic diets have been observed to increase both the number and functional capacity of mitochondria, particularly in the hippocampus, the brain’s memory hub. [5]

Beyond their metabolic benefits, ketones appear to influence the brain’s electrical rhythm—helping to calm the neural circuits that can become overactive in Alzheimer’s Disease. By serving as a steady, non-glycolytic energy source, ketones help stabilize fluctuations in cellular energy levels. But they also bring about a more subtle shift in the brain’s neurochemical environment.

One of the effects of ketosis is a mild rise in systemic alkalinity, which, in turn, promotes the synthesis of GABA (gamma-aminobutyric acid)—the brain’s primary inhibitory neurotransmitter. GABA acts like a brake pedal, tempering excessive excitatory signals from neurons that use glutamate, its more stimulating counterpart. In a healthy brain, this balance between excitation and inhibition is tightly regulated. But in Alzheimer’s Disease, that balance can be lost. [5]

Overactive glutamate signaling is a known contributor to neuronal damage in Alzheimer’s. It drives excitotoxicity—a destructive process where excessive stimulation causes neurons to take in too much calcium, generate more ROS, and ultimately die. It also promotes the spread of tau pathology across synaptically connected brain regions. In this hyperexcitable state, neurons are more vulnerable to stress and degeneration. [5]

By boosting GABA and dampening runaway glutamate activity, ketones may help restore equilibrium to these disrupted circuits. This is more than just a calming effect—it’s a protective one. Stabilizing neural network activity reduces oxidative stress, prevents calcium overload, and slows the molecular cascades that drive disease progression. [5]

Beyond fueling the brain and stabilizing its networks, ketones wield influence at the genetic and molecular signaling level—helping to reshape how neurons respond to stress, injury, and inflammation. Among the most studied is beta-hydroxybutyrate (BHB), which acts not only inside the cell but at the level of gene regulation and cell signaling. [8]

Inside the nucleus, BHB inhibits a group of enzymes known as class I histone deacetylases (HDACs). These enzymes normally remove acetyl groups from histones—proteins that help package DNA—thereby tightening DNA structure and reducing gene expression. When HDACs are inhibited, histones remain acetylated, the DNA becomes more accessible, and specific sets of protective genes are turned on. [8]

Among these are genes regulated by Nrf2, a master transcription factor that orchestrates the antioxidant defense system. By boosting Nrf2 activity, BHB helps increase the production of detoxifying enzymes and antioxidant proteins, strengthening the brain’s ability to neutralize ROS and maintain cellular homeostasis. Ketone signaling also upregulates BDNF (brain-derived neurotrophic factor), a neurotrophin essential for supporting synaptic plasticity, neuronal survival, and cognitive function. In a brain vulnerable to degeneration, this enhanced gene expression may offer critical resilience. [8]

BHB also acts at the membrane level, activating HCAR2 (hydroxycarboxylic acid receptor 2), a receptor found on microglia and other immune-responsive cells. Activation of HCAR2 suppresses pro-inflammatory pathways, including NF-κB and the NLRP3 inflammasome—two key molecular drivers of neuroinflammation. These pathways are not only involved in general immune activation, but are also known to amplify amyloid and tau pathology. [8]

By downregulating inflammatory signaling and promoting antioxidant defenses at the transcriptional level, ketones extend their influence well beyond metabolism. In the early stages of Alzheimer’s—when inflammation, oxidative stress, and synaptic disruption begin to take hold—these signaling effects may help alter the course of disease before irreversible damage accumulates. [8]

Evidence from Animal Studies: Ketogenic Interventions in Alzheimer’s Disease

The stark contrast between how glucose and ketones affect Alzheimer’s Disease pathology has prompted growing interest in metabolic therapies, interventions designed to shift the brain’s energy substrate from glucose to ketones. Over the past decade, researchers have investigated a range of ketogenic strategies, including high-fat low-carbohydrate diets, medium-chain triglyceride (MCT) supplements, and exogenous ketone esters.

