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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