Mechanisms of Risk and Resilience to Age-Related Cognitive Decline: A 60-Year Prospective Prenatal Cohort

与年龄相关的认知衰退的风险和恢复力机制：60 年预期产前队列

• 批准号: 10256822
• 负责人: STEPHEN L BUKA
• 金额: $ 112万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10256822
• 关键词: 7 year old; Address; Adolescence; Adult; Affect; Age; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-42; Amyloid beta-Protein; Anatomy; Apolipoprotein E; Birth; Brain; Brain Pathology; Child; Childhood; Clinical; Cognition; Cognitive; Cognitive aging; Cohort Studies; Data Collection; Development; Economic Burden; Economics; Education; Elderly; Equilibrium; Etiology; Failure; Family; Functional Magnetic Resonance Imaging; Genotype; Health Status; Healthcare Systems; Impaired cognition; Incidence; Income; Individual; Individual Differences; Investigation; Lead; Life; Life Experience; Link; Longevity; Longitudinal cohort; Measures; Neurocognitive; Neuropsychology; Occupational; Onset of illness; Outcome; Participant; Pathology; Pathway interactions; Pattern; Perinatal; Phase; Physical activity; Plasma; Population; Pregnancy; Prevention strategy; Race; Research; Risk; Saliva; Sampling Studies; Social Behavior; Structure; System; Therapeutic; Time; age related; childhood adversity; cognitive ability; cognitive control; cognitive function; cognitive neuroscience; cognitive testing; cohort; early childhood; effective therapy; ethnic diversity; indexing; insight; lifestyle factors; member; middle age; neural network; neuroimaging; novel; novel strategies; pre-clinical; prenatal; prevent; programs; prospective; racial and ethnic; resilience; social

PROJECT SUMMARY/ABSTRACT The failure to find any effective treatment for Alzheimer’s disease (AD) despite over four decades of research underscores the critical need for new strategies to prevent or delay disease onset. The proposed investigation aims to examine mechanisms of risk and resilience to age-related cognitive decline by leveraging recent advances in cognitive neuroscience and a unique 60-year longitudinal prenatal cohort. The concept of reserve has been developed to account for the large individual differences in cognitive aging trajectories, with nascent understanding of potential modifiable determinants of reserve. However, fundamental questions remain regarding, for instance, the impact of education, cognitively stimulating activities in adulthood, or early childhood enrichment on reserve mechanisms and cognitive decline. Previous investigations have been hampered by a number of limitations, including the lack of: 1) prospective measures of early childhood cognition, needed to address critical issues of reverse causation plaguing this field; 2) indices of adult cognitive decline over a large time window; 3) measures of relevant sociobehavioral factors across the entire lifespan; and 4) economic and racial/ethnic diversity of study samples. This proposal addresses these limitations by extending our continued study of the Providence RI cohort of the US Collaborative Perinatal Project (CPP). The original CPP involved systematic data collection from pregnancy through age 7 years, including measures of three key early life factors thought to influence cognitive trajectories in later life: early childhood IQ, family SES, and childhood adversity. We conducted a comprehensive cognitive assessment of 720 members of this cohort at age 35. We propose to reassess these participants (now approaching age 60) with a detailed neuropsychological battery to examine cognitive decline over a 25-year period. We will also assess engagement in cognitively stimulating activities, physical activity, occupational complexity, income, and health status. Participants will provide biosamples for plasma beta-amyloid (Aβ) 42/40 ratio and apolipoprotein E (APOE) genotype, and will undergo structural and functional MRI, providing operationally-defined brain measures of reserve. Finally, we propose a novel conceptual framework linking lifespan factors to cognitive outcomes through distinct brain mechanisms. This framework drives our aims which are: (1) Determine the relative influence of educational attainment, early life, and adult lifestyle factors on cognitive level and decline in late middle-aged adults; (2) Determine the relative contributions of specific brain reserve mechanisms to cognitive decline; and (3) Identify major determinants of brain reserve mechanisms in later life. A projected doubling of the elderly population by 2050 will place tremendous AD-related burden on the U.S. healthcare system. By providing novel insights into mechanisms of risk and resilience, findings may lead to new strategies to significantly reduce this burden by delaying cognitive decline and the onset of Alzheimer’s Disease.

项目总结/文摘