In a 2016 study, 3xTg-AD mice with amyloid plaques and tau tangles were administered exogenous ketone bodies. The treatment led to reduced Aβ accumulation, preservation of synaptic structure, and improved performance on memory tasks. These benefits were not solely due to the provision of alternative energy; mechanistic investigations revealed that ketones blocked the cellular entry of Aβ, preventing intracellular accumulation that would usually impair mitochondrial function and trigger oxidative stress. As a result, mitochondrial complex I activity was preserved, and markers of synaptic plasticity were restored. [4]

Another compelling study used 5xFAD mice, which model aggressive Aβ plaque deposition. Mice were placed on a ketogenic diet for eight months, resulting in significantly fewer soluble Aβ deposits, suppressed neuroinflammation, and enhanced learning and memory. These effects were accompanied by reductions in microglial activation and pro-inflammatory cytokine levels, suggesting that ketosis dampens the neuroinflammatory environment that often drives Alzheimer’s Disease progression. [10]

A more recent 2022 study by Xu et al. extended these findings by showing that ketogenic feeding calmed overactive microglia, reduced oxidative damage markers, and improved spatial learning behavior in several Alzheimer’s Disease mouse models.  These findings support the idea that ketosis creates a neuroprotective metabolic state, one that not only restores energy production but also rebalances the inflammatory and oxidative milieu of the Alzheimer’s Disease brain. [10] 

Mechanistically, these improvements are underpinned by several key processes: enhanced mitochondrial efficiency and biogenesis, reduced reactive oxygen species, and modulation of insulin/Akt signaling, which may inhibit tau phosphorylation by suppressing GSK-3β. Some studies also suggest that ketone bodies stimulate autophagy, potentially aiding in the clearance of misfolded proteins, including Aβ and tau.

Evidence from Human Studies on Ketogenic Interventions in Alzheimer’s Disease

While human trials are fewer and smaller, early findings are promising, especially in mild cognitive impairment (MCI) and early-stage Alzheimer’s Disease. In the BENEFIC trial (2019), participants with MCI took a daily MCT supplement for six months. The result: improved episodic memory, particularly in individuals without the APOE ε4 risk allele. Importantly, the supplement raised ketone levels and boosted brain energy metabolism without any major side effects. [11]

Another randomized controlled trial looked at a modified Mediterranean–ketogenic diet in older adults at risk for Alzheimer’s Disease. The diet improved cerebral perfusion and ketone uptake on PET scans and shifted key cerebrospinal fluid (CSF) biomarkers: Aβ₄₂ levels rose, tau remained stable, and neurodegeneration markers like neurofilament light chain (NFL) declined. Since higher CSF Aβ often correlates with lower brain plaque burden, this pattern suggests a beneficial response at the molecular level.

Building on these early-stage findings, ketogenic interventions have also shown promise in individuals with mild-to-moderate Alzheimer’s Disease. A 12-week pilot study found that participants who followed a ketogenic diet improved on the Alzheimer’s Disease AS-Cog, a standard cognitive assessment. In another trial, daily MCT oil over nine months stabilized or improved cognition in about 80% of patients, a particularly surprising outcome. [12]

Not everyone responds the same way. Genetics, particularly APOE4 status, seems to play a meaningful role in determining therapeutic response. People without the APOE4 allele tend to show more robust cognitive improvements from ketone interventions, possibly due to greater metabolic flexibility, more efficient ketone uptake, or differences in neuronal insulin sensitivity. In contrast, APOE4 carriers may have reduced transport of ketone bodies across the blood–brain barrier or altered mitochondrial function, which could blunt the metabolic benefits of ketosis. However, this does not mean APOE4-positive individuals cannot benefit, only that their responses may be more variable, and potentially require higher or more sustained levels of ketosis to see meaningful effects. [12]

Pharmacological Ketone Enhancers

While ketogenic diets and exogenous ketones are well-studied for their neuroprotective effects, recent research suggests that certain medications—originally developed for type 2 diabetes—may offer similar benefits by gently shifting metabolism toward ketone production.

SGLT2 Inhibitors: A Pharmacological Route to Mild Ketosis

SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, bexagliflozin) reduce blood glucose by promoting urinary glucose excretion. This glycosuria induces a compensatory shift toward fat oxidation, leading to a modest but sustained increase in circulating ketone bodies, particularly β-hydroxybutyrate (BHB). Empagliflozin, for instance, was shown to raise fasting BHB levels from 0.24 mmol/L to 0.56 mmol/L in individuals with diabetes, and from 0.14 mmol/L to 0.27 mmol/L in those without diabetes. While these levels are far below those seen in nutritional ketosis, they may still be therapeutically relevant. Research suggests that BHB concentrations between 0.5 and 3 mmol/L may be sufficient to support mitochondrial energetics and reduce oxidative stress. [13]

Mechanistically, these drugs promote lipolysis and lower the insulin-to-glucagon ratio, which favors hepatic β-oxidation and ketogenesis. The increase in ketone production is rapid, often preceding weight loss or improvements in insulin sensitivity, suggesting a direct metabolic effect.

