In this review, we discuss insulin resistance in the context of prominent neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis) and summarize the potential molecular mechanisms regulating exercise-associated insulin resistance in neurodegenerative diseases, and contribute to the improvement and alleviation of these disorders. Here, INS is linked to amyotrophic lateral sclerosis.