The proteolytic cleavage of the transmembrane (TM) domain of the amyloid precursor protein (APP) releases amyloid-beta (A beta) peptides, which accumulation in the brain tissue is an early indicator of Alzheimer's disease. We used multiscale molecular dynamics simulations to investigate the stability of APP-TM dimer in realistic models of the synaptic plasma membrane (SPM). Between the two possible dimerization motifs proposed by NMR and EPR, namely G(709)XXXA(713) and G(700)XXXG(704)XXXG(708), our study revealed that the dimer promoted by the G(709)XXXA(713) motif is not stable in the SPM due to the competition with highly unsaturated lipids that constitute the SPM. Under the same conditions, the dimer promoted by the G(700)XXXG(704)XXXG(708) motif is instead the most stable species and likely the most biologically relevant. Independently of the dimerization state, both these motifs can be involved in the recruitment of cholesterol molecules.