Hyperspherical geometry positions the lipidome as a partly independent axis of human brain organization

Abstract The brain’s transcriptome is well mapped, but the spatial organization of lipids—over half of brain dry mass—remains poorly defined. We profiled lipidomic (419 species) and transcriptomic (15,013 genes) signatures from 35 anatomically defined regions in four healthy adult donors, measured from the same tissue samples. Both modalities recapitulate major neuroanatomical divisions, yet the lipidome shows distinctive features: a pronounced white–gray asymmetry, a smooth neocortical rostrocaudal gradient, and limbic-specific lipid clusters absent in transcriptomic space. Using regression against gene-expression principal components and two null models (random and anatomy-aware), we define three data-driven classes of lipid–gene relationships: Synchronizers (10%) tightly coupled to gene programs, Anchors (67%) predictable at levels expected from gross anatomy and cell-type composition, and Drifters (23%) largely transcription-independent. A simple geometric framework unifies these patterns: after centering and normalization, molecular profiles lie on a hypersphere where two interpretable coordinates—polar latitude relative to transcriptome-defined white/gray poles and nearest-gene angular distance—jointly index coupling; an analytical null quantitatively explains the observed scaling. Key effects are robust in leave-one-donor-out analyses and position the lipidome as a partly independent organizational axis of the human brain. Broadly, our results provide an interpretable geometric framework for multi-omics integration, supported by an interactive platform. Competing Interest Statement The authors have declared no competing interest.