Dementia is an increasingly prevalent disorder as the world population ages, with Alzheimer disease the most common cause. Twin studies find concordance to be substantially higher among monozygotic as compared with dizygotic twin pairs. While a few genes have been identified that are responsible for early-onset Alzheimer disease, they account for well under 5 % of all cases. Among susceptibility genes for Alzheimer disease identified by association studies, population attributable fraction for the most prominent of these—apolipoprotein E—is estimated to be about 25 %, whereas other genes at best predict another 20 %. There are few strong environmental risk or protective factors, with vascular risks the best established, although with mechanisms still not fully understood. It seems likely that clusters of risk alleles, interactions between risk alleles and environmental exposures, and epigenetic mechanisms play a role in explaining Alzheimer disease, with different combinations of influences culminating in the observed pathophysiology. In particular, environmental exposures early in life could lead to deleterious changes in gene expression in late life.