Associations of Blood Lipid Traits with Cognitive-Related Outcomes and Their Sensitivity to APOE-Region Instrumental Variables: A Mendelian Randomization and Colocalization Study

Background: Neurodegenerative, cognitive, and cerebrovascular outcomes are central to brain health. Previous studies have linked blood lipid traits to these outcomes, but associations differ across lipid components and outcome types. However, the contribution of APOE remains unclear. We compared these patterns, quantified their dependence on APOE, and identified shared signals outside the region. Methods: We used two-sample Mendelian randomization to examine associations between four blood lipid traits from the Global Lipids Genetics Consortium and seven cognitive-related outcomes from FinnGen R11, followed by regional colocalization analysis. We stratified instruments into APOE and non-APOE regions and compared region-specific estimates. Robust non-APOE signals supported by colocalization were further assessed using UK Biobank BIG40 imaging-derived phenotypes. Results: Genetically predicted high-density lipoprotein cholesterol (HDL-C) was inversely associated with the FinnGen composite endpoint of stroke excluding SAH and with cerebrovascular sequelae. Total cholesterol (TC) was positively associated with Alzheimer disease (AD) and dementia.Colocalization supported shared regional signals for TC-AD near TSBP1/TSBP1-AS1, LDL-C-AD within the extended HLA region, and HDL-C-stroke excluding SAH near ILRUN. Estimates for AD, dementia, and memory loss were sensitive to APOE-region exclusion, whereas the HDL-C-stroke estimate was materially unchanged. In separate exploratory analyses of 13 BIG40 imaging phenotypes, HDL-C colocalized with left lateral and right medial orbitofrontal gray–white matter intensity contrast. Conclusions: Lipid-related genetic effects differ across brain outcomes. AD and dementia estimates were sensitive to APOE-region instruments, whereas the HDL-C-associated signal for the composite stroke endpoint persisted after their exclusion. Exploratory imaging results nominate orbitofrontal intensity contrast as an HDL-C correlate.