Alzheimer's disease (AD) is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited. Over-activation of N-methyl-D-aspartate (NMDA) receptors, amyloid β (Aβ) aggregation, a decrease in cerebral blood flow (CBF), and downstream pathological events play important roles in the disease progression of AD. A novel memantine nitrate was found to inhibit Aβ accumulation, prevent neuronal and dendritic spine loss, and consequently attenuate cognitive deficits in APP/PS1 transgenic mice and in triple-transgenic

(3×Tg-AD) mice. In vitro, the compound could bind to and antagonize NMDA receptors, inhibit the calcium influx, and reverse the dysregulations of ERK and PI3K/Akt/GSK3β pathway, subsequently preventing glutamate-induced neuronal loss. In addition, the compound had favorable pharmacokinetics, blood-brain barrier penetration, and safety profiles in rats and beagle dogs.