By the year 2050, there will be approximately 2.1 billion elderly people in the world.1 Among the elderly population, Alzheimer’s disease is the most common form of dementia. Recent studies indicate that Alzheimer’s disease and diabetes mellitus may have a close relationship, also known as type 3 diabetes or brain diabetes.2-6 Although research suggests a correlation between Alzheimer’s disease and diabetes, studies are still inconclusive. Nevertheless, with the growing population of patients with diabetes, physicians should be aware of the possible correlation and provide further workup, and/or ensure appropriate referrals for dementia in patients with diabetes exhibiting mental decline.
Studies have shown an increased risk of developing Alzheimer’s disease when there is insulin resistance as one would see in patients with type 2 diabetes.6-9 The reduction of insulin receptor expression and insulin levels results in a deficiency in the signaling pathways of the brain.2,6,10,11 More recent studies have suggested that a crucial factor in developing dementia is reduced utilization of glucose by the brain.6,12-15 Insulin receptors in the brain are distributed heavily in the hippocampus and cerebral cortex. If the insulin receptors in these areas are affected, it will impact cognition and memory.6,16–18 One study evaluating 45 post-mortem brains of patients in various stages of neurodegeneration found an 80 percent decrease in insulin receptors in patients with Alzheimer’s disease in comparison to normal individuals.6,19-21
Insulin resistance, or lack of insulin, contributes toward the process of brain degeneration through several pathways.6,16 It can cause weakening of insulin transition by the blood-brain barrier and weakening of the expression and/or activity of insulin receptors. There is also modulation of protein phosphorylation of insulin receptors and reduction of the activated insulin receptor phosphorylation of phosphatidylinositol kinase.6,22,23 Blocking the kinase disrupts insulin-dependent glucose transporter type 4 (GLUT-4), particularly in the hippocampus.6,24 Synaptic plasticity in the hippocampus is reduced due to insulin resistance-related mitochondrial dysfunction and increased oxidative stress.6,25,26 The increased oxidative stress also causes changes in the endoplasmic reticulum of hippocampal cells, which increases insulin resistance, causing further negative changes in the cell structure.6,27
Diabetes-related impairment of function in the hypothalamic pituitary adrenal axis results in a reduced response of the corticotropin releasing factor, which causes an increase in cortisol levels and enhanced severity of insulin resistance in the hippocampus.6,28 In addition, a diet that has high levels of fat elevates and enhances the expression of pro-inflammatory cytokines.6,29 Interleukin 1-beta (IL-1β) is a pro-inflammatory cytokine that causes neuroplasticity disabling in the hippocampus, which can lead to deficits of memory and learning.6,30 Conversely, insulin activates the signaling pathways associated with long-term memory, learning, plasticity regulation, energy metabolism and neuron survival required for memory and learning.6,16,31
Key Diagnostic Considerations
A thorough review of several meta-analytical studies indicates there are no symptoms of dementia that are specific to diabetes-induced dementia. However, one should always consider a diagnosis of dementia in a patient with diabetes who has had a gradual or sudden change in behavior. In type 1 diabetes, symptoms are consistent with a slowing of cognitive speed and mental flexibility. In addition to these symptoms, learning and memory are also affected in patients with type 2 diabetes.32,33
The diagnosis of dementia in patients with diabetes follows a similar workup as that of dementia in the presence of other disease states. Typically, a magnetic resonance image (MRI) or computed tomography (CT) scan is sufficient for diagnosis.32 With the exception of Alzheimer’s disease, there are no other researched neurogenic causes of dementia, such as Lewy body dementia or Huntington’s disease, that show correlation between diabetes and concomitant neurological dementia.34 The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is the currently utilized diagnostic guide for the clinical workup of suspected dementia. High frequencies of hyperglycemia, as evidenced through HbA1c values greater than 8 percent in a patient older than 65, should lend to considerations of dementia changes, especially if the patient in question begins to behave differently than at prior office visits.
Current Treatment Concepts
There are two facets for the treatment of diabetes-induced dementia to decelerate further cognitive decline: the use of pharmacologic agents for the diabetes and the use of pharmacologic agents for the dementia.
When controlling diabetes in patients with dementia, it is important to consider medications that are not going to increase the risk of hypoglycemia. The first line of therapy is metformin while the second is the addition of dipeptidyl peptidase-4 (DPP-4) inhibitor if the glucose is not lowered with only metformin.35-37 In addition, intranasal insulin is a novel therapy that one would administer to normalize the amount of insulin in the brain.38
To reduce the chances of hypoglycemic attacks, it is recommended that the patient’s HbA1c levels are less than 9 percent but not quite in the normal range. If HbA1c is higher than normal, a hypoglycemic episode will bring the patient within normal limits. Therefore, one should prescribe sulfonylureas scarcely in the elderly population due to the higher incidence of hypoglycemia noted.35
One should work with the patient’s primary care physician and mental health professionals to ensure the patient is receiving treatment for both diabetes and Alzheimer’s disease together in order to prevent worsening of both conditions while taking care to avoid hypoglycemia. The two classes of drugs that researchers recommend for dementia or Alzheimer’s disease are acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor inhibitors such as memantine (Namenda, Allergan).35
Emphasizing Appropriate Screening, Exercise And Attention To Potential Polypharmacy Issues
There are several methods clinicians can utilize for prevention of diabetes-induced dementia. Elderly patients residing in care facilities should have cognitive screening with the staff and have nutritionists review their diets.39 Both exercise and diet control are vital. Not only will an increase in physical activity reduce the occurrence of diabetes but it will also keep the brain engaged, preventing cognitive decline.37
A study entitled Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) reports no changes in cognitive function with diet but found that exercise negated the effect of diabetes on dementia.39,40 Follow-up studies in regard to ACCORD-MIND are underway.39,40 It is also important to keep polypharmacy in perspective, especially in the elderly. Drug-drug interactions may cause both diabetes and dementia.38 Therefore, one should assess medications frequently with attention to any drugs that may cause hypoglycemia.
While there is increasing evidence regarding the relationship between diabetes and Alzheimer’s disease, additional research is needed. Further studies on molecular mechanisms, medicinal chemistry, pathological evidence and epidemiological research of sporadic Alzheimer’s disease will help provide answers about this controversial topic and potentially lead to better Alzheimer’s disease prevention and diagnosis in those with diabetes.6
Dr. Swain is a board-certified wound specialist physician (CWSP) of the American Board of Wound Management, and a Diplomate of the American Board of Podiatric Medicine. He is the Medical Director of the St. Vincent’s Wound Care and Hyperbaric Center at St. Vincent’s Southside Hospital in Jacksonville, Fla., and is in private practice in Jacksonville, Fla.
Dr. Anwar is a second-year resident with the Trinity Regional Medical Center Residency Program in Fort Dodge, Iowa.
Dr. Seelman is a first-year resident with the St. Vincent’s Medical Center Podiatric Surgical Residency Program in Jacksonville, Fla.
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