The causes of the sporadic form of Alzheimer's disease (AD) are unknown. In this study we show that copper (Cu) critically regulates low-density lipoprotein receptor-related protein 1-mediated Aβ clearance across the blood-brain barrier (BBB) in normal mice. Faulty Aβ clearance across the BBB due to increased Cu levels in the aging brain vessels may lead to accumulation of neurotoxic Aβ in brains. In a mouse model of AD low levels of Cu also influences Aβ production and neuroinflammation. Our study suggests that Cu may also increase the severity of AD.