AbstractThe bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer’s disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.
Alzheimer’s Disease Susceptibility Gene Apolipoprotein E (APOE) and Blood Biomarkers in UK Biobank (N = 395,769)