The ε4 allele of the apolipoprotein E (APOE) gene is a strong risk factor for developing late-onset Alzheimer’s disease (LOAD), accounting for about half of the genetic component of the disease risk. Recent investigations into the mechanisms by which APOE4 contributes to the pathology of LOAD is offering new perspectives on how the disease may be treated in the future, and even though further research is needed before any such drugs will be made available, we may see the emergence of strategies for genotype-specific prevention and therapy. Current efforts are focused on how apolipoprotein E isoforms affect different aspects of the disease process, including the production and clearance of amyloid-β peptide, amyloid neurotoxicity, tangle formation, cholesterol homeostasis, and synaptic plasticity and repair. Since carrier status at present offers no benefits in terms of more accurate prognosis or better therapy, genotyping is discouraged for all other purposes than research, and there are concerns about the mental health of susceptible individuals receiving discouraging results. There are ethnical and geographical variations in the distribution of the APOE4 allele and in its association with LOAD. This, along with the fact that the APOE4 allele is neither sufficient nor necessary for the development of LOAD, prompts us to think that we are only beginning to get a grasp on how to counteract this leading cause of dementia, in a world where demographics are presenting us with more care demanding elderly than ever before.