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Accumulation of the β‐amyloid peptide (Aβ) in the brain is a major pathological hallmark of Alzheimer's disease (AD), leading to synaptic dysfunction, neuronal death, and memory impairment. The levels of neprilysin, a major Aβ‐degrading enzyme, are decreased in AD brains and during aging. Because neprilysin cleaves Aβ in vivo, its down‐regulation may contribute to the pathophysiology of AD. The aim of this study was to assess the consequences of neprilysin deficiency on accumulation of murine Aβ in brains and associated pathologies in vivo by investigating neprilysin‐deficient mice on biochemical, morphological, and behavioral levels. Aged neprilysin‐deficient mice expressed physiological amyloid precursor protein (APP) levels and exhibited elevated brain Aβ concentrations and amyloid‐like deposits in addition to signs of neuronal degeneration in their brains. Behaviorally, neprilysin‐deficient mice …