Cognitive Reserve, Alzheimer's Neuropathology, and Risk of Dementia: A Systematic Review and Meta-Analysis

Abstract

Cognitive reserve (CR) may reduce the risk of dementia. We summarized the effect of CR on progression to mild cognitive impairment (MCI) or dementia in studies accounting for Alzheimer's disease (AD)-related structural pathology and biomarkers. Literature search was conducted in Web of Science, PubMed, Embase, and PsycINFO. Relevant articles were longitudinal, in English, and investigating MCI or dementia incidence. Meta-analysis was conducted on nine articles, four measuring CR as cognitive residual of neuropathology and five as composite psychosocial proxies (e.g., education). High CR was related to a 47% reduced relative risk of MCI or dementia (pooled-hazard ratio: 0.53 [0.35, 0.81]), with residual-based CR reducing risk by 62% and proxy-based CR by 48%. CR protects against MCI and dementia progression above and beyond the effect of AD-related structural pathology and biomarkers. The finding that proxy-based measures of CR rivaled residual-based measures in terms of effect on dementia incidence underscores the importance of early- and mid-life factors in preventing dementia later.

Keywords: Aβ; CSF; Cognitive reserve; Dementia; MRI; Tau.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart illustrating the process for final selection of articles. Search terms included: cognitive reserve, cognitive capacity, brain reserve, neural reserve, brain maintenance, residual variance, transition, cognitive decline, cognitive deterioration, progress*, conver*, neurodegeneration, risk, incident, longitudinal, magnetic resonance imaging, MRI, grey matter, gray matter, white matter, positron emission tomography, PET, beta amyloid, tau, mild cognitive impairment, MCI, Alzheimer*, AD, dement*, mild neurocognitive disorder, and major neurocognitive disorder

Fig. 2

Forest plot conveying the risk of progression to MCI or all-cause dementia. Petkus et al. (2019), Pettigrew et al. (2017), Soldan et al. (2015), and van Loenhoud et al. (2017; 2019) controlled for structural indicators of Alzheimer’s disease such as hippocampal volume. Hohman et al. (2016), Soldan et al. (2013), and Udeh-Momoh et al. (2019) controlled for biomarkers of Alzheimer’s disease such as Aβ or tau. Further, Hohman et al. (2016), Petkus et al. (2019), and van Loenhoud et al. (2017; 2019) examined cognitive reserve using the residual variance approach, whereas Pettigrew et al. (2017), Soldan et al. (2013; 2015), Udeh-Momoh et al. (2019), and Xu et al. (2019) used the composite proxy approach

Fig. 3

Funnel plot of the included studies to estimate publication bias. The long-dotted line is the fixed-effect model estimate and the short-dotted line is the random-effects model estimate. Egger’s Test of the Intercept: p = 0.22