Association between idiopathic normal pressure hydrocephalus and Alzheimer's disease: a bidirectional Mendelian randomization study

Abstract Observational studies have suggested a bidirectional relationship between idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s disease (AD). However, the causal association between these two neurodegenerative disorders remains unclear. This study aimed to explore the causal relationship between iNPH and AD using a two-sample bidirectional Mendelian randomization (MR) method. Large-scale genome-wide association studies of iNPH (Ncase = 767, Ncontrol = 375,610) and AD (Ncase/proxy = 111,326, Ncontrol = 677,663) in European individuals were used to screen genetic instruments for MR analysis. Inverse variance-weighted (IVW) method was used as the main analysis, other MR methods and a series of sensitivity analyses were performed to ensure the reliability. In the forward MR analysis, genetic predisposition to iNPH had no effects on the risk of AD development. Likewise, in the reverse MR analysis, AD did not demonstrate a significant causal effect on iNPH. Sensitivity analyses bolstered the reliability of the MR results. Our MR study indicated no genetic evidence supporting a suggestive association between AD and iNPH in either direction, and provided evidence on the dichotomy between true iNPH and neurodegenerative NPH.