The transmembrane protease complex γ‐secretase is a key enzyme in Alzheimer disease pathogenesis as it liberates the neurotoxic amyloid β‐peptide (Aβ); however, the mechanism of regulation of its activity in various cell types and subcellular compartments is largely unknown. Several γ‐secretase inhibitors have been developed, but none have been released due to side‐effects that appear to arise from reduced processing of Notch, one of many γ‐secretase substrates. Hence, it is desirable to specifically inhibit Aβ production. In our previous studies, we have identified several γ‐secretase‐associated proteins (GSAPs) from brain, which affect Aβ production without having any major effects on Notch processing. In the present study using detergent‐resistant membranes prepared from brain, we have identified four GSAPs that affect Aβ production to a greater extent than Notch processing. We evaluated the interaction between GSAPs and γ‐secretase in various cell types and their mRNA expression in various human organs. Using an in situ proximity ligation assay, we demonstrated that many GSAPs showed considerably greater interaction with γ‐secretase in neurons than in human embryonic kidney cells stably over‐expressing APP, and showed that several GSAPs are highly expressed in human brain. This study underscores the importance of studying protein‐protein interactions in relevant cell types, and suggests that reducing Aβ production by interfering with brain‐ or neuron‐specific γ‐secretase/GSAP interactions may reduce the risk of unwanted side‐effects associated with treatment of Alzheimer disease.