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Analysis of Functional Polymorphisms of Metalloproteinase Genes in Persons With Vascular Dementia and Alzheimer's Disease

Laboratory of Vascular Biology and Genetics, ² Department of Medicine and Angiology, and ³ Department of Internal Medicine and Geriatrics, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy.
⁴ IRCCS Associazione Oasi Maria SS, Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.

Address correspondence to Roberto Pola, MD, PhD, Istituto di Medicina Interna e Geriatria, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, L.go A. Gemelli 8, 00168 Rome, Italy. E-mail: rob_pola{at}hotmail.com

Background. Vascular dementia (VAD) and Alzheimer's disease (AD) may share common neuropathological mechanisms. Matrix metalloproteinases (MMPs) may induce destruction of the extracellular matrix, neuronal dysfunction, and death. Increased expression of these molecules has been found in a number of neurological diseases, including cerebral ischemia and AD. Expression and activity of MMPs may be genetically influenced by common polymorphisms in the promoter regions of the corresponding genes. The purpose of this study was to evaluate whether functional polymorphisms of MMP genes are associated with dementia.

Methods. This is a cross-sectional study including a total of 599 individuals: 193 with VAD, 183 with AD, and 223 controls. Polymorphisms of the MMP-1, MMP-3, and MMP-9 genes were studied.

Results. MMP-1 2G2G, MMP-1 1G2G, MMP-3 5A5A, and MMP-9 TT genotypes were significantly and independently associated with VAD (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4–4.4, OR = 1.7, 95% CI, 1.0–2.7, OR = 2.9, 95% CI, 1.5–5.9, and OR = 6.8, 95% CI, 1.3–35.1, respectively). MMP-1 2G2G and MMP-3 5A5A genotypes were associated with increased risk of AD only in persons who carry the apolipoprotein E (APOE) 4 allele (OR = 6.0, 95% CI, 2.3–15.5, and OR = 14.3, 95% CI, 3.2–63.0, respectively). Interestingly, the odds of VAD and AD was further increased in persons concomitantly carrying more than one MMP gene variation, compared to individuals that only had one high-risk genotype.

Conclusions. Our study suggests that MMP gene polymorphisms are associated with VAD and AD, although these results need to be treated with caution until replicated. MMP genotypes may influence the risk of dementia and merit further investigation as potential genetic markers of disease.