Using a transgenic mouse model carrying five human AD-linked mutations (5xFAD), we found that obesity induced by high-fat diet accelerated the onset of disease manifestations, including recognition-memory impairment, which was associated with increased splenic levels of exhausted CD4+ T effector memory cells, CD4+FOXP3+ regulatory T cells, and increased blood levels of the metabolite N-acetylneuraminic acid. Here, CD4 is linked to obesity due to melanocortin 4 receptor deficiency.