Although current research on brain aging is dominated by Alzheimer's disease (AD), many other brain changes arise during middle age in humans and in rodent models that are independent of AD-like neurodegeneration. Differences and continuities between normal and pathological aspects of neuronal aging reveal the relative contributions and interactions of genetic and environmental factors. Apolipoprotein E alleles might be prototypes for genetic polymorphisms associated with functional changes that arise during middle age. Mice are valuable models for these aspects of aging because most genotypes show little neurodegeneration, and none accumulate beta-amyloid unless human transgenes are introduced. As further human genes are found to modify normal and pathological neuronal aging, this zoo of aging-animal variants will facilitate analysis both of pathways of age-related neuronal dysfunction and of environmental influences on these pathways.