Hypothetical model depicting the mechanisms by which caspase-9 can lead to alteration typical of neurodegenerative disorders: memory loss, dystrophic neurites and neuronal loss. A and B, Previous work from our laboratory has shown that due to loss of BRI2 protein (loss of function model), APP processing is increased during synaptic transmission and memory acquisition in FDD leading to increased production of sAPPβ and β-CTF, leading to synaptic/memory deficits. We now show that caspase-9 is activated, via and unknown mechanisms, in FDD. This increased caspase-9 activation leads to synaptic/memory deficits via a yet to be defined mechanism. In C, we postulate a hypothetical pathway in which caspase-9 is activated by β-CTF and/or sAPPβ, perhaps via interaction with a membrane-bound receptor, sAPPβ-R, such as DR6 . Whether sAPPα and/or α-CTF can also trigger this pathway remains to be determined. In this context, it is worth noting that BRI2 also inhibits α-secretase processing of APP [4, 28, 29]. Further studies will be needed to assess the role of the α-processing pathway of APP in dementia. D and E, Aberrant activation of caspase-9 in synaptosomes causes functional impairments leading to synaptic plasticity and memory acquisition deficits, with no noticeable anatomical changes. In F, we hypothesize that repetitive cycles of high caspase-9 activity can lead to dystrophy of neurites. Prolonged and sustained activation of caspase-9 increases the probability that in any given neuron caspase-9 activity may leak to the cell body and prompt the demise of the neuron.