Link Between Diabetes and Alzheimer’s Disease

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Mindy J. Kim-Miller, MD, PhD

Type 2 diabetes mellitus (DM2) is associated with an increased risk of Alzheimer’s disease (AD) and vascular dementia. Among persons at otherwise low risk of developing AD, having DM2 may increase that risk three to five times. Elevated hemoglobin A1C (a measure of average blood glucose level for the past few months) has been associated with an approximately 1.5-fold higher risk of developing cognitive impairment. Persons with AD are twice as likely to have impaired fasting glucose (blood glucose that is higher than normal but not high enough to be considered diabetes) than persons without AD. Although the exact mechanism of this link between DM2 and AD remains unclear, recent studies suggest that multiple processes are involved.

First, diabetes is associated with an increased risk of cardiovascular disease, which appears to increase the risk for AD. Diabetes is well known to cause large and small vessel disease, which can lead to strokes and a brain environment that may accelerate cognitive decline and dementia. Additionally, there are strong interactions with other risk factors such as hypertension (high blood pressure), dyslipidemia (high blood cholesterol and fats), and the ApoE4 genotype (a gene associated with AD, diabetes, and atherosclerosis). Controlling blood pressure has been shown to decrease the risk for AD.

Second, high blood glucose may have toxic effects on the brain through two potential pathways. One pathway involves the formation of glucose metabolites called Advanced Glycation End-products (AGE), which circulate in the blood and bind to amino acids (the building blocks of protein). AGE increase clumping of beta-amyloid proteins, which is associated with senile plaques. AGE also facilitate the formation of tau neurofibrillary tangles. Amyloid plaques and neurofibrillary tangles are some of the hallmarks of AD. One form of AGE appears to have a directly toxic effect on brain cells and triggers cell death. The second glucose-mediated pathway appears to involve oxidative stress (an imbalance between formation and neutralization of free radicals, which are highly reactive, unstable molecules that can lead to DNA damage, mitochondrial malfunction, and cell membrane damage). High blood glucose leads to the formation of excess free radicals, which ultimately leads to cell damage.
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Third, insulin may contribute to AD through multiple pathways. Recent studies suggest that those with AD have an increased rate of insulin abnormalities and insulin resistance. Insulin plays an important role in brain metabolism, learning and memory. Disturbances in the insulin signaling pathways may contribute to cognitive decline such as that seen with AD. The brain of a person with AD is insulin resistant (has decreased insulin receptors), which may be associated with dysfunctional learning and memory loss. The insulin imbalance may decrease new brain cell formation and repair of damaged brain cells. Insulin also regulates the metabolism of beta-amyloid and tau proteins. In DM2, there may be increased formation of amyloid plaques and neurofibrillary tangles. Insulin may also contribute to AD by increasing inflammation and oxidative stress.

Controlling or preventing DM2 may be one way to prevent AD and cognitive decline. A class of drugs used to treat DM2 called thiazolidinediones has been shown to reduce the rate of dementia among diabetics, and preliminary studies suggest that these drugs may slow AD progression among nondiabetics. Treating insulin resistance may reduce the risk or retard the development of AD. A class of cholesterol-lowering drugs called statins may reduce the risk of DM, stroke, and AD. Despite the complex relationship between AD and DM2, the simple message from numerous studies is that preventing or controlling DM2 may help prevent or delay the onset of AD.

Table 1:

Tips for Preventing Type 2 Diabetes Mellitus

  • Maintain a healthy weight
    • Don’t eat more calories than you use up every day
    • If you are overweight, start a weight loss program that includes exercise and a healthy, lean diet
  • Eat a healthy diet that is
    • nutritious and well-balanced
    • low in saturated fat, trans fat, and cholesterol
    • high in fiber
      • This includes fruits, vegetables, whole grains, beans, nuts, seeds
  • Get at least a total of 30 minutes of moderate physical activity on most days of the week or, if possible, every day
    • Walking is great for regulating blood glucose levels
  • Get regular screening for diabetes.
    • The American Diabetes Association recommends screening for everyone at age 45 or sooner for those with two or more risk factors for diabetes (such as being overweight and sedentary lifestyle)
  • Watch for symptoms of diabetes such as:
    1. Frequent urination
    2. Increased thirst
    3. Increased hunger
    4. Fatigue
    5. Unintended weight loss
    6. Muscle aches or cramps
    7. Blurred vision
    8. Headaches
    9. Nausea or vomiting
    10. Dry skin, rashes, or skin infections that heal poorly
    11. Thrush or Candida
    12. Urinary tract infections
    13. Sweet, fruity smelling breath
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