Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

Abstract

The 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.

Identification of candidate DNA methylation biomarkers related to Alzheimer’s disease risk by integrating genome and blood methylome data

“…These results are intriguing and warrant further investigation. BIN1 encodes bridging integrator 1 and is a key susceptibility gene for LOAD [ 68 ]. The lower methylation levels of BIN1 promoter in peripheral blood for Chinese subjective cognitive declining participants with significant AD biological characteristics were found when compared with controls based on analyses of the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database [ 68 ].…”

Epigenetic Peripheral Biomarkers for Early Diagnosis of Alzheimer’s Disease

“…Using a population characterized by neurological examination and CSF biomarkers, one study focused on subjects with subjective cognitive decline (SCD), an earlier stage of AD compared to MCI, which were characterized by lower BIN1 methylation levels when compared with cognitively normal individuals [ 69 ]. Furthermore, BIN1 methylation correlated with CSF biomarkers, particularly in the SCD group.…”

“…Particularly, methylation of the PM20D1 gene has been frequently associated with AD pathogenesis, and has been found to be highly sensitive to disease progression. Another promising peripheral biomarker is the methylation of the BIN1 gene, which has been found altered in SCD patients, indicating that its methylation levels are altered in the very early stages of the disease [ 69 ]. Moreover, BIN1 methylation levels are associated with CSF p-tau and t-tau levels, which are specifically altered in AD pathogenesis and are sensitive to the neurodegenerative process, thus suggesting that this peripheral biomarker could be used to monitor the progression of neurodegeneration [ 110 ].…”

Advances in Genetics and Epigenetic Alterations in Alzheimer’s Disease: A Notion for Therapeutic Treatment

“…Using 330 and 484 subjects with and without Aβ-related pathology, such as cognitive impairment, the researchers analyzed whether BIN1 methylation levels in peripheral blood were associated with susceptibility AD and with early-stage changes in LOAD cerebrospinal fluid (CSF). The authors found that subjects with AD traits had a characteristic hypomethylation status in BIN1, independent of the ApoE4 genotype, and also showed higher p-tau levels and lower CSF levels of an important AD biomarker, Aβ42, compared to the control group [ 136 ].…”