TOMM40 genetic variants show sex-specific effects on brain cholesterol and Alzheimer's biomarkers in mice
A new mouse study found that a specific 'Short' variant of the TOMM40 '523' poly-T gene sequence is associated with higher brain cholesterol, triglycerides, and amyloid-beta 42 levels compared to the 'Very Long' variant, but only in male mice. Researchers used a humanized mouse model carrying the full human APOE3-TOMM40 genetic locus to isolate the effects of two common TOMM40 genotypes. The findings suggest TOMM40 variants may contribute to Alzheimer's disease risk through a lipid-metabolism pathway, offering a potential mechanistic explanation for previously observed genetic associations.
Researchers publishing on bioRxiv investigated how two common variants of the TOMM40 '523' poly-T sequence — Short (S/S) and Very Long (VL/VL) — affect lipid levels in brain, liver, and white adipose tissue using a humanized mouse model containing the entire human APOE3-TOMM40 locus. Male mice carrying the S/S genotype showed significantly elevated brain cholesterol and triglyceride levels compared to VL/VL carriers, and also had greater brain content of amyloid-beta 42, a key Alzheimer's disease biomarker. These lipid differences were mirrored in white adipose tissue but were largely absent in the liver, where only a trend toward higher triglycerides in VL/VL mice was observed in a sex- and age-dependent manner. Notably, female mice did not exhibit the same brain lipid or amyloid-beta differences, indicating a strong sex-specific component to the genotype's effects. The study builds on prior work showing that suppression of Tomm40 in mice raises brain cholesterol, and together the results point to a plausible biological pathway by which TOMM40 variants could modulate Alzheimer's disease risk through altered lipid metabolism.
What's missing
This is a preprint that has not yet undergone peer review, so findings should be considered preliminary. The study does not establish causality in humans, and it is unclear whether the sex-specific effects observed in mice translate to human populations. The molecular mechanism by which the poly-T length difference in TOMM40 alters lipid metabolism remains unexplained. The study also does not address tau biomarker differences in detail despite mentioning tau measurement in the methods.
What different sources said
- bioRxivCenter
TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model
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