Insulin degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid peptide implicated in Alzheimer's disease (AD). We reexamined data on five previously reported IDE polymorphisms stratifying the analysis by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele. Three IDE variants were associated with AD within epsilon4-negative subjects (genotype exact test P-values < or =0.02). A haplotype containing the minor variant at each of these sites represented an estimated 4.2% of case haplotypes versus 12.3% of control haplotypes among epsilon4-negative subjects. Lack of this minor haplotype may be predictive of AD, potentially explaining some fraction of disease within subjects without the APOE epsilon4 risk allele. Confirmation of this finding with a larger sample of cases and controls is warranted.