A study initiated by Lourenco and collaborators found that the level of irisin is significantly reduced in the hippocampal slices of patients with Alzheimer’s disease, and in AD animal models, blocking Irisin/FNDC5 can weaken the protective effect of exercise on synaptic plasticity and memory impairment caused by AD; interestingly, increasing the level of irisin/FNDC5 in the brain can rescue this defect in AD mice (Lourenco et al., 2019). Here, FNDC5 is linked to early-onset autosomal dominant Alzheimer disease.