Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia in the elderly, affecting almost 44 million people worldwide. Despite decades of research, genetic factors that predispose individuals to LOAD are not clearly understood. With a growing elderly population in the U.S. and many other developed countries, there is an urgent need for precise prognostic biomarkers and viable treatment options. Apart from advanced age, variants in the apolipoprotein E (APOE) gene are a strong predictor of disease risk. Those who carry the ε4 variant have a higher risk of developing Alzheimer’s, while those who carry a different variant, ɛ2, are typically protected. Surprisingly, many individuals do not conform to these rules—a puzzle that has confounded researchers. Some people with APOEɛ4 remain disease-free while some APOEɛ2 carriers develop the disease.