Biomarkers

The hippocampus, a critical brain structure for learning and memory, exhibits left-right volumetric differences (LHCV and RHCV) and asymmetry. However, the molecular underpinnings of these features remain largely unknown in the general population.

We performed a meta-analysis of epigenome-wide association studies (EWAS) across six population-based cohorts (8,156 individuals, 53% women, mean age: 60.7 years, age range: 30 to 92 years) to identify blood-based methylation signatures associated with LHCV, RHCV, and hippocampal asymmetry. Integrative cross-omics analyses using individual-level genetic, methylation, and gene expression data from Rhineland Study participants (n > 2,624) was employed to elucidate the underlying molecular mechanisms. We further evaluated the relationships between ten dietary patterns, baseline methylation signatures, and longitudinal changes in hippocampal volumes and asymmetry.

Distinct CpG sites and differentially methylated regions (DMRs) for LHCV, RHCV, and hippocampal asymmetry converged on pathways related to neuronal differentiation and development. Integrative analyses identified 15 CpG/DMR-gene expression pairs associated with LHCV and 18 pairs with RHCV, implicating immnue-related (i.e. LGALS3BP and TREM5) and synaptic function genes (i.e. MIR181A1HG and CORO1B). Baseline methylation at these loci was significantly associated with rates of bilateral hippocampal loss over time, explaning over 10% of the variation in hippocampal atrophy rates. Four CpGs were consistently associated with hippocampal asymmetry cross-sectionally and longitudinally, with sex-specific differences. Moreover, higher adherence to healthy dietary patterns was associated with these methylation signatures.

Our findings reveal methylation signatures as potential biomarkers or therapeutic targets for age- or neurodegeneration-related hippocampal atrophy. They further underscore the influence of modifiable dietary patterns on methylation and hippocampal health.