For instance, many efforts were made to link exercise-induced increases in irisin to central effects such as the release of brain-derived neurotrophic factor (BDNF), synaptic plasticity, and neuronal survival with potential application in neurodegenerative diseases like Alzheimer’s disease (AD) or Parkinson’s disease.125–127 However, a crucial caveat of these efforts concerned the question whether irisin mobilized from skeletal muscle tissue was able to confer effects inside the CNS, i.e., whether peripheral irisin was able to cross the BBB. This evidence concerns the gene FNDC5 and early-onset autosomal dominant Alzheimer disease.