A link between cholesterol and Alzheimer's disease (AD) had been suggested. Hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) is the rate limiting enzyme in the synthesis of cholesterol. A single nucleotide polymorphism (SNP) in the promoter of this gene, never described in Italian AD population, was investigated in case-control studies. Genotype distribution and allele frequency in two groups of AD patients and non demented controls were investigated. A cohort of AD patients were also followed up for 2 years, cognitive performances recorded and a possible influence of this SNP on the disease progression was tested. The CC genotype of the HMGCR gene was associated with a reduced risk of AD. Conversely the A allele of this polymorphism was over represented in AD patients. The presence of the A allele was also associated with an accelerated cognitive deterioration in AD patients followed up for 2 years. However, transfection experiments showed that this polymorphism did not directly influence functional activity in luciferase reporter gene assays. This polymorphism of the HMGCR gene appears to be linked to both AD risk and disease progression. Present findings reinforce the notion that abnormal regulation of cholesterol metabolism is a key factor in the pathogenesis of the disease.