Physical exercise has a well-recognized defensive role against age-associated neurodegeneration [115], and senescence-accelerated prone mice (SAMP-10 mice) subjected to a program of passive motor exercise showed a selective increase in irisin expression in brain areas, such as the hippocampus and medial prefrontal cortex [134], which play a critical function in AD-associated cognitive decline. Here, FNDC5 is linked to Alzheimer disease.