Although the levels of irisin and FNDC5 have been found to increase in CSF from aged individuals, they are decreased in Alzheimer’s disease (AD), whereas in mouse models of AD, both peripheral and central overexpression of FNDC5 and irisin enhances synaptic plasticity, diminishes glial activation, and improves cognition [262,263]. This evidence concerns the gene FNDC5 and early-onset autosomal dominant Alzheimer disease.