Unresolved Controversies: The Effect of Benzodiazepines on Cognition and Alzheimer’s Disease

Background: Benzodiazepines (BZDs) are commonly prescribed for anxiety, insomnia, and muscle relaxation, but concerns remain regarding their potential long-term cognitive effects. Prior reviews have reported inconsistent associations between BZD use and cognitive risk, often limited by methodological heterogeneity and unresolved biases. Objective: This systematic review critically evaluates the evidence on BZD exposure and cognitive outcomes, with a specific focus on study design, potential biases, and other factors of methodological heterogeneity. Methods: Following PRISMA 2020 guidelines, we searched PubMed and Google Scholar for studies published between 2010 and 2025. The final search was conducted on 1 July 2025. Eligible studies assessed cognitive performance or incident dementia in community-dwelling adults with regard to BZD use. One reviewer independently screened titles, abstracts, and full texts to determine the eligibility of each study. The other two reviewers participated in the inclusion and exclusion decisions. Any disagreements were resolved by consensus among all three reviewers to minimize bias. No statistical data handling, data conversions, or missing imputation was conducted, as this review did not include quantitative synthesis or meta-analysis. Results: Of 79 references screened by titles, abstracts, and full texts, seventeen articles met the inclusion criteria for this review. Participants in the cohort studies were mostly older adults and cognitively healthy at baseline, while those from case–control studies were dementia patients and their matched controls. Overall, findings remain inconsistent, with five studies reporting an association between BZD use and cognition in the entire cohort, six reporting effects only in specific contexts or subgroups, and six finding no evidence at all. Potential contributing factors to this variability include protopathic bias, operational definitions of BZD exposure, and whether analyses were stratified by factors such as sex, drug half-life, or dose. Conclusions: Due to inconsistencies among findings and limitations in study design rigor, the current review cannot determine whether BZDs independently raise cognitive risk. Future research should adopt more rigorous study designs, with particular attention to addressing protopathic bias, and clarify limitations related to the operational definition of BZD. In addition, our findings support the need for further investigation of BZD association with vulnerable populations, including those with sex-specific susceptibility, low socioeconomic status, and exposure to high-risk prescribing practices.