Association between statin therapy and dementia risk: evidence from All of Us and UK Biobank with coenzyme Q7-related mediation analysis

Background Statins are widely prescribed for cardiovascular disease prevention in older adults; however, their association with dementia remains controversial. Given the high prevalence of both statin use and cognitive decline in aging populations, clarifying this relationship has critical implications for geriatric clinical practice and shared decision-making. Methods We conducted a population-based retrospective cohort study using the All of Us Research Program (discovery cohort, n = 83,355; 31,513 statin users) and UK Biobank (replication cohort, n = 173,282; 43,976 statin users). Participants were adults aged ≥40 years who self-identified as White, followed from 2006 through 2023 (discovery) and 2017 (replication). Inverse probability of treatment weighting balanced baseline characteristics. Dementia risk was estimated using Cox proportional hazards models. An exploratory mediation analysis examined low-density lipoprotein cholesterol (LDL-C) and coenzyme Q7, a protein involved in CoQ10 biosynthesis, as potential pathways linking statin use and dementia. Results Statin use was associated with significantly increased dementia risk in both cohorts (discovery: adjusted HR 2.22, 95% CI 2.02–2.44; replication: adjusted HR 2.54, 95% CI 1.98–3.33). Clear intensity-dependent relationships were observed, with high-intensity statins conferring 14% greater risk than moderate-to-low intensity therapy. In the exploratory mediation analysis, the estimated indirect effect through coenzyme Q7 was statistically significant and accounted for 8.2% of the total association, whereas the indirect effect through LDL-C was not statistically significant. Conclusion Statin use was associated with higher dementia risk in both cohorts, and exploratory mediation findings suggested a modest statistical indirect association through COQ7, which should be considered hypothesis-generating. Given the observational design and conflicting evidence in the literature, these findings warrant further investigation before informing clinical decisions about statin therapy.