Genetic and Lifestyle Determinants of Cognitive Resilience in Midlife

中年认知弹性的遗传和生活方式决定因素

• 批准号: 9014375
• 负责人: OZIOMA C OKONKWO
• 金额: $ 32.46万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014375
• 关键词: Adult; Adverse effects; Age; Age Factors; Age-associated memory impairment; Aging; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Animals; Apolipoprotein E; Attenuated; Biological Assay; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Cognitive aging; Data; Deterioration; Disease; Elderly; Enrollment; Epidemic; Exhibits; Family history of; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Health; Heterogeneity; Human; Impaired cognition; Individual; Investigation; Life Style; Link; Liquid substance; Longevity; Mediating; Modality; Mus; N-Methyl-D-Aspartate Receptors; Neuronal Plasticity; Neurons; Participant; Pathology; Pathway interactions; Physical activity; Process; Public Health; Registries; Research; Resources; Risk; Risk Factors; Sampling; Serum; Suppressor Genes; Symptoms; Synaptic plasticity; Syndrome; Testing; Variant; Wisconsin; abeta accumulation; age effect; attenuation; brain health; clinically relevant; cognitive function; cohort; curative treatments; effective therapy; insight; lifestyle data; lifestyle factors; middle age; neuroimaging; neurotoxic; public health relevance; resilience; translational study

 DESCRIPTION (provided by applicant): Advancing age and the apolipoprotein E ε4 (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.