TOMM40 '523' poly-T variants alter cholesterol and triglyceride levels in sex- and tissue-specific ways in humanised mice

A preprint deposited on bioRxiv on 10 June 2026 investigates the functional consequences of TOMM40 '523' poly-T variants — genetic differences in an intronic repeat within the TOMM40 gene — in an APOE-TOMM40 humanised mouse model. Both APOE and TOMM40 reside at a locus strongly associated with Alzheimer's disease (AD) risk, though the precise contribution of TOMM40 variants, distinct from APOE, has remained poorly characterised mechanistically.

Prior work from the same group had shown that suppression of Tomm40 in mice increased brain cholesterol content, a recognised AD risk factor. The present study extended this by comparing brain and peripheral tissue lipid profiles in mice carrying the Short (S) versus Very Long (VL) '523' poly-T variants, hypothesising that these genotypes may alter cholesterol and triglyceride metabolism differentially. The data indicate that the variants do produce measurable differences in lipid content, and that these effects are both sex-specific and tissue-specific — a finding with implications for understanding why genetic associations at this locus show heterogeneity across demographic groups in human studies.

The work is a preprint and awaits peer review. The mouse model approach, whilst informative, involves important differences from human physiology that limit direct extrapolation.