Intranasal Insulin and Memory in Early Alzheimer’s Disease

Lay Summary

Imaging Assessment of Treatment to Improve Memory Performance in Alzheimer’s Disease

Investigators will test the effects of insulin administered through a nasal spray to enhance memory function in patients with early stage Alzheimer’s disease (AD), and they will use conventional brain functional MRI (fMRI) and Arterial Spin Labeling (ASL) imaging techniques to assess underlying responses in the brain’s hippocampus that are associated with the treatment’s effects.

While insulin immediately brings to mind diabetes, insulin also has a major role in the brain. The brain’s hippocampus, where memory and learning functions occur, has many insulin receptors. Prior research has established that insulin signaling is involved in synaptic plasticity and strength. It influences receptors for several neurotransmitters, and insulin receptors are activated during short-term memory. Based on these observations, the investigators hypothesize that memory loss in AD patients may be associated with low brain insulin levels and that intranasal insulin administration (which goes directly into the brain but not the rest of the body) will enhance memory performance through increased functional activation in the medial temporal lobe of the hippocampus. They also hypothesize that the treatment will be effective in AD patients who do not have the apoE4 gene, which genetically predisposes people to AD, but will not be effective in patients who have this gene.

They will enroll 36 patients, 24 with early stage AD (50 percent with the apoE4 gene and 50 percent without it) and 12 healthy adult participants. No participants will have diabetes, since diabetes alters insulin signaling. After memory testing, participants will undergo fMRI scans and cognitive testing on two occasions, after receiving intranasal insulin on one occasion and intranasal placebo on the other. The investigators will compare performance on cognitive tests and fMRI hippocampal activation when participants receive insulin vs. placebo.  ASL imaging will be used to assess the role of altered cerebral blood flow to account for global changes in cortical activity related to insulin administration.  These tests will provide a preliminary indication about insulin’s role in memory functions, how the brain responds to intranasal insulin therapy in early AD, and whether the therapy should be pursued in AD patients who do not have the apoE4 gene, but not in those with the gene.

Significance: If preliminary results indicate that intranasal insulin administration enhances memory function in patients with early AD who do not have the apoE4 gene, the study could lead to large-scale tests of this potential new therapy in that population.

Abstract

Intranasal Insulin and Memory in Early Alzheimer's Disease

Background: Accumulating evidence suggests that insulin dysregulation may be a central pathophysiological process in AD that contributes to the neurodegenerative and neuropathological progression of AD. The acute administration of insulin has memory-enhancing effects in individuals with AD, and this effect may be more prominent in individuals negative for the apolipoprotein E4 allele (Apoe4). Functional imaging to examine the underlying neural response to insulin administration has not been assessed.

Objectives: Our primary aim is to assess the effect of insulin on memory performance and the underlying neural response in the hippocampus in early-stage AD and nondemented controls (aim 1). Secondary objectives include assessing the role of apoE4 genotype in modulating brain insulin responses (aim 2) and global responses to insulin (blood flow and cortical activity (aim 3). Our overall hypothesis is that the acute administration of insulin to the brain, via the intranasal route, will have benefits on memory function related to increased functional activation in the medial temporal lobe, an area rich in insulin receptors. Additionally, we hypothesize that this effect will be most prominent in ApoE4 non-carriers and will not be explained by global effects (increased blood flow or alterations in the cortical activity) induced by insulin administration.

Methods: A total of 36 subjects will be enrolled—24 individuals with early-stage AD (Clinical Dementia Rating [CDR] 0.5, very mild dementia) and 12 nondemented controls (CDR 0). The early AD subjects will be stratified by apolipoprotein E4 (apoE4) status, with 12 apoE4 positive and 12 apoe4 negative participants. After a thorough clinical evaluation including clinical and psychometric testing, participants will have functional MRI (fMRI) scans and cognitive testing on two occasions after receiving blinded, counterbalanced doses of intranasal insulin and placebo. The effect of insulin on cognition will be assessed by comparing performance on a battery of cognitive tests after the administration of insulin and placebo. To assess the neural response to insulin, a paradigm utilizing novel and repeat images known to activate the bilateral hippocampi will be used during fMRI scanning. Differences in the extent of hippocampal activation will serve as the primary fMRI outcome measure. Additionally, arterial spin labeling will be used to assess the role of altered cerebral blood flow and an fMRI motor control task will be used to account for global changes in cortical activity related to insulin administration.

Significance: This study seeks to understand how the brain, and in particular the memory system, responds to insulin. The study will provide valuable information about insulin’s role in brain function in AD and possibly identify a subset of AD patients (those without the ApoE4 gene) who are most likely to benefit from insulin. This information will guide our future efforts in more precisely defining the role of insulin dysregulation in AD and has the potential to lead to therapeutic interventions for AD, new strategies for promoting healthy brain aging, and the development of novel prognostic or diagnostic AD biomarkers.