Cerebral accumulation of amyloid beta (Abeta) protein is a pathological hallmark of Alzheimer disease (AD), and likely plays a fundamental role in its pathogenesis. Research has focused on Aa manipulation as a mechanism for reducing or treating AD, but the clinical utility of findings is limited by lack of a simple way to identify early those at high risk of AD; Abeta levels in the CSF have been measured in some settings, but are impractical for widespread clinical applications. Abeta appears in circulating plasma, and a central aim of this proposal is to investigate the value of plasma Abeta as an early indication of AD risk by exploring its relation to cognitive decline, an early stage in the path of AD development. An additional aim of this proposal is to explore the function of insulin in cognitive decline, and its interaction with Abeta; irecent research has established that insulin modulates levels of Abeta in vitro and in vivo, however, little work has examined the long-term effects of insulin on cognition, or the possibility of different effects in subgroups of the population. This proposal represents a collaboration between basic scientists and epidemologists to test novel hypotheses in men and women regarding plasma Abeta levels, insulin levels, and insulin secretion (as measured by c-peptide) in non-diabetics and their ability to predict development of cognitive decline. The investigation will be conducted within the Nurses' Health Study, including women currently aged 70- 81 years and followed since 1976, and the Physician's Health Study II including men aged 65 years and older and followed since 1982. From each cohort, we will select 2,000 subjects with stored plasma samples collected at two points over 10 years, and with serial tests of cognitive function (3 repeated interviews by telephone, at 1.5-year intervals). The test battery measures general cognitive status, verbal memory, executive function, speed of processing, and working memory; we have conducted extensive demonstrations of the validity and reliability of the telephone method compared to in-person assessments, and have previously detected strong relations with numerous established risk factors for decline. Thus, these two established populations provide a highly cost-efficient setting in which to examine biomarkers of early cognitive decline, and gender and genetic interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024215-04
Application #
7269828
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Anderson, Dallas
Project Start
2004-09-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$540,125
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Townsend, Mary K; Okereke, Olivia I; Xia, Weiming et al. (2012) Relation between insulin, insulin-related factors, and plasma amyloid beta peptide levels at midlife in a population-based study. Alzheimer Dis Assoc Disord 26:50-4
Koyama, Alain; Okereke, Olivia I; Yang, Ting et al. (2012) Plasma amyloid-ýý as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. Arch Neurol 69:824-31
Evans, Denis A; Grodstein, Francine; Loewenstein, David et al. (2011) Reducing case ascertainment costs in U.S. population studies of Alzheimer's disease, dementia, and cognitive impairment-Part 2. Alzheimers Dement 7:110-23
Okereke, Olivia I; Kurth, Tobias; Pollak, Michael N et al. (2010) Fasting plasma insulin, C-peptide and cognitive change in older men without diabetes: results from the Physicians' Health Study II. Neuroepidemiology 34:200-7
Okereke, Olivia I; Xia, Weiming; Selkoe, Dennis J et al. (2009) Ten-year change in plasma amyloid beta levels and late-life cognitive decline. Arch Neurol 66:1247-53
Okereke, Olivia I; Selkoe, Dennis J; Pollak, Michael N et al. (2009) A profile of impaired insulin degradation in relation to late-life cognitive decline: a preliminary investigation. Int J Geriatr Psychiatry 24:177-82
Okereke, Olivia I; Xia, Weiming; Irizarry, Michael C et al. (2009) Performance characteristics of plasma amyloid-beta 40 and 42 assays. J Alzheimers Dis 16:277-85
van Oijen, Marieke; Okereke, Olivia I; Kang, Jae Hee et al. (2008) Fasting insulin levels and cognitive decline in older women without diabetes. Neuroepidemiology 30:174-9
Okereke, Olivia I; Pollak, Michael N; Hu, Frank B et al. (2008) Plasma C-peptide levels and rates of cognitive decline in older, community-dwelling women without diabetes. Psychoneuroendocrinology 33:455-61
Okereke, Olivia I; Kang, Jae H; Cook, Nancy R et al. (2008) Type 2 diabetes mellitus and cognitive decline in two large cohorts of community-dwelling older adults. J Am Geriatr Soc 56:1028-36

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