Alzheimer's, Memory and Insulin Resistance

CNS Drugs. 2003;17(1):27-45.

The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment.


An emerging body of evidence suggests that an increased prevalence of insulin abnormalities and insulin resistance in 

Alzheimer's disease may contribute to the disease pathophysiology and clinical symptoms. It has long been known that 

insulin is essential for energy metabolism in the periphery. In the past 2 decades, convergent findings have begun to 

demonstrate that insulin also plays a role in energy metabolism and other aspects of CNS function. Investigators reported 20 

years ago that insulin and insulin receptors were densely but selectively expressed in the brain, including the medial 

temporal regions that support the formation of memory. It has recently been demonstrated that insulin-sensitive glucose 

transporters are localised to the same regions supporting memory and that insulin plays a role in memory functions. 

Collectively, these findings suggest that insulin may contribute to normal cognitive functioning and that insulin abnormalities 

may exacerbate cognitive impairments, such as those associated with Alzheimer's disease. Insulin may also play a role in 

regulating the amyloid precursor protein and its derivative beta-amyloid (Abeta), which is associated with senile plaques, a 

neuropathological hallmark of Alzheimer's disease. It has been proposed that insulin can accelerate the intracellular 

trafficking of Abeta and interfere with its degradation. These findings are consistent with the notion that insulin abnormalities 

may potentially influence levels of Abeta in the brains of patients with Alzheimer's disease. The increased occurrence of 

insulin resistance in Alzheimer's disease and the numerous mechanisms through which insulin may affect clinical and 

pathological aspects of the disease suggest that improving insulin effectiveness may have therapeutic benefit for patients 

with Alzheimer's disease. The thiazolidinedione rosiglitazone has been shown to have a potent insulin-sensitising action that 

appears to be mediated through the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma 

agonists, such as rosiglitazone, also have anti-inflammatory effects that may be of therapeutic benefit in patients with 

Alzheimer's disease. This review presents evidence suggesting that insulin resistance plays a role in the pathophysiology 

and clinical symptoms of Alzheimer's disease. Based on this evidence, we propose that treatment of insulin resistance may 

reduce the risk or retard the development of Alzheimer's disease.

[PubMed - indexed for MEDLINE]