Alzheimer's disease (AD) and Type 2 Diabetes (T2D) are two of the most common diseases in older adults and their prevalence is increasing with an aging population. Numerous studies have demonstrated that T2D and insulin resistance are risk factors for AD, and reduced markers of insulin signaling are apparent in brain tissue from those affected by AD. Interestingly, in culture, insulin signaling is protective against A?-mediated synapse degeneration, and insulin may promote A? membrane trafficking and release. This relationship is bidirectional, as A? itself can cause decreased insulin receptor expression. These and other molecular studies that demonstrate an interplay between insulin and amyloid provide the rationale for clinical studies to more directly investigate the relationship between amyloid and insulin resistance in humans. The goal of this project is to further understand the relationship between metabolic function, cognition, and cerebral amyloid beta deposition. Post-mortem studies have shown a relationship between insulin signaling and amyloid, and clinical literature supports a role for insulin in cognitive function and memory. We will investigate these relationships in cognitively normal older adults with and without cerebral amyloid. For this project, our cohort will consist of subjects known to be positive or negative for A? but without cognitive impairment. A? positive subjects are thought to comprise a cohort in the very earliest stages of AD, or "preclinical AD." We will use the gold standard for measuring insulin resistance, the hyperinsulinemic-euglycemic clamp, to assess metabolic function. We will also evaluate cognitive performance in the insulin-stimulated state and determine whether amyloid status and level of insulin resistance affect cognition. This project will build upon studies that show intravenous or intranasal insulin improve memory in various cohorts. By investigating insulin sensitivity in subjects with or without cerebral amyloidosis, we will determine whether these factors influence insulin- mediated cognitive improvement in the very earliest stages of AD.

Public Health Relevance

Alzheimer's Disease is a chronic and progressive neurodegenerative disease with no cure and a huge economic impact, estimated at $185 billion in 2011. Type 2 Diabetes, characterized by insulin resistance, is growing at an alarming rate, with total health care costs estimated at $174 billion in 2007. Given the number of individuals affected by these diseases and skyrocketing health care costs, is imperative that we work to understand the relationship between metabolic function and brain amyloid deposition in the earliest stages of AD, where intervention strategies are most likely to have an effect.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AG044953-01A1
Application #
8647911
Study Section
Special Emphasis Panel (ZRG1-F01-F (20))
Program Officer
Wagster, Molly V
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$56,182
Indirect Cost
Name
University of Kansas
Department
Neurology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Morris, Jill K; Vidoni, Eric D; Honea, Robyn A et al. (2014) Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol Aging 35:585-9
Morris, Jill K; Honea, Robyn A; Vidoni, Eric D et al. (2014) Is Alzheimer's disease a systemic disease? Biochim Biophys Acta 1842:1340-9
Wilkins, Heather M; Harris, Janna L; Carl, Steven M et al. (2014) Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet 23:6528-41
Smittkamp, Susan E; Morris, Jill K; Bomhoff, Gregory L et al. (2014) SOD1-G93A mice exhibit muscle-fiber-type-specific decreases in glucose uptake in the absence of whole-body changes in metabolism. Neurodegener Dis 13:29-37
Morris, J K; Vidoni, E D; Perea, R D et al. (2014) Insulin resistance and gray matter volume in neurodegenerative disease. Neuroscience 270:139-47
Morris, Jill K; Vidoni, Eric D; Honea, Robyn A et al. (2014) Impaired glycemia and Alzheimer's disease. Neurobiol Aging 35:e23
Vidoni, Eric D; Morris, Jill K; Raider, Kayla et al. (2014) Reducing post-lumbar puncture headaches with small bore atraumatic needles. J Clin Neurosci 21:536-7