Abstract
INTRODUCTION: The causal association between pulmonary function and Alzheimer's disease (AD) remains unclear. This study aimed to investigate whether low pulmonary function has a causal relationship with the risk of AD. METHODS: We conducted prospective cohort and two-sample Mendelian randomization (MR) studies. In the cohort study, 333,816 UK Biobank participants were eligible for analysis. Forced expiratory volume in the first second (FEV(1)), forced vital capacity (FVC), FEV(1)/FVC ratio, percentage of predicted normal value of FEV(1) (FEV(1)% pred), and peak expiratory flow (PEF) were measured at baseline. Longitudinal associations were investigated using cox-proportional hazard models. We conducted univariate and multivariable MR analyses on genome-wide association study (GWAS) data from 421,986 Europeans for FEV(1), FVC, and PEF. Inverse-variance weighting was employed as the primary MR analysis approach. RESULTS: Over a median follow-up of 12.8 years (10.3-15.0 years), 2275 incident cases of AD were identified in the cohort study. Compared to the highest quartile, the lowest quartile for pulmonary function exhibited a higher risk of incident AD, and hazard ratios (95% CI) were as follows after adjustment for risk factors: 1.81 (1.32-2.48; FEV(1)), 1.97 (1.44-2.69; FVC), and 1.86 (1.39-2.47; PEF). In the MR study, genetically determined high FEV(1) was associated with a decreased risk of AD (odds ratio: 0.68, 95% CI: 0.53-0.88). The results remained robust after sensitivity and multivariable MR analyses. CONCLUSION: Our findings suggest the potential causal association between high FEV(1) and decreased risk of AD.