The proposed randomized, double-blind, placebo-controlled trial will examine the effects of intranasal insulin administration on cognition, cerebral glucose metabolism, and p-amyloid (AP) for persons with Alzheimer's disease (AD). Growing evidence suggest that insulin's role in central nervous system energy metabolism is dysregulated in AD. Patients with AD have an increased risk of peripheral hyperinsulinemia and insulin resistance (reduced insulin efficiency) which down-regulate transport of insulin to the brain, and increase neuropathological features of AD. AD is associated with reduced CSF insulin levels, and intravenous insulin administration (while maintaining euglycemia) improves memory, possibly by augmenting low brain levels or by overcoming insulin resistance. Peripherally administered insulin is not a viable treatment, however, due to the risk of hypoglycemia. Intranasal administration of insulin may effectively raise CNS insulin levels without the risk of hypoglycemia. Following intranasal administration, rapid bulk flow transport of insulin occurs through extracellular pathways to brain structures supporting memory. Consistent with these findings, our preliminary data show that acute intranasal insulin administration improves verbal memory in persons with AD without inducing hypoglycemia. The proposed study will build on these findings to test the hypotheses that four months of treatment with intranasal insulin will: (1) improve cognition and daily function in patients with AD, compared to placebo; (2) increase glucose metabolism in regions that typically show reduced metabolic rates in patients with AD; and (3) modulate plasma and CSF Abeta and neuroendocrine markers. Participants will receive four months of treatment with placebo or one of two doses of insulin. A subset of participants will undergo fluorodeoxyglucose positron emission tomography (FDG PET) prior to, and at the end of treatment to determine whether intranasal insulin increases cerebral glucose metabolism. A subset of participants will also receive two baseline lumbar punctures (LPs) on separate days, 30-minutes after intranasal insulin or placebo administration to determine acute effects of insulin on CSF Abeta levels. After four months, CSF will be collected again to examine the effects of treatment on Abeta. The proposed study will provide valuable data regarding the safety, feasibility, and potential efficacy of this novel therapeutic approach and drug delivery methodology that can guide future large-scale clinical trials with insulin or other promising compounds. We will also obtain critical information about the overarching theory that lowered CNS insulin and peripheral insulin resistance contribute to AD pathophysiology.

R01AG027415

2006-09-01

2010-08-31