The interplay between impaired kidney function and hypertension in dementia: A 13-year longitudinal study

Background Hypertension and kidney function impairment (KFI) are established risk factors for dementia and may reinforce each other. However, whether their coexistence confers excess dementia risk remains unclear. Objective To examine the multiplicative and additive interactions between hypertension and KFI in relation to incident dementia and explore potential biological pathways. Methods We included 218,858 dementia-free adults followed for a mean of 13.2 years. KFI was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m 2 . Cox proportional hazards models assessed independent associations and multiplicative interaction, while additive interaction was evaluated using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). Plasma proteomic data on 2911 proteins were available for 6127 participants. Results Hypertension was associated with dementia risk (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.17–1.31; p < 0.001), whereas KFI was not (HR, 1.02; 95% CI, 0.94–1.11; p = 0.571). A significant multiplicative interaction was observed (p = 0.018). KFI was associated with dementia only among participants with hypertension (HR, 1.15; 95% CI, 1.01–1.29; p = 0.023). A positive additive interaction was also observed (RERI, 0.27; 95% CI, 0.05–0.49; AP, 0.17; 95% CI, 0.05–0.29; SI, 1.84; 95% CI, 1.11–3.07), although it was attenuated after full adjustment. Proteomic analyses implicated immune and inflammatory pathways. Conclusions Hypertension may modify the association between impaired kidney function and dementia risk. Their coexistence may identify individuals at higher risk, but further studies are needed to confirm these findings and clarify the underlying mechanisms.