Abstract Polymorphisms affecting the expression of matrix metalloproteinases (MMPs), i.e. proteolytic enzymes that degrade intercellular material, have been found at position −1607 (1G/2G) in MMP1 and at −1171 (5A/6A) in MMP3. Interestingly, elevated levels of MMP1 and MMP3 have been observed in the brains of Alzheimer’s disease (AD) patients and those of tissue inhibitors of MMPs in the cerebrospinal fluid of AD and Parkinson’s disease (PD) patients, suggesting a role for MMPs in these disorders. The aim was to investigate a possible association between the afore-mentioned MMP1 and MMP3 polymorphisms and the risk of developing AD or PD. The polymorphisms were genotyped in 97 AD, 52 PD and 101 control patients. We found an interaction between MMP3*5A and APOE ε4 alleles ( P < 0.0001) which increases the risk of AD (OR: 23.7, 95% CI: 5.8–144.9, P < 0.0001) compared to those who possess neither MMP3*5A nor APOE ε4. In conclusion, our finding suggests that the MMP3 gene, especially together with APOE ε4, may contribute to the development of AD.