The first association between type-2 diabetes and Alzheimer’s disease were observed as early as the 1990s. In the Rotterdam Study, diabetics were found to have about twice the risk of Alzheimer’s disease than non-diabetics [1]. This correlation was explained by vascular processes, such as those found in diabetes in the context of microangiopathy (damage to the smaller blood vessels). Today, it is also known that glucose metabolism is significantly reduced in the brains of Alzheimer’s disease patients, and thus the impaired energy supply of the brain has increasingly come into the focus of causality. This impaired glucose utilization, and the associated energetic shortage of neurons could also be visualized in imaging techniques, in the so-called PET scan with 18F-labeled fluorodeoxyglucose [2].

Affected by this energy crisis in the brain are mainly the structures of the hippocampus, the brain region responsible for our memory consolidation. One might assume that this energy deficiency due to decreased glucose oxidation is a consequence of Alzheimer’s disease. However, the opposite has been found to be true: Alzheimer’s dementia is the result of the deficiency. The reduction of energy production in the hippocampus is considered a very early event in the course of the disease and precedes the disease by years to decades. In this context, the physician Suzanne de le Monte coined the term “type-3 diabetes” in 2008 for this cerebral (affecting the cerebrum) form of insulin resistance: according to this, Alzheimer’s dementia represents a form of diabetes that selectively affects the brain and has molecular and biochemical features that overlap with type-2 diabetes mellitus. That is, the onset of Alzheimer’s disease can be promoted by the massive insulin resistance that is present in type 2 diabetes. But insulin resistance can also be present in the brain in isolation: there are also Alzheimer’s patients with cerebral energy deficit who do not have type-2 diabetes [3]. This should not be confused with type-3c diabetes, called pancreatogenic diabetes. This form of diabetes results from diseases or injuries of the pancreas that, among other things, impair insulin secretion.

Furthermore, studies also show a close correlation between cerebral glucose deficiency (measured in PET scans) and the reduced cognitive abilities of Alzheimer’s patients. We now know that the brain’s starvation state leads in the long term to the breakdown of its specific functions and the death of brain cells, which is particularly strikingly evident in the impairment of memory. But how does this cerebral undersupply occur?

Insulin resistance in the brain

Unlike muscle and fat tissue, the brain was long thought to be an insulin-independent organ. Since the discovery of insulin receptors, which are found in almost all brain cells, and the high density of insulin-dependent glucose transporters GLUT4 in the hippocampal region, it has become clear that insulin is a key component in the brain and especially for memory processes in the hippocampus (see info box). Since the brain depends on insulin to function, it is not surprising that it is also capable of producing its own insulin.

However, if insulin resistance is already present in the body, the blood-brain barrier provides only a reduced amount of insulin transporters for protection, which prevents the hormone insulin produced in the pancreas from passing into the brain tissue. Also, the brain’s own insulin synthesis may be decreased in response to insulin resistance in the body. In this way, insulin deficiency develops in the brain, a condition known as cerebral hypoinsulinemia, which has already been demonstrated in brains of people with Alzheimer’s disease. We now also speak of insulin resistance of the brain, which, however, is represented in the brain by an insulin deficiency, whereas in the insulin-resistant body there is rather an excess of insulin [4].

The resulting reduced insulin action is obviously amplified by impaired formation of important components of the insulin signaling cascade: thus, in addition to the insulin deficiency, a striking reduction of insulin receptors, of the insulin-like growth factor IGF and its receptors has been detected in the brains of Alzheimer’s patients. Even if sufficient insulin were present, it would not be able to exert its effect in this case because the signaling cascade is damaged. The AD brain thus becomes insulin resistant [4].

Physiological functions of insulin in the brain

The connections between Alzheimer’s disease and cerebral insulin deficiency become quite clear when one looks at the multiple tasks of insulin in the brain – besides glucose uptake [5]:

  • Regulation of the physiological phosphorylation of the tau protein and thereby prevention of the formation of the neurofibrillary tangles typical for Alzheimer’s disease.
  • Regulation of the cleavage of the amyloid precursor protein APP: thereby inhibiting the formation of pathological amyloid-ß proteins and promoting synapse formation and neuronal development.
  • Removal of the amyloid-ß plaques typical of Alzheimer’s disease by stimulating their degradation and removal.
  • Promotion of the formation of the neurotransmitter acetylcholine, which has a stimulating effect on cognitive functions.
  • Protection against neuronal apoptosis, the programmed death of brain cells.
  • Promotion of normal mitochondrial function and thus maintenance of cellular energy production.
  • General protection against oxidative stress and neuroinflammation.

Another hypothesis seeks the link between insulin resistance and Alzheimer’s disease not only on insulin problems per se. It is also possible that the insulin-degrading enzyme (IDE), which breaks down insulin after it has done its work in the blood, may also neutralize amyloid-ß proteins in the brain. However, when high insulin levels in the body exceed IDE production, IDE has limited capacity to degrade amyloidogenic proteins in the brain, and as a result, more Alzheimer’s-specific amyloid-ß plaques may build up in the brain [6].

