Purpose of review Apolipoprotein E (apoE) plays a pivotal role in lipid metabolism in the peripheral circulation and in the brain. This has been recognized for decades; however, the importance of the full spectrum of variation in the APOE gene has been less investigated. This review focusses on current progresses in this field with main focus on apoE in dyslipidemia and vascular disease. Recent findings Whereas e4 is the risk increasing allele for Alzheimer disease, e2 is associated with increased risk for age-related macular degeneration. Rare functional e2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but recent findings suggest a simultaneous high risk of age-related macular degeneration, in line with observations for the e2 allele. Summary ApoE plays an important and well established role in dyslipidemia, vascular disease, and dementia. Recent evidence from large general population studies now also suggests that apoE is involved in age-related macular degeneration. ApoE-targeted therapeutics are being developed for multiple purposes; this heralds a promising change in the approach to disease processes involving apoE. The different risk profile for dementia and age-related macular degeneration should, however, be kept in mind when developing drugs targeting mechanisms resembling these variants.