A growing number of studies on mouse models of Alzheimer's disease (AD) and AD patients recently focused the attention on the neuroprotective effects of irisin, a myokine released by muscles upon exercise. Based on these findings, in the present study we aimed to investigate, in a large cohort of AD patients, the levels of irisin in the cerebrospinal fluid (CSF) and plasma, and their correlations with disease biomarkers. Biological samples were obtained from patients with Alzheimer's dementia (n=82), mild cognitive impairment (n=44) and subjective memory complaint (n=20) biologically characterized according to the recent amyloid/tau/neurodegeneration scheme of the National Institute of Age-Alzheimer’s Association. Irisin levels were correlated with fluid and clinical AD biomarkers [CSF Aβ 1-42 (Aβ42), hyperphosphorylated tau (p-tau), and total tau (t-tau), and Clinical Dementia Rating scale Sum of Boxes (CDR-SOB)]. Possible sex interactions with irisin in the CSF and plasma of AD patients were also evaluated.Our results evidenced that CSF irisin was reduced in AD dementia patients (p<0.0001), with lower levels in female patients. Moreover, CSF irisin correlated positively with Aβ42 in both female (r=0.379, p<0.001) and male (r=0.262, p<0.05) and negatively with CDR-SOB (r=-0.234, p<0.05) only in female patients. A negative trend was also observed between CSF irisin and t-tau levels in all patients (r=-0.144, p=0.082) and in the female subgroup (r=-0.189, p=0.084). Our results demonstrate the relationship between irisin levels and biomarkers of AD pathology, especially in females. Furthermore, our findings offer interesting perspectives toward the use of irisin as a biomarker of AD-continuum.