Insomnia-Driven Hippocampal Atrophy: Evidence From Bidirectional Mendelian Randomization

Observational studies link insomnia to hippocampal atrophy, yet causal inference remains limited by confounding and reverse causality. While Mendelian randomization (MR) studies have explored sleep-brain associations, bidirectional causality between insomnia and hippocampal subfield volumes remains unaddressed.

We conducted bidirectional two-sample MR using genome-wide association study (GWAS) summary data. Genetic instruments for insomnia (N = 462,341) and eight hippocampal volume imaging-derived phenotypes (IDPs; N ≈ 31,968-33,219) were selected (p < 5 × 10⁻⁸, LD r² < 0.001), with F-statistics > 10 ensuring robustness. Primary analyses employed inverse-variance weighted regression, supplemented by sensitivity analyses (MR-Egger, weighted median, MR-PRESSO) to assess pleiotropy and heterogeneity. Multiple testing was controlled using Benjamini-Hochberg FDR.

Forward MR revealed inverse associations between genetically proxied insomnia and six of eight hippocampal phenotypes: T1 left hippocampus volume (OR = 0.62, 95% CI = 0.43-0.89; P _FDR = 0.014), left hippocampus gray matter volume (OR = 0.63, 95% CI = 0.47-0.84; P _FDR = 0.008), right hippocampus gray matter volume (OR = 0.69, 95% CI = 0.49-0.98; P _FDR = 0.035), left and right hippocampal volumes from automated subcortical segmentation (ORs = 0.60, 95% CI = 0.42-0.86, P _FDR = 0.010; and 0.71, 0.51-0.99, P _FDR = 0.037), and right whole-hippocampus volume from subfield segmentation (OR = 0.61, 95% CI = 0.43-0.86; P _FDR = 0.010). Sensitivity analyses supported robustness; reverse MR detected no evidence of effects of hippocampal volumes on insomnia (P _FDR = 1).

Genetically proxied insomnia shows strong genetic evidence consistent with a causal reduction in hippocampal volumes. Clinically, early intervention in insomnia, particularly through cognitive-behavioral therapy for insomnia, may help preserve hippocampal health. This study highlights the importance of addressing insomnia as a public health priority. Future research should investigate the underlying biological mechanisms and incorporate more diverse cohorts to enhance the generalizability of these findings.