Cerebral accumulation of beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). Several proteases were shown to hydrolyze Abeta in vitro or in cell-based assays, and are likely candidates for a role in Abeta clearance in brain. Previous reports suggest that matrix metalloproteinases (MMPs) could be involved in such a mechanism. A functional polymorphism at position -1171 (5A/6A) in MMP-3 was examined in two independent studies to investigate the impact of this polymorphism on the risk of developing dementia. We found that subjects APOE epsilon4 non-carriers and 6A/6A homozygous for the MMP-3 polymorphism were at increased risk of dementia. Our findings support the hypothesis that MMPs may influence the risk of dementia.