Impact of nucleos(t)ide analogue therapy on the incidence of Alzheimer’s disease in patients with chronic hepatitis B virus infection

Long-term therapy with nucleos(t)ide analogs (NUCs) is inevitable for chronic hepatitis B (CHB) patients. However, how NUC therapy on the developing Alzheimer's disease (AD) in these patients remains controversial. This retrospective cohort study used the Korean National Health Insurance Service claims database from January 1, 2013, to December 31, 2013, treatment naïve CHB patients and those without previously diagnosed with AD. Participants were followed from the index date until either the diagnosis of AD or the study's conclusion on December 31, 2021. The primary outcome was the incidence of AD, compared between the group with initiated NUC therapy (n = 18,365) at cohort entry and the group without NUC therapy (n = 212,820). During the study, 416 patients were diagnosed with AD. After propensity-score matching (18,365 pairs), the 5- to 7-year follow-up showed a significantly lower hazard ratio (HR) in the NUC-treated group compared to the untreated group (HR 0.31-0.40), with HRs remaining constant over time. Subgroup analysis showed more pronounced benefits of NUC therapy in patients under 65 years (HRs: 0.22 vs. 1.23; P < 0.05) and those without dyslipidemia (HRs: 0.14 vs. 1.09; P < 0.05). Protective effects were also observed across subgroups with hypertension, chronic kidney disease, heart disease, and a history of brain trauma, consistent with AD risk factor trends. Our study analyses suggest that NUC therapy appears to have a protective effect against the development of AD in patients with CHB.