The multifactorial causes impacting the risk of developing sporadic forms of Alzheimer's disease (AD) remain to date poorly understood. Epidemiologic studies in humans and research in rodents have suggested that hypothyroidism could participate in the etiology of AD. Recently, we reported that adult-onset hypothyroidism in rats favors β-amyloid peptide production in the hippocampus. Here, using the same hypothyroidism model with the antithyroid molecule propythiouracyl, we further explored AD-related features, dysfunctional cell-signaling mechanisms and hippocampal-dependent learning and memory. In vivo MRI revealed a progressive decrease in cerebral volume of propythiouracyl-treated rats. In the hippocampus, hypothyroidism resulted in Tau hyperphosphorylation and increases in several pro-inflammatory cytokines. These modifications were associated with impaired spatial memory and reduced hippocampal expression of signaling molecules important for synaptic plasticity and memory, including neurogranin, CaMKII, ERK, GSK3β, CREB and expression of the transcription factor EGR1/Zif268. These data strengthen the idea that hypothyroidism represents an important factor influencing the risk for developing sporadic forms of AD. © 2014 Wiley Periodicals, Inc.