This application seeks renewal of R37-AG10880, "Glucose Regulation and Memory in Alzheimer's Disease". Our continuing focus is periptieral insulin resistance (i.e., high plasma insulin levels and reduced insulin effectiveness) as an antecedent or risk factor for Alzheimer's disease (AD). A key hypothesis posits that a specific form of insulin resistance, one that is associated with hypertension (hereafter, termed hypertension-associated insulin resistance or "HAIR"), interferes with peripheral and brain vascular function, and p-amyloid (AP) regulation. We hypothesize that HAIR creates a pathophysiological foundation for AD, and that this foundation is laid down in mid-life, a timeframe which allows for early detection and treatment. To test these hypotheses we will use a highly sensitive model developed in our current funding cycle: ingestion of a high saturated fat/high glycemic index diet (HSF/HGI) for 4 weeks, a time sufficient to induce mild metabolic changes characteristic of HAIR in a safe manner. We provide preliminary data supporting the validity and safety of this model. We will also investigate beneficial effects of a low saturated fat/low glycemic index diet (LSF/LGI) on metabolic and AD markers. Our preliminary data suggest that improving insulin resistance through this diet enhances cognitive function for normal and memory-impaired adults. Participants will include four groups of middle-aged (45-65 yr) adults: 1) pre-hypertensive (systolic blood pressure ranging from 120-139 mm/Hg) with insulin resistance (homeostasis model assessment of insulin resistance or HOMA-IR >3.7), a group we term "pHAIR";2) pre-hypertensive without insulin resistance;3) normotensive with insulin resistance;and 4) normotensive without insulin resistance. Endpoints will be cognition, CSF and plasma Ap levels, lipoprotein/lipid levels, and cerebral blood flow (arterial spin labeling perfusion MRI). We hypothesize that adults with pHAIR will show abnormal AD biomarker patterns, cerebral blood flow, and cognition, and that diet interventions will produce the greatest changes in these adults.The proposed studies will provide evidence that pHAIR is associated with a pathological midlife pattern ofAD markers and provide evidence for dietary strategies that may benefit patients who have mild cognitive impairment or AD.

Public Health Relevance

The proposed studies will test the hypothesis that diet modulates cognitive and biologic markers of Alzheimer's disease, and that a specific form of insulin-resistance, characterized by hypertension, is associated with abnormal patterns of these markers in midlife. Identification of a clear metabolic risk profile in middle age may offer an opportunity for preventative strategies. The proposed study will address one such strategy;consumption of a low saturated fat/low glycemic index diet.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37AG010880-21
Application #
8460853
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ryan, Laurie M
Project Start
1992-09-10
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
21
Fiscal Year
2013
Total Cost
$574,628
Indirect Cost
$186,366
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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-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
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
Watson, G Stennis; Baker, Laura D; Cholerton, Brenna A et al. (2009) Effects of insulin and octreotide on memory and growth hormone in Alzheimer's disease. J Alzheimers Dis 18:595-602
Vanfossen, Brian T; Watson, G Stennis; Baker, Laura D et al. (2009) Statin Users Without an APOE-epsilon4 Allele have Increased Insulin Resistance. J Alzheimers Dis :
Pedersen, Ward A; McMillan, Pamela J; Kulstad, J Jacob et al. (2006) Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199:265-73
Watson, G Stennis; Craft, Suzanne (2003) The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs 17:27-45
Craft, Suzanne; Asthana, Sanjay; Cook, David G et al. (2003) Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 28:809-22

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