Sporadic Alzheimer's disease is a polygenic disease and the relation between many genetic risk factors and the development of Alzheimer's disease has been controversial. Accumulation of amyloid β-protein (Aβ) in the brain is the neuropathological hallmark and thought to be a key event in the upstream stage of pathological cascade of the disease. Although increased production of Aβ is established in the pathogenesis of familial Alzheimer's disease due to mutations in presenilin 1, 2, and amyloid β-protein precursor genes, there is no evidence of up regulated synthesis of Aβ in the brains of patients with sporadic Alzheimer's disease. In addition, aging is the most major risk factor for the disease. These findings suggest the possibility that reduction of the catabolic system of Aβ due to aging causes the formation of senile plaques in sporadic disease. Therefore, proteolytic enzymes of Aβ might be related to the development of sporadic Alzheimer's disease.

One of the enzymes responsible for the degradation of Aβ is neprilysin (NEP).1 This is a membrane bound metallopeptidase which is widely expressed in many tissues including the CNS. It cleaves Aβ 1–42 between amino acids 9 and 10 and between amino acids 37 and 38.2 Reduced mRNA and protein concentrations of NEP in the brain from patients with Alzheimer's disease were reported, suggesting that low concentrations of NEP contributed to the accumulation of Aβ.3 Recent investigation showed that NEP inhibitor infusion into the brain resulted in increased deposition of Aβ, indicating that NEP regulates proteolytic catabolism of Aβ in vivo.2 There is a dinucleotide repeat polymorphism in the 5′ region of the NEP gene. A lower molecular weight allele of NEP gene polymorphism is associated …