Cholesterol (CH) and oxysterols have been consistently implicated in brain aging, Alzheimer’s disease (AD) and otherhuman neurodegenerative conditions, althoughthe mechanisms underlying these relationships remain poorly understood. Heme oxygenase-1 (HO-1) is a highly-inducible stress protein responsible for the catabolism of heme to free iron, carbon monoxide (CO) and biliverdin/bilirubin. HO-1 mRNA and protein levels are augmented in Alzheimer-diseased neural tissues where they may promote pathological iron deposition and oxidative mitochondrial damage characteristic of this disorder. Here, we review evidence derived from cultured rat astroglia, post-mortem human AD brain samples, novel GFAP. HMOX1 transgenic mice and a triple transgenic AD mouse model (3xTg-AD) implicating HO-1 as a pivotal transducer of noxious ambient stimuli into abnormal patterns of brain sterol/oxysterol homeostasis germane to the pathogenesis of AD and other aging-related neurodegenerative disorders.