Both apolipoprotein E varepsilon4 allele (APOE varepsilon4) and neuropeptide Y (NPY) Pro(7)-variant have been reported to be associated with higher serum levels of total and LDL cholesterol. Since APOE varepsilon4 allele is also a major risk factor for the development of Alzheimer's disease (AD) and the genetic polymorphism of NPY has not previously been studied in dementing disorders, we have examined whether a novel polymorphism in a signal peptide of NPY gene is associated with AD alone or in combination with APOE varepsilon4. A total of 125 sporadic AD cases and 110 control individuals from Finland were genotyped for APOE and NPY genes using the polymerase chain reaction and restriction enzyme analysis. The APOE varepsilon4 allele frequency was significantly increased in the AD group compared with controls as expected. Instead, no significant differences were found between sporadic AD patients and controls either in the NPY genotype or allele frequencies or in combination with the APOE varepsilon4 allele. We conclude that APOE varepsilon4 allele represents a strong predictor of risk for AD.