OBJECTIVE: Obesity and type 2 diabetes are associated with an increase in the incidence and prevalence of Alzheimer's disease (AD) and an impaired cognitive function. Because peripheral blood mononuclear cells (MNC) express amyloid precursor protein (APP), the precursor of β-amyloid, which forms the pathognomonic plaques in the brain, we hypothesized that APP expression diminishes after the marked caloric restriction and weight loss associated with Roux-en-Y gastric bypass (RYGB) surgery. RESEARCH DESIGN AND METHODS: Fifteen type 2 diabetic patients with morbid obesity (body mass index, 52.1 ± 13 kg/m(2)) underwent RYGB, and the expression of inflammatory and AD-related genes was examined before and after 6 months in plasma and in MNC. RESULTS: Body mass index fell to 40.4 ± 11.1 kg/m(2) at 6 months after RYGB. There was a significant fall in plasma concentrations of glucose and insulin and in homeostasis model of assessment for insulin resistance. The expression of APP mRNA fell by 31 ± 9%, and that of protein fell by 36 ± 14%. In addition, there was a reduction in the expression of other AD-related genes including presinilin-2, ADAM-9, GSK-3β, PICALM, SORL-1, and clusterin (P < 0.05 for all). Additionally, the expression of c-Fos, a subunit of the proinflammatory transcription factor AP-1, was also suppressed after RYGB. These changes occurred in parallel with reductions in other proinflammatory mediators including C-reactive protein and monocyte chemoattractant protein-1. CONCLUSIONS: Thus, the reversal of the proinflammatory state of obesity is associated with a concomitant reduction in the expression of APP and other AD-related genes in MNC. We conclude that obesity and caloric intake modulate the expression of APP in MNC. If indeed, this effect also occurs in the brain, this may have implications for the pathogenesis and the treatment of AD. It is relevant that cognitive function has been shown to improve with weight loss following bariatric surgery.