Trajectories of Cognition in Middle Age: Implications for Alzheimer's Disease and Related Dementias in the U.S.

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PROJECT SUMMARY/ABSTRACT The number of Americans with Alzheimer's disease and related dementias (ADRD) is projected to reach 13.8 million by 2050. Given the current lack of disease-modifying treatments for ADRD coupled with evidence that ADRD develops over decades, there is growing interest in developing prevention strategies. Middle age (i.e., 45-64 years) is increasingly recognized as a key life course period to target modifiable risk factors for cognitive decline and ADRD. Prior studies have identified individual-level risk factors in middle age, including chronic conditions such as hypertension and obesity and health-related behaviors such as excessive alcohol use. The 2020 Lancet Commission estimated that addressing these mid-life risk factors could result in up to 15% of dementias being prevented or delayed. However, recent data suggests the need to look beyond individual- level factors to examine the potential role of environmental exposures to improve health outcomes in mid-life and reduce overall dementia burden. Since 1990, the prevalence of chronic conditions that are risk factors for ADRD has increased in middle-aged adults, particularly in individuals with lower socioeconomic status (SES). The reasons for these trends are not yet fully understood, but a leading hypothesis is that lower SES in middle age is leading to premature onset of aging-related conditions through exposures in the social and physical environment (e.g., levels of social support, crime, food insecurity, pollution). A growing number of studies have linked such environmental factors to risk of cognitive decline and ADRD in older adults, and these factors could also be impacting cognitive trajectories and risk of ADRD in middle age. However, key knowledge gaps remain. First, it is unknown if cognitive outcomes are worsening in middle-aged adults, nor if environmental exposures increase the risk of cognitive decline in middle age. Additionally, whereas cognitive decline and ADRD in older adults result from the interplay of environmental and genetic risk factors, it is unclear how genetic risk contributes to cognitive decline in middle age. A longitudinal study of middle-aged adults that includes measures of environmental exposures and genetic data is needed to address these questions. The objective of the proposed project is to examine if cognitive outcomes are worsening in middle age and how environmental and genetic risk factors contribute to cognitive decline in this age group. The specific aims are to: (1) examine the epidemiology of cognitive impairment in middle-aged adults in the U.S., including identifying cognitive trajectories and incidence of “cognitive impairment no dementia” (CIND) over time; (2) determine if environmental and genetic factors predict cognitive trajectories and incident CIND; and (3) replicate our analyses in a second dataset. We will complete these aims using longitudinal nationally representative data from the NIA-funded Health and Retirement Study. Findings will help elucidate the burden and mechanisms of cognitive decline in middle age and inform policy planning to mitigate the projected burden of dementia.