Can Cognitive Reserve Offset APOE-Related Alzheimer's Risk? A Systematic Review

Sayonara Pereira da Silva; Charikleia Lampraki; Tainá Dos Santos Rêgo; Paolo Ghisletta; Matthias Kliegel; Jürgen Maurer; Matthias Studer; Élvio Rúbio Gouveia; Marcelo de Maio Nascimento; Andreas Ihle

doi:10.1016/j.arr.2025.102809

Can Cognitive Reserve Offset APOE-Related Alzheimer's Risk? A Systematic Review

Ageing Res Rev. 2025 Jun 17:102809. doi: 10.1016/j.arr.2025.102809. Online ahead of print.

Affiliations

¹ Department of Psychology, University of Geneva, Geneva, Switzerland; Center for the Interdisciplinary Study of Gerontology and Vulnerability, University of Geneva, Geneva, Switzerland; Lemanic Neuroscience Doctoral School, Geneva and Lausanne, Switzerland; Swiss Centre of Expertise in Life Course Research LIVES, Lausanne and Geneva, Switzerland. Electronic address: Sayonara.Pereiradasilva@unige.ch.
² Department of Psychology, University of Geneva, Geneva, Switzerland; Center for the Interdisciplinary Study of Gerontology and Vulnerability, University of Geneva, Geneva, Switzerland; Swiss Centre of Expertise in Life Course Research LIVES, Lausanne and Geneva, Switzerland.
³ Department of Neurology, University Hospital Zurich, Zurich, Switzerland; Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
⁴ Department of Psychology, University of Geneva, Geneva, Switzerland; Swiss Centre of Expertise in Life Course Research LIVES, Lausanne and Geneva, Switzerland.
⁵ Swiss Centre of Expertise in Life Course Research LIVES, Lausanne and Geneva, Switzerland; Department of Economics, University of Lausanne, Lausanne, Switzerland.
⁶ Swiss Centre of Expertise in Life Course Research LIVES, Lausanne and Geneva, Switzerland; Institute of Demography and Socioeconomics, University of Geneva, Geneva, Switzerland.
⁷ Department of Physical Education and Sport, University of Madeira, Funchal, Portugal.
⁸ Department of Physical Education, Federal University of Vale do São Francisco, Petrolina, Brazil.

PMID: 40553976
DOI: 10.1016/j.arr.2025.102809

Abstract

Alzheimer's disease (AD) is a neurocognitive disorder that affects a significant part of the population. Its symptoms include progressive loss of memory and executive dysfunction. Genetic susceptibility to AD can be influenced by allele variants of the APOE gene. On the other hand, lifelong experiences such as educational attainment, occupational complexity, and leisure activities, known proxies for cognitive reserve (CR), may modulate gene expression, ultimately impacting AD susceptibility. In this study, we systematically investigated research that explored the interaction between APOE-related AD outcomes and CR. The literature search was conducted using PubMed and all Web of Science databases. We screened 33,861 references, of which 15 met the inclusion criteria. The studies varied in research design, population characteristics, proxies for CR, and measured outcomes. The publications presented mixed results, with some indicating protective effects (n = 7), others showing detrimental effects (n = 4), and still others suggesting no significant interaction effects (n = 4). Some of these findings may be attributed to the reliance on individual proxies, which may capture only limited aspects or different dimensions of the broader CR framework. Overall, our analysis suggests that individual risk factors may interact in complex ways and that even genetic predispositions can potentially be influenced by CR. Implications for CR and aging research as well as public health policies are discussed.

Keywords: Aging; Dementia; Genetic risk; Lifestyle; Sociodemographic factors.

Publication types

Review