Age-dependent neurodegeneration in Alzheimer disease (AD) may be viewed as a complex interaction among: (i) susceptibility polymorphisms, (ii) somatic mutations or alterations that occur over extended periods of time, and (iii) environmental interactions. Putative “sporadic” diseases appear to have a much stronger genetic component than had been considered previously. For example, in Alzheimer disease, apolipoprotein E is a major susceptibility locus that accounts for approximately half the heritability. Specific APOE genotypes are associated with different relative risks and age of onset distributions. Disease may be expressed as a confluence of several genetic risk factors, superimposed upon the age-dependent increments of somatic mitochondrial mutations, and environmental determinants such as head injury, stroke, or hypoxia. A matrix involving each of these complex factors may influence the age of onset of AD in a particular individual. With careful clinically based family and epidemiological studies, it is now possible to tease out the relevant genetic contributions from the confluence of other factors leading to complex disease affecting specific sets of neurons. The highly intricate maze of contributing factors provides many potential unanticipated opportunities to design rational therapeutic and preventative strategies.