Neurotrophic factors (NTFs), once known for their role in development, have recently been shown to contribute to the maintenance and plasticity of the adult nervous system. This knowledge has provoked hypotheses implicating NTFs in neurodegenerative conditions, particularly Alzheimer's disease (AD). Many of these hypotheses, however, fail to place the possibility of trophic factor dysfunction in the context of recent advances in the molecular pathogenesis of AD. Most notable has been the discovery of several genetic risk factors and three causative Alzheimer's genes. Genetic advances, in turn, have not yet shed much light on an important pathological feature of AD, synaptic loss. We propose here an hypothesis based on recent cell biological research that attempts to integrate findings in these areas. Our hypothesis states that AD pathogenesis results from disruption of cholesterol uptake and metabolism and that this in turn results in abnormal trafficking of membrane proteins critical to normal neuronal function and synaptic plasticity.