In addition to serving as a more efficient fuel, BHB acts as a signaling molecule, inhibiting class I histone deacetylases and activating HCAR2 receptors—mechanisms that reduce inflammation, support mitochondrial function, and may even inhibit the NLRP3 inflammasome, a key driver of neurodegeneration. [13]

While most data focus on cardiovascular and renal outcomes, these same anti-inflammatory and mitochondrial-enhancing effects could logically extend to the brain. Indeed, emerging evidence links SGLT2 inhibitor use with reduced risk of cognitive decline and dementia in patients with type 2 diabetes.

In mouse models, SGLT2 inhibitors have been shown to reduce markers of microglial activation, suppress pro-inflammatory cytokines, and improve cognitive performance—all potentially linked to this modest rise in ketones. This suggests that even low-level ketosis can shift the immune tone of the brain from one of chronic activation to one of surveillance and repair. [13]

In this way, BHB serves as both fuel and feedback, modulating the brain’s immune response from within. In a disease where inflammation fans the flames of degeneration, such metabolic signaling could offer a new route to immunomodulation—without the need for direct immunosuppressive drugs.

Comparative Ketone Elevation Profiles: How Much Is Enough?

Not all ketone-producing interventions are created equal. While ketogenic diets, fasting, and ketone supplements can rapidly increase circulating ketone levels, pharmacological strategies like SGLT2 inhibitors and acarbose induce much milder elevations. Understanding these differences is key to evaluating their therapeutic potential—especially in the context of chronic neurodegenerative diseases like Alzheimer’s, where sustained metabolic shifts may matter more than acute surges.

In nutritional ketosis, achieved through strict carbohydrate restriction or prolonged fasting, blood levels of β-hydroxybutyrate (BHB) typically rise to 1.0–3.0 mmol/L, with higher levels seen in extended fasting or endurance athletes. Exogenous ketone esters can acutely raise BHB to 2.0–5.0 mmol/L, although these spikes are transient and often require repeated dosing to maintain. [13]

By contrast, SGLT2 inhibitors produce a modest but sustained increase in BHB, generally in the range of 0.3–0.6 mmol/L, with some studies reporting doubling of fasting ketone levels after just a few weeks of therapy. This rise is not enough to induce ketoacidosis in most individuals with type 2 diabetes, but it may be sufficient to activate key metabolic signaling pathways associated with mitochondrial efficiency, antioxidant defenses, and protein homeostasis. [13]

The takeaway is this: you don’t always need high ketone levels to achieve therapeutic effects. The brain may benefit from a chronic, low-grade ketotic state—enough to support mitochondrial function and dampen neuroinflammation, but not enough to trigger risk. This makes pharmacological enhancers an intriguing option for long-term metabolic modulation.

Ongoing Research

Larger, more rigorous trials are currently underway to validate and build upon these early findings. Some are exploring multi-modal approaches, combining ketogenic diets with exercise, cognitive training, or other lifestyle interventions. Others are testing pharmacological ketone boosters, like 1,3-butanediol, which can induce ketosis without the need for strict dietary changes. These compounds offer a way to deliver consistent ketone levels regardless of a person’s daily food intake, which may improve adherence and precision. While ketogenic therapies are not yet standard in Alzheimer’s care, they are rapidly gaining traction as a potential tool to target the disease’s metabolic roots. Consistent findings from animal studies and growing clinical evidence suggest that Alzheimer’s is more than just a disease of plaques and tangles; it may also represent a metabolic failure that, in some cases, can be partially stabilized through strategic intervention.

That said, implementing a ketogenic diet isn’t always easy, especially for older adults or individuals already managing cognitive decline. Strict carb restriction, meal planning, and potential side effects can make long-term adherence difficult without support. But with the help of nutritionists, health coaches, or clinical programs, patients and caregivers can develop personalized approaches that make ketosis both sustainable and safe. Professionals can guide food choices, monitor biomarkers, and help troubleshoot challenges along the way, making the therapeutic potential of ketosis far more accessible.

As research progresses, key questions remain: Which strategies (dietary, supplemental, or combined) offer the most significant benefit? How does APOE genotype influence outcomes? And how deeply, or how long, must one stay in ketosis to achieve durable cognitive protection?

What is becoming increasingly clear is this: the future of Alzheimer’s therapy may not rest solely in targeting amyloid or tau. It may also depend on reengineering how the brain is fueled, restoring metabolic resilience at the cellular level, long before neurons are damaged.