Complex molecular mechanisms

The molecular mechanisms leading to the disturbance of cerebral glucose or insulin metabolism are complex and not yet fully understood. The so-called “advanced glycation end products”, also called AGEs, are suspected. AGEs are reaction products of glucose molecules with cellular protein structures. They are formed as a direct consequence of the constantly (too) high blood glucose levels in diabetic patients. AGEs can lead to peripheral inflammatory responses and disrupt normal cell signaling. This results in impaired insulin signaling and is considered a major contributor to insulin resistance in diabetic cells. According to recent scientific findings, these processes also appear to play a causal role in cerebral insulin resistance as it occurs in neurodegenerative diseases. It is suspected that, independent of the inflammatory focus, proinflammatory messenger substances pass the blood-brain barrier and thus trigger brain-specific inflammatory reactions, a so-called neuroinflammation.

Also, the insulin-resistant state of the brain leads to the morphological (structural) changes typical of Alzheimer’s disease, the deposition of amyloid-ß proteins and the formation of neurofibrillary tangles (also called Alzheimer’s fibrils), specific protein accumulations. These can interfere with the binding of insulin to its receptor, either through degradation or inhibition processes. A downhill cycle begins, steadily worsening the neurodegenerative aspect of insulin resistance [5].


The link between diabetes mellitus and Alzheimer’s disease has been known for a long time. Today, it is also understood that the dysfunction of glucose metabolism in the hippocampus leads to energy insufficiency due to an impairment of the insulin signaling cascade. Insulin has numerous critical regulatory functions in the central nervous system in addition to glucose uptake. The cerebral insulin resistance that occurs in Alzheimer’s disease is characterized by insulin deficiency and can have devastating consequences: Energy deficiency, loss of synaptic plasticity, amyloid-ß and neurofibrillary deposition, acetylcholine deficiency, mitochondrial dysfunction, and neuroinflammation, all of which are essential hallmarks in Alzheimer’s pathology.

Thus, it is becoming increasingly clear that Alzheimer’s dementia represents a complex neuro-endocrine disorder that is similar to, but also distinct from, type 2 diabetes and is therefore properly referred to as type 3 diabetes. Since these dysfunctions occur long before the symptoms typical of Alzheimer’s disease, early recognition and treatment of insulin resistance in particular is crucial in the prevention and treatment of Alzheimer’s disease.

Briefly noted

Glucose enters the cells from the blood with specific glucose transporters (GLUT). Fat cells and muscle cells (heart and skeletal muscle) possess the insulin-dependent glucose transporter GLUT4. This is stored inside the cell in membrane vesicles. When blood glucose levels rise, insulin mediates the transport of GLUT4 to the cell membrane by binding to the insulin receptor, making it available for glucose uptake. In contrast, the insulin-independent glucose transporters (e.g., GLUT1, GLUT2, and GLUT3) are permanently incorporated into the cell membrane and can transport glucose even without insulin action. GLUT1 is found in almost all body cells, GLUT2 in liver, intestinal and kidney cells. The nerve cells in the brain predominantly possess GLUT1 and GLUT3. In the brain, the insulin-dependent glucose transporter GLUT4 is also found in neuronal zones with high energy demand. Neurons in the hippocampus have a high density of GLUT4. This has led researchers to speculate that GLUT4 probably supports GLUT3, the major neuronal glucose transporter, in meeting the glucose supply needs of neurons during periods of elevated energy demand. Also, this role of GLUT4 appears to be specific to neurons: In the hippocampus, GLUT4 is abundant wherever insulin receptors are present. In contrast, however, insulin receptors have also been identified in many other brain cell types, such as astrocytes, endothelia, microglia, which lack GLUT4. The latter makes it clear that insulin or its receptors have other important roles in the brain besides glucose uptake [7].


  1. A Ott, RP Stolk, A Hofman, F van Harskamp, DE Grobbee & MMB Breteler (1996) Association of diabetes mellitus and dementia: The Rotterdam Study. Diabetologia 39: pp 1392–1397. DOI 10.1007/s001250050588
  2. L Mosconi (2005) Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. European Journal of Nuclear Medicine and Molecular Imaging 32: pp 486–510. DOI 10.1007/s00259-005-1762-7
  3. SM de la Monte, JR Wands (2008) Alzheimer’s disease is type 3 diabetes-evidence reviewed. Diabetes Sci Technol 2(6): pp 1101-13. DOI: 10.1177/193229680800200619
  4. ↑2 E Steen, BM Terry, EJ Rivera, JL Cannon, TR Neely, R Tavares, XJ Xu, JR Wands JR, SM de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? Journal of Alzheimer’s Disease 7(1): pp 63-80. DOI: 10.3233/jad-2005-7107
  5. ↑2 JCC Shieh, PT Huang, YF Lin (2020) Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies. Molecular Neurobiology 57:1966–1977 DOI: 10.1007/s12035-019-01858-5
  6. H. Li et al. (2018) Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer’s disease: possible mechanisms of IDE in T2D and AD. Bioscience Reports. Vol. 38/1:1-10.
  7. EC McNay, J Pearson-Leary (2020) GluT4: A central player in hippocampal memory and brain insulin resistance. Exp Neurol 323/113076: 1-9.
    DOI 10.1016/j.expneurol.2019.113076