Association of Early-Life Cognitive Enrichment With Alzheimer Disease Pathological Changes and Cognitive Decline

Abstract

Importance: Indicators of early-life cognitive enrichment (ELCE) have been associated with slower cognitive decline and decreased dementia in late life. However, the mechanisms underlying this association have not been elucidated.

Objective: To examine the association of ELCE with late-life Alzheimer disease (AD) and other common dementia-related pathological changes.

Design, setting, and participants: This clinical-pathological community-based cohort study, the Rush Memory and Aging Project, followed up participants before death for a mean (SD) of 7.0 (3.8) years with annual cognitive and clinical assessments. From January 1, 1997, through June 30, 2019, 2044 participants enrolled, of whom 1018 died. Postmortem data were leveraged from 813 participants. Data were analyzed from April 12, 2019, to February 20, 2020.

Exposures: Four indicators of ELCE (early-life socioeconomic status, availability of cognitive resources at 12 years of age, frequency of participation in cognitively stimulating activities, and early-life foreign language instruction) were obtained by self-report at the study baseline, from which a composite measure of ELCE was derived.

Main outcomes and measures: A continuous global AD pathology score derived from counts of diffuse plaques, neuritic plaques, and neurofibrillary tangles.

Results: The 813 participants included in the analysis had a mean (SD) age of 90.1 (6.3) years at the time of death, and 562 (69%) were women. In a linear regression model controlled for age at death, sex, and educational level, a higher level of ELCE was associated with a lower global AD pathology score (estimate, -0.057; standard error, 0.022; P = .01). However, ELCE was not associated with any other dementia-related pathological changes. In addition, a higher level of ELCE was associated with less cognitive decline (mean [SD], -0.13 [0.19] units per year; range, -1.74 to 0.85). An indirect effect through AD pathological changes constituted 20% of the association between ELCE and the rate of late-life cognitive decline, and 80% was a direct association.

Conclusions and relevance: These findings suggest that ELCE was associated with better late-life cognitive health, in part through an association with fewer AD pathological changes.

Figure 1.. Association of Early-Life Cognitive Enrichment (ELCE) With Alzheimer Disease (AD) Pathology Indices

Each partial residual plot is derived from linear regression models with 1 of the AD pathology indices as the separate outcome and ELCE as the variable, controlled for age at death, sex, and educational level. Higher levels of ELCE were associated with lower levels of AD pathology indices. Dotted line indicates the linear regression.

Figure 2.. Mediation Analysis of the Association Among Early-Life Cognitive Enrichment (ELCE), Global Alzheimer Disease (AD) Pathology Score, and the Cognition Decline Rate

Early-life cognitive enrichment constitutes the causal variable; global AD pathology score, the intervening variable; and rate of cognitive decline, the outcome. The estimates are given as standardized coefficients (standard error), with P values derived from a path analysis including age at death, sex, and educational level as the covariates. The line’s thickness is proportional to the relative effect sizes of the estimates, and dashed lines indicate insignificant associations. The result shows that direct relation of ELCE with the rate of cognition decline constituted 80% and the indirect relation through AD pathology score constituted 20% of the total association of higher levels of ELCE with slower rates of late-life cognitive decline.