Explore what research says about Alzheimer's disease, amyloid, insulin resistance, brain energy metabolism, and the limits of dietary interventions.
9 min read
Imagine a world where your memories, the very essence of who you are, begin to fade. This is the stark reality for millions affected by Alzheimer’s disease, a condition that’s rapidly becoming a leading cause of death worldwide 1.
Researchers are investigating whether insulin resistance and altered brain-energy metabolism contribute to this devastating illness alongside amyloid plaques, tau tangles, inflammation, vascular disease, and other processes. Metabolic dysfunction is an important area of study, but it is not an established replacement for these other explanations.
Could the informal label “Type 3 Diabetes”2 illuminate one part of Alzheimer’s biology? It is a research concept, not a recognized diagnosis or a complete explanation of the disease.
For decades, a major line of Alzheimer’s research has centered on amyloid-beta, a protein fragment that can aggregate into soluble assemblies and plaques. The amyloid cascade hypothesis proposes that abnormal amyloid accumulation helps initiate a longer disease process involving tau pathology, inflammation, synaptic injury, and neuronal loss. The hypothesis remains debated and has evolved substantially; it has not been disproven, and visible plaques alone are not considered a complete explanation of Alzheimer’s disease.
Many amyloid-targeting drugs have failed in clinical trials, and removing amyloid has not been shown to restore lost cognition. However, it is no longer accurate to say that plaque-reducing drugs have consistently failed to slow progression. In trials involving people with early symptomatic Alzheimer’s disease, lecanemab and donanemab substantially reduced amyloid and produced a statistically significant but modest slowing of cognitive and functional decline; neither drug cured the disease, and both can cause serious adverse effects such as amyloid-related imaging abnormalities 3.
These mixed results suggest that amyloid can matter without being the disease’s sole cause. They also leave open important questions about treatment timing, clinical significance, safety, and the roles of tau, vascular injury, inflammation, and metabolism.
Amyloid plaques are not exclusive to people who had dementia. Autopsy studies have found substantial Alzheimer’s-type pathology in some older adults who remained cognitively normal during life 4. This may reflect cognitive resilience, an early or preclinical disease stage, differences in coexisting pathology, or the imperfect relationship between plaque burden and symptoms. It is one reason researchers do not treat plaque burden by itself as a complete account of cognitive decline.
An influential 2006 paper about a specific amyloid-beta assembly called Aβ*56 was retracted in 2024 after an investigation found problems with figures and concluded that the findings were unreliable 5. Allegations surrounding that work are serious, but the paper was not the first foundation of the amyloid hypothesis: amyloid had been studied for decades, and the hypothesis drew on genetic, pathological, biochemical, and clinical evidence from many independent groups.
The episode undermines confidence in that study and its particular claims. It does not establish that the entire body of amyloid research was fabricated or invalidate every version of the amyloid hypothesis.
The record is more complicated than either complete vindication or complete failure. Amyloid research has produced repeated drug failures, two treatments with modest evidence of slowing early disease, continuing safety and cost concerns, and a broader recognition that Alzheimer’s has multiple interacting causes.
Alongside amyloid and tau, researchers are examining the brain’s metabolic health and its ability to utilize energy. These lines of research can complement one another rather than requiring a choice between a purely amyloid or purely metabolic explanation.
Alzheimer’s disease is associated with reduced glucose metabolism in affected brain regions, and researchers are studying whether impaired insulin signaling contributes to this change. Insulin resistance may be one contributor or risk marker, but evidence does not establish it as the single root cause of Alzheimer’s disease.
This has led some researchers to even propose the term “Type 3 Diabetes” to describe Alzheimer’s. However, it’s important to clarify that this isn’t necessarily a new form of diabetes in the traditional sense.
Instead, some researchers use the term to highlight parallels between Alzheimer’s and diabetes, particularly altered insulin signaling and glucose metabolism in the brain. Major medical organizations do not recognize “Type 3 Diabetes” as a formal diagnosis, and not everyone with Alzheimer’s has diabetes or measurable systemic insulin resistance.
To understand this connection, it’s crucial to appreciate the brain’s unique energy demands. The brain is an incredibly active and “hungry” organ, possessing a remarkably high metabolic rate 6. This means it requires a constant and substantial supply of energy to function optimally, powering everything from memory formation to basic cognitive processing.
Under ordinary fed conditions, glucose is the brain’s primary fuel. During prolonged fasting, sustained carbohydrate restriction, or other states that raise circulating ketones, the brain can increase its use of ketone bodies as an alternative fuel; it does not ordinarily prefer ketones over glucose.
Glucose crosses the blood-brain barrier and enters most brain cells through glucose transporters that are largely independent of insulin. Insulin still has important roles in the brain, including effects on signaling, synaptic function, appetite, and metabolism, and some cell types and regions express insulin-responsive transporters. The muscle-cell “key” analogy therefore does not accurately describe most brain glucose uptake.
