No association between Glu298Asp endothelial nitric oxide synthase polymorphism and Italian sporadic Alzheimer’s disease Roberto Monastero a , Angelo B. Cefalu ` b , Cecilia Camarda a , Carmela M. Buglino b , Marina Mannino a , Carlo M. Barbagallo b , Gianluca Lopez a , Lawrence K.C. Camarda a , Salvatore Travali c , Rosolino Camarda a, * , Maurizio R. Averna b a Department of Neurology and Rehabilitation, Centre for Aging Brain and Dementia, Institute of Neuropsychiatry, University of Palermo, Palermo, Italy b Department of Internal Medicine, University of Palermo, Via La Loggia 1, 90129 Palermo, Italy c Department of Biomedical Sciences, Section of Clinical Pathology and Molecular Oncology, University of Catania, Catania, Italy Received 11 October 2002; received in revised form 24 January 2003; accepted 6 February 2003 Abstract A great amount of evidence suggests that neuroinflammation may be a major pathogenetic mechanism in the pathophysiology of sporadic Alzheimer’s Disease (sAD). Recently, polymorphisms in the endothelial nitric oxide synthase (NOS3) gene have been associated to late onset Alzheimer’s Disease in a British population. However, other groups failed to replicate this finding in Asiatic and Caucasian populations. We conducted a case-control study including a clinically well-defined group of 149 sAD patients and 149 age and sex matched controls to test the association between NOS3 Glu298Asp polymorphism and sAD in an ethnically homogenous Italian population. All subjects were genotyped at NOS3 and apolipoprotein E. No significant difference was found in either allele or genotype frequencies between cases and controls, even after stratification for Apolipoprotein E4 carrier status. The NOS3 Glu298Asp polymorphism does not appear to influence the risk of developing sAD in an Italian population. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Alzheimer’s Disease; Nitric oxide synthase 3 (NOS3); Polymorphism; Apolipoprotein E; Case-control study Alzheimer’s Disease (AD) is the most common form of dementia in the elderly. The prevalence of AD rises exponentially with increasing age [7], thus it is considered as a major public health concern. Both genetic and environmental factors may contribute to the development of the disease. Most AD cases are sporadic, while less than 5% of them are familial with dominant autosomal fashion of inheritance [15]. Although only the apolipoprotein E gene (APOE) has been confirmed as genetic risk factor for sporadic AD (sAD) [3], the role of other candidate genes has been investigated. Several lines of evidence suggest a role of neuroin- flammation in AD pathogenesis. Inflammation is more evident in the brain areas mainly involved in AD (i.e. frontal and limbic neocortex) [1]. Further, inflammatory mediators are more expressed in proximity of amyloid deposits, where beta-amyloid (Ab) has been found to be associated with various acute phase proteins (i.e. complement component C1q, a1-ACT, a2- antichymotrypsin, a2-macroglobulin) [1]. These molecules bind Ab influencing its aggregation. Moreover, Ab activates the microglial release of flogistic mediators; this process seems to be modulated by Apolipoprotein E [1]. Several hallmarks of oxidative damage (i.e. glycation end products, free radicals) have been described in AD brains [1]. Free radicals could play a role in AD pathogenesis either leading to direct cellular injury or activating the transcription of proinflammatory genes [1]. Beta-amyloid can lead to a burst of superoxide radicals; superoxide and nitric oxide (NO) can form peroxynitrite, a noxius substance for the cells [1]. Finally, clinical and epidemiological studies suggest that conventional anti-inflammatory drugs could protect from AD, delaying the onset or slowing the progression of dementia [1,20]. 0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00210-6 Neuroscience Letters 341 (2003) 229–232 www.elsevier.com/locate/neulet * Corresponding author. Tel.: þ39-91-655-5112-20; fax: þ 39-91-655- 5113. E-mail address: rcamarda@neuro.unipa.it (R. Camarda).