The cellular mechanism of neuronal apoptosis in Alzheimer's disease (AD) is poorly understood. Many hypotheses have been put fourth to explain the underlying reason for neuro-degeneration in AD. Here, it is demonstrated that all neurotrophins that activated p75, without co-activation of the relevant Trk co-receptor, mediated apoptosis in hippocampal neurons. Thus, proneurotrophins and amyloid beta peptides (Abeta) can induce p75-mediated apoptosis in hippocampal neurons since they do not bind or activate Trk receptors. Based on the combined effects of aging, proneurotrophins, neurotrophins, and Abeta, a novel model of pathogenesis in AD is proposed. This mini-review explores the ligand and cell type based signaling pathways of the neurotrophin receptor p75 relating to Alzheimer's disease.