Passive and voluntary exercise combined with 40 Hz acousto-optic stimulation significantly increased BrdU+ newborn cells and DCX+ immature neurons in the hippocampus of AD mice (p < 0.001), promoting differentiation into NeuN+ mature neurons and GFAP+ astrocytes (p < 0.0001). The intervention improved cognitive function (p < 0.05), reduced anxiety-and depression-like behaviors (p < 0.01), activated the BDNF/TrkB/Akt pathway, and regulated metabolic pathways. Here, BDNF is linked to major depressive disorder.