The scenario is even more severe among patients with neurodegenerative disorders such as Alzheimer's disease (AD), where circadian misalignment is more extreme due to mechanisms related to the neurodegeneration process itself (loss of the circadian “pace-maker” vasoactive intestinal peptide-expressing neurons in the CNS, direct effects of amyloid on clock genes expressions and other hypothesized factors) (291), to virtually absent exposition to external synchronizers and to manifold medication side effects (292). Here, CLOCK is linked to Alzheimer disease.