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Cognitive and Brain Reserve as Modifiers of Early Alzheimer Disease–Related Cognitive Vulnerability
Journal article   Open access   Peer reviewed

Cognitive and Brain Reserve as Modifiers of Early Alzheimer Disease–Related Cognitive Vulnerability

Kelsey R. Sewell, Patricio Solis-Urra, Haiqing Huang, Thomas K. Karikari, George Grove, Arthur F. Kramer, Edward McAuley, Jeffrey M. Burns, Charles H. Hillman, Eric D. Vidoni, …
Neurology, Vol.106(9), e214833
2026
DOI: https://doi.org/10.1212/WNL.0000000000214833
PMID: 41980229
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Open Access CC BY-NC-ND V4.0

Abstract

Background and Objectives Maintaining cognitive function despite the presence of Alzheimer disease (AD) pathology is the foundation of cognitive reserve. Although the theory of cognitive reserve is strongly supported by empirical research, the field lacks standardized, validated methods for quantifying cognitive and brain reserve. We tested whether associations between AD pathology and cognitive function were modified by proxy measures of cognitive reserve (years of education, socioeconomic status; SES) and brain reserve (brain-predicted age difference, and a volumetric AD signature). We hypothesized that greater structural brain integrity, higher education, and higher SES would attenuate the association between greater AD pathology and poorer cognitive performance. Methods This cross-sectional study analyzed baseline data from a multisite randomized clinical trial, which was conducted at 3 US universities and enrolled cognitively unimpaired, physically inactive, community-dwelling adults. AD pathology was measured via plasma assays for phosphorylated tau (p-tau)-217 in the whole cohort, and PET for β-amyloid (Aβ) in a subset of participants as a secondary analysis. The primary outcome of cognitive function was evaluated by a comprehensive cognitive assessment. SES was measured via the MacArthur Socioeconomic Status Index, and magnetic resonance imaging was used to calculate brain-predicted age difference (brain-PAD) and a volumetric AD signature. Data were analyzed using linear regression models with interaction terms for moderation analyses. Results A total of 621 participants (aged 69.9 ± 3.8, 71% female) had available data for the main analyses and 355 had PET Centiloid data available. Brain-PAD moderated the association between AD pathology (measured by p-tau217) and multiple cognitive domains, including episodic memory (β = −0.09 [−0.16 to −0.02]), processing speed (β = −0.08 [−0.15 to −0.01]), working memory (β = −0.10 [−0.18 to −0.03]), and executive function/attentional control (β = −0.08 [−0.15 to −0.01]). Specifically, the negative association of greater AD pathology with poorer cognition was weakest in individuals with younger appearing brains. A latent SES score also moderated the relationship between p-tau217 and episodic memory (β = 0.08 [0.01–0.16]), but this did not survive correction for multiple comparisons. Neither years of education nor the volumetric AD signature moderated pathology-cognition associations. Discussion These results support the hypothesis that higher cognitive and brain reserve may help buffer the cognitive consequences of AD pathology. Strategies to increase both cognitive and brain reserve could help to boost resilience against emerging AD pathology; however, longitudinal studies are needed to confirm these conclusions.

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