Functional and genetic studies suggest that insulin-degrading enzyme (IDE) may be a strong functional and positional candidate. As there is a lack of consensus in regards to the level and location of IDE association signals we aimed to clarify these discrepancies through genotyping 28 SNPs in a large case-control collective together with quantitative measures of cognitive ability (MMSE). Four SNPs (rs11187007, rs2149632_ide12, rs11187033, rs11187040) were found to be associated with AD (nominal p<0.01). Tests with MMSE scores adjusted for disease duration identified associations, with the most significant result for rs1999763 (nominal p=0.008). Similarly, different reconstructed IDE haplotypes were associated with AD and higher MMSE scores. The association signals are only borderline significant after adjustment for multiple testing, but add further evidence to previous published results on the association between IDE and AD or MMSE. A subgroup analysis indicated more prominent associations with AD in younger, and with MMSE in older patients. There may be two independent effects mediated by IDE variants, risk for AD and modification of disease progression.