The proposed studies will investigate peripheral insulin resistance (high plasma insulin and reduced insulin effectiveness) as an antecedent or risk factor for Alzheimer's disease (AD). In work accomplished during our current funding period, we identified several potential mechanisms through which abnormal glucose and insulin metabolism may contribute to AD pathology and symptoms. We showed that raising plasma insulin levels increased plasma and CSF Abeta42 levels, as it increased CSF levels of pro-inflammatory cytokines and F2-Isoprostanes (markers of brain lipid peroxidation). Importantly, insulin-induced changes in plasma Abeta42 levels were closely related to changes in the inflammatory cytokine, tumor necrosis factor-alpha (TNFalpha). This pattern was most evident in people with higher body mass indices, a recently identified risk for AD. These findings suggest that insulin-induced increases in TNFalpha and free fatty acid (FFA) levels that occur with obesity may affect AS regulation and thereby increase the risk of AD. In contrast, we showed that in mild AD, treatment with me insulin-sensitizing, anti-inflammatory agent rosiglitazone preserves cognition and modulates plasma Abeta levels. A key hypothesis that has emerged from this previous work posits that insulin resistance induces inflammation and FFA elevation, which interact with insulin-associated increases in pathogenetic beta-amyloid (Abeta42). To test this hypothesis, we will conduct three studies examining the effects of induced or improved insulin resistance on cognition, on plasma and CSF Abeta levels, and on inflammatory reactants: 1. ingestion of a high saturated fat/high glycemic index diet for 4 weeks, a time sufficient to induce metabolic changes of insulin resistance; 2. infusion of a triglyceride emulsion, an established procedure for induction of insulin resistance through FFA elevation; and 3. administration of rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist which improves sensitivity and reduces inflammation. We predict that induced insulin resistance will increase plasma Abeta42 and CSF inflammatory markers and impair cognition. We further predict that the magnitude of change will be greater for adults with AD, and for those adults with greater central adiposity. We also hypothesize that cognitive enhancement following treatment of insulin resistance with the rosiglitazone will be associated with reduced levels of insulin, FFA, and inflammation. The proposed studies will provide important information about the mechanisms through which peripheral insulin resistance increases the risk of AD, and about therapeutic approaches to ameliorating this risk.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AG010880-13
Application #
6920490
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Buckholtz, Neil
Project Start
1992-09-10
Project End
2010-04-30
Budget Start
2005-05-15
Budget End
2006-04-30
Support Year
13
Fiscal Year
2005
Total Cost
$470,526
Indirect Cost
Name
University of Washington
Department
Psychiatry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Neth, Bryan J; Craft, Suzanne (2017) Insulin Resistance and Alzheimer's Disease: Bioenergetic Linkages. Front Aging Neurosci 9:345
Hugenschmidt, Christina E; Sink, Kaycee M (2015) No pain, functional gain: the importance of pain management in older adults with cognitive impairment. Pain 156:1377-8
Chichester, Lee; Wylie, Ashley T; Craft, Suzanne et al. (2015) Muscle heat shock protein 70 predicts insulin resistance with aging. J Gerontol A Biol Sci Med Sci 70:155-62
Hanson, Angela J; Bayer, Jennifer L; Baker, Laura D et al. (2015) Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ?4 Carriers and Adults with Mild Cognitive Impairment. J Alzheimers Dis 48:205-18
Utzschneider, Kristina M; Bayer-Carter, Jennifer L; Arbuckle, Matthew D et al. (2013) Beneficial effect of a weight-stable, low-fat/low-saturated fat/low-glycaemic index diet to reduce liver fat in older subjects. Br J Nutr 109:1096-104
Hanson, Angela J; Bayer-Carter, Jennifer L; Green, Pattie S et al. (2013) Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol 70:972-80
Baker, Laura D; Bayer-Carter, Jennifer L; Skinner, Jeannine et al. (2012) High-intensity physical activity modulates diet effects on cerebrospinal amyloid-? levels in normal aging and mild cognitive impairment. J Alzheimers Dis 28:137-46
Cudaback, Eiron; Li, Xianwu; Yang, Yue et al. (2012) Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation. J Neuroinflammation 9:192
Bayer-Carter, Jennifer L; Green, Pattie S; Montine, Thomas J et al. (2011) Diet intervention and cerebrospinal fluid biomarkers in amnestic mild cognitive impairment. Arch Neurol 68:743-52
Sonnen, J A; Larson, E B; Walker, R L et al. (2010) Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology 75:1203-10

Showing the most recent 10 out of 18 publications