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

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.

Grant Number: 5R01AG070885-04
NIH Institute/Center: NIH
Principal Investigator: Rebecca Brown