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 beinfluenced 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.