Rodent and cell models offer strong mechanistic proof: adiponectin administration lowers Aβ42 burden in AD mice, improves cognition, and partially restores glucose metabolism; resistin increases pro-inflammatory cytokines and small Aβ aggregates; leptin reduces Aβ plaques and tau phosphorylation while enhancing synaptic function, effects that are significantly blunted by obesity-induced dysfunction. Here, MAPT is linked to obesity due to melanocortin 4 receptor deficiency.