The adipocyte plasma membrane-associated protein APMAP is expressed in the brain where it associates with γ-secretase, a protease responsible for the generation of the amyloid-β peptides (Aβ) implicated in the pathogenesis of Alzheimer's disease (AD). In this study, behavioral investigations revealed spatial learning and memory deficiencies in our newly generated mouse line lacking the protein APMAP. In a mouse model of AD, the constitutive deletion of APMAP worsened the spatial memory phenotype and led to increased Aβ production and deposition into senile plaques. To investigate at the molecular level the neurobiological functions of APMAP (memory and Aβ formation) and a possible link with the pathological hallmarks of AD (memory impairment and Aβ pathology), we next developed a procedure for the high-grade purification of cellular APMAP protein complexes. The biochemical characterization of these complexes revealed a series of new APMAP interactomers. Among these, the heat shock protein HSPA1A and the cation-dependent mannose-6-phosphate receptor (CD-M6PR) negatively regulated APP processing and Aβ production, while clusterin, calnexin, arginase-1, PTGFRN and the cation-independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) positively regulated APP and Aβ production. Several of the newly identified APMAP interactomers contribute to the autophagy-lysosome system, further supporting an emergent agreement that this pathway can modulate APP metabolism and Aβ generation. Importantly, we have also demonstrated increased alternative splicing of APMAP and lowered levels of the Aβ controllers HSPA1A and CD-M6PR in human brains from neuropathologically verified AD cases.