Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

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Milk promotes activity in the kappa opioid system of the rat fetus and reduced responsiveness in a behavioral bioassay of cutaneous sensitivity. In this study, E20 rat fetuses were presented with an artificial nipple (CS) and intraoral infusions of milk (US) to condition opioid activity. Paired presentations of the CS and US resulted in conditioned changes in perioral cutaneous sensitivity, which was not evident in groups exposed to the CS alone, US alone, or explicitly unpaired presentations of US and CS. Selective opioid antagonists administered between conditioning and testing revealed that reexposure to the nipple resulted in activation of the endogenous opioid system. The nipple promoted activity at mu, not kappa, opioid receptors. Conditioned opioid activity to an artificial nipple in the fetus, which lacks experience with milk or other suckling stimuli, implies that conditioned changes in the endogenous opioid system of the newborn rat may develop quickly during the first suckling episodes.

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Classical conditioning in the rat fetus (Embryonic Day 20) was investigated in 4 experiments. Reexposure to a conditioned stimulus (CS; sucrose), after 3 pairings with an unconditioned stimulus (US; milk), reduced fetal facial wiping in a bioassay of perioral cutaneous responsiveness. Reduced responsiveness was evident only in subjects that received paired presentations of the CS and US and cannot be attributed to habituation, sensitization to the CS, or protracted effects of US exposure during conditioning trials. Fetuses attended to the chemosensory, not the tactile, qualities of the sucrose infusion during CS reexposure. Changes in fetal responsiveness resulted from conditioned activity in the endogenous opioid system, specifically at mu opioid receptors. These data confirm that the rat fetus is capable of exhibiting a conditioned opioid response in utero.