Brain glucose metabolism is often reduced in Alzheimer’s disease, but this does not mean insulin resistance simply locks glucose out of neurons. The relationship may involve changes in neuronal activity, glucose transport and metabolism, blood flow, mitochondrial function, and insulin signaling. Researchers are still determining which changes are causes, consequences, or both.
Ketones can provide the brain with an alternative fuel when their concentration in the blood rises, such as during fasting or a ketogenic diet. Some studies suggest that the Alzheimer’s brain retains an ability to use ketones despite impaired glucose metabolism, which has motivated clinical research. The brain is not automatically forced into substantial ketone use, however, because ketone availability is normally low unless the body is producing them.
Insulin suppresses ketone production after eating, which is normal physiology. Whether deliberately raising ketones improves meaningful clinical outcomes in Alzheimer’s disease remains uncertain; small studies of ketogenic diets or ketone supplements are not evidence of disease reversal.
Researchers sometimes describe the mismatch between reduced cerebral glucose metabolism and preserved energy needs as an “energetic gap.” It is a useful hypothesis, not a settled account of why neurons fail. Alzheimer’s symptoms and progression reflect multiple interacting pathologies rather than a demonstrated shortage of dietary fuel alone.
The compelling link between insulin resistance and Alzheimer’s is compelling, but what does the research actually show about how many Alzheimer’s patients are also insulin resistant? Studies examining this connection have yielded varied findings, with estimates ranging from approximately 40% to as high as 80% of individuals with Alzheimer’s exhibiting signs of insulin resistance 7.
These seemingly disparate numbers highlight a crucial point: measuring insulin resistance is complex, and the different methodologies used in these studies can significantly influence the results. For instance, some studies may rely on fasting glucose levels as a proxy for insulin resistance, while others may use more sophisticated measures like the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) or glucose tolerance tests.
The sensitivity and specificity of these different methods can vary, potentially contributing to the observed range in prevalence estimates.
Notably, Dr. Suzanne de la Monte at Brown University has been a leading voice in advocating for the “Type 3 Diabetes”2 concept, emphasizing the profound metabolic dysfunction that often underlies Alzheimer’s disease. Her research has consistently drawn attention to the high prevalence of insulin resistance in Alzheimer’s patients, reinforcing the idea that impaired glucose metabolism is a critical factor in the development and progression of the disease.
Even with the variability in prevalence estimates, the evidence strongly suggests that a significant proportion of individuals with Alzheimer’s also exhibit insulin resistance. This underscores the importance of considering metabolic factors when assessing risk and developing potential interventions for this devastating condition.
Further research is needed to refine our understanding of the interplay between insulin resistance, brain energy metabolism, and the pathogenesis of Alzheimer’s disease. Standardizing the way that insulin resistance is measured will undoubtedly help in future studies as well.
Metabolic health is relevant to dementia risk and deserves attention alongside established Alzheimer’s pathology. Managing diabetes, blood pressure, physical activity, sleep, and other vascular risk factors can support overall health and may reduce dementia risk, but these measures are not proven cures for Alzheimer’s disease.
No established evidence shows that a ketogenic diet, carbohydrate restriction, or an insulin-sensitivity strategy reverses Alzheimer’s disease. People living with Alzheimer’s should not replace prescribed care with a restrictive diet, and substantial dietary changes should be discussed with a qualified clinician. Insulin signaling, fuel use, and brain energy remain worthwhile research targets, but the evidence should not be presented as a proven metabolic cure.
Nichols, E., Steinmetz, J.D., Vollset, S.E. et al. Global burden of Alzheimer’s disease and other dementias, 1990 - 2016. Lancet Neurol. 18, 87 - 104 (2019). ↩
De la Monte, Suzanne M., and Jack R. Wands. “Alzheimer’s disease is type 3 diabetes - evidence reviewed.” Journal of diabetes science and technology 2.6 (2008): 1101-1113. ↩ ↩2
van Dyck CH, et al. “Lecanemab in Early Alzheimer’s Disease.” New England Journal of Medicine. 2023;388:9-21; Sims JR, et al. “Donanemab in Early Symptomatic Alzheimer Disease.” JAMA. 2023;330(6):512-527. ↩
Price JL, McKeel DW Jr, Buckles VD, Morris JC. Neuropathology of nondemented elderly subjects. Ann Neurol. 2009 Nov;66(5):591-604. ↩
Lesné S, et al. Retraction Note: A specific amyloid-β protein assembly in the brain impairs memory. Nature. 2024. ↩
Raichle ME, Mintun MA. Brain work and brain imaging. Annu Rev Neurosci. 2006;29:449-76. ↩
de la Monte SM. Insulin resistance and neurodegeneration: progress towards the development of new therapeutics for Alzheimer’s disease. Drugs. 2017 Jul;77(1):47-65. ↩
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