Hippocampal-to-Ventricle Ratio as a Head-Size-IndependentBiomarker: Sex Differences and Cognitive Associations in 27,680UK Biobank Participants

Abstract

Hippocampal volume is a key biomarker for Alzheimers disease and brain aging, yet reported sex differences vary substantially depending on head-size adjustment methods. We examined whether the hippocampal-to-ventricle ratio (HVR), a self-normalizing measure, provides more consistent sex difference estimates than conventional adjustment approaches. Using a subset of UK Biobank structural MRI data (N = 27,680; 56% female; ages 45-82), we compared sex differences across four adjustment methods (unadjusted, proportions, stereotaxic, residualized) and in samples matched on age and on intracranial volume (ICV). Hippocampal sex differences reversed direction across methods, ranging from d = -0.89 (males larger, unadjusted) to d = 0.58 (females larger, proportions), with a range of 1.5 standard deviations across analytical choices. In contrast, HVR showed a consistent female advantage (d = 0.52) that persisted in the ICV-matched subsample (d = 0.19), confirming this effect is not a head-size artifact. Males exhibited steeper cross-sectional age-related HVR differences (1.7x female rate, p < 10-50), consistent with males showing ventricular expansion at younger ages. Structural equation modeling revealed that HVR predicted general cognition comparably to hippocampal volume ({beta} = 0.04, overlapping CIs), and unlike residualized hippocampal volume, HVR maintained significant brain-cognition associations in both sexes. We provide sex-specific normative centile curves for clinical application. These findings indicate that apparent hippocampal sex differences largely reflect methodological choices rather than biology, while HVR captures consistent morphological variation related to brain aging that may have clinical utility.