Association between Alzheimer's disease and the NOS3 gene

Alzheimer's disease (AD) is the most common form of neurodegenerative disor der of later life. Genetic studies have demonstrated that the apolipoprotei n E (ApoE) gene is an important susceptibility locus; however, other enviro nmental and genetic factors operating alone or in combination with ApoE mus t also be involved. Among candidate genes that may contribute to this resid ual risk is the endothelial nitric oxide synthase (NOS3) gene. NO release f rom vascular endothelium accounts in large pan for endothelium-derived rela xing factor bioactivity. Abnormalities of cerebral small vessels occur earl y in AD, and it has been demonstrated recently that beta-amyloid interacts with endothelial cells in blood vessels to produce an excess of superoxide radicals. We have genotyped 122 cases of early-onset AD (EOAD) and 317 case s of late-onset AD (LOAD) as well as 392 controls for a common structural p olymorphism Glu/Asp at codon 298 in the NOS3 gene. We find a highly signifi cant enrichment for Glu/Glu homozygotes in LOAD compared with controls. The effect appears to be independent of ApoE status. NOS3 may be a new genetic risk factor for LOAD.