Investigating the Link between Alzheimer's Disease and Diabetes

Emerging evidence shows a link between cognitive impairment, specifically Alzheimer’s disease, and diabetes. Speaking at the 2014 Cardiometabolic Health Congress, C. Ronald Kahn, MD, of Harvard Medical School, Boston, MA, discussed the link between Alzheimer’s disease and diabetes, beginning with epidemiological studies 14 years ago. The studies in question showed that patients with type 2 diabetes mellitus had between a 1.5- and 2-fold increased risk of developing Alzheimer’s disease.

Both diabetes and Alzheimer’s disease show similar pathologies, with amyloid protein accumulation in different organs — amyloid-βprotein in the brain and islet amyloid polypeptide in the pancreas. These observations have led to models suggesting that insulin resistance, which drives the pathology of diabetes, is worsening the pathology of Alzheimer’s disease through accumulation of amyloid proteins and possibly vascular factors.

Alzheimer’s disease is not the only brain dysfunction that patients with type 1 and type 2 diabetes mellitus are at risk of developing. Patients with diabetes have higher rates of depression than the general population and other patients who have diseases that require daily control. Patients with type 1 diabetes also have a higher prevalence of eating disorders (variants of anorexia nervosa).

Accumulating evidence shows that insulin levels in the brain can reach levels similar to the systemic circulation. Insulin in the brain can also exert short-term signaling and long-term neuronal trophic effects. This insulin originates primarily from pancreatic β-cells and is transported to the brain in cerebrospinal fluid or through a carrier.

Researchers have documented many links between Alzheimer’s disease and diabetes. Patients with Alzheimer’s disease have decreased insulin levels and insulin receptor levels in the brain. Type 2 diabetes-associated hyperinsulinemia has been shown to increase amyloid-β peptide accumulation, which is a pathological hallmark of Alzheimer’s disease.

Insulin receptors are widely distributed in the brain of rodents and humans. Kahn and colleagues used genetic research techniques, namely a knockout mouse that lacked brain insulin receptors, to determine if these insulin receptors had functionality. The knockout mice developed mild metabolic syndrome, exhibiting increased food intake, increased white fat mass, and higher plasma insulin and triglyceride levels. These results suggest that insulin action in the brain and liver is necessary to stimulate hepatic glucose output.

Further research with the knockout mice showed that when insulin signaling is removed from the brain, there is increased hepatic glucose output, decreased response to hypoglycemia, decreased gonadotropin release, and decreased thermogenesis.

Kahn showed video examples of several tests for behavior in which the knockout mice showed increased anxiety and increased depression compared to the wild type mice. The depression-like behavior was reversed with antidepressant therapy.

With all of this evidence linking Alzheimer’s disease with diabetes, the obvious question is whether patients with Alzheimer’s disease should be treated with anti-diabetic therapies. Several clinical trials are examining that hypothesis, with strategies ranging from intensive insulin therapy, to intranasal insulin, to GLP-1 analog therapy.