Abstract To better understand how sleep/wake dysregulation affects Alzheimer’s disease (AD) we compared the cerebrospinal fluid (CSF) orexin and histamine levels from early to late phases of 82 patients with Alzheimer’s process including 41 probable AD with high level of evidence and 41 MCI due to AD (i.e 27 MCI due to AD-high likelihood and 14 MCI due to AD-intermediate likelihood) according to the NIA diagnosis criteria guidelines, 24 other neurological disorders (OND) and 24 controls. We determined the relationships between these biomarkers, the CSF amyloid-β42 , total-tau, phosphorylated-tau (p-tau) concentrations and the sleep profile based on clinical interview and sleep validated questionnaires (n=86). CSF orexin-A, but not histamine/tele-methylhistamine (HA/t-MHA) levels were higher in MCI due to AD and AD than OND and controls (p=0.0003). CSF orexin-A correlated to CSF amyloid-β42 within the Alzheimer process (p=0.03). This relation is not explained by age, gender, MMSE, total-tau, p-tau, histamine nor sleep parameters. Nighttime sleep duration was longer in MCI due to AD and AD patients than controls (p=0.004). In MCI due to AD, nighttime sleep duration was negatively correlated with CSF amyloid-β42 level and MMSE. To conclude, CSF orexin-A was upregulated in AD and correlated with amyloid-β42 level. No CSF HA and t-HMA level differences were observed within the Alzheimer’s process. Lower levels of CSF amyloid-β42 were associated with longer night-sleep duration in MCI due to AD patients. Our data suggested a change in the sleep-wake pattern at an early stage of the disease that needs further investigation to better understand the mechanistic interplay between sleep and Alzheimer.