Advancing age and the apolipoprotein E ?4 (APOE4) allele are key determinants of the accumulation of pathophysiological abnormalities related to Alzheimer's disease (AD), as well as the clinical manifestation of AD syndrome. However, there is substantial interindividual heterogeneity in cognitive aging and the accrual of AD pathology such that some individuals remain cognitively intact and harbor minimal AD-related brain changes even into old age, and despite being APOE4 positive. Further, although there is replicable evidence for an association between AD pathophysiological changes and cognitive impairment, this relationship is imperfect. Some individuals continue to exhibit intact cognition despite harboring substantial AD pathology. These findings underscore the existence of factors that confer resilience to (i) the influence of age and APOE4 on cognitive course and biomarker profile, and (ii) the impact of biomarker alterations on cognitive trajectory. In this project, we leverage the wealth of multimodal genetic, neuroimaging, biomarker, cognitive, and lifestyle data acquired in the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center to study three such factors: the aging-suppressor gene KLOTHO and its systemic expression, the neuroplasticity-promoting gene brain-derived neurotrophic factor (BDNF) and its systemic expression, and physical activity. Our investigations are organized around two integrative and translational aims that seek to ascertain the extent to which KLOTHO, BDNF, and physical activity singly or jointly modify the effect of age and APOE4 on cognitive trajectory (Aim 1) and neuroimaging and fluid biomarkers of AD (Aim 2) in middle-aged adults (N ? 2000) at increased risk for AD. We will also determine whether these resilience factors alter the pernicious influence of biomarker changes on cognitive course. Together, this complementary set of studies will provide critical insights into putative avenues for promoting brain and cognitive health, particularly against the constraints imposed by advancing age and APOE4 genotype.

Public Health Relevance

The aging of the Baby Boomers and the lack of effective therapies for Alzheimer's disease (AD) raises real concerns that the disease will become a public health epidemic in the near future. In this study, we investigate whether a discrete set of genetic and lifestyle factors might confer resilience to the adverse effects of core AD risk factor and pathologies in at-risk middle-aged adults, thereby ultimately delaying the onset of AD symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG051858-01
Application #
9014375
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wagster, Molly V
Project Start
2016-05-15
Project End
2018-02-28
Budget Start
2016-05-15
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Dougherty, Ryan J; Lindheimer, Jacob B; Stegner, Aaron J et al. (2018) An Objective Method to Accurately Measure Cardiorespiratory Fitness in Older Adults Who Cannot Satisfy Widely Used Oxygen Consumption Criteria. J Alzheimers Dis 61:601-611
Vesperman, Clayton J; Pozorski, Vincent; Dougherty, Ryan J et al. (2018) Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort. Alzheimers Res Ther 10:97
Okonkwo, Ozioma C; Vemuri, Prashanthi (2017) Stemming the Alzheimer tsunami: introduction to the special issue on reserve and resilience in Alzheimer's disease. Brain Imaging Behav 11:301-303
Dougherty, Ryan J; Ellingson, Laura D; Schultz, Stephanie A et al. (2016) Meeting physical activity recommendations may be protective against temporal lobe atrophy in older adults at risk for Alzheimer's disease. Alzheimers Dement (Amst) 4:14-7