The effect of the apolipoprotein E (APOE) epsilon 4 allele on age of onset was analyzed in two groups of families with early-onset Alzheimer's disease (AD), (1) Volga German (VG) kindreds, in which AD is caused by an unknown locus and (2) early-onset non-VG families showing evidence of linkage to chromosome 14. The epsilon 4 allele did not have a detectable effect on age of onset in either group. This finding suggests some forms of early-onset familial AD are not modifiable by APOE status, or that AD can be caused by APOE-independent pathways.