Dementia is a prevalent and, based on severity, disabling neurocognitive disorder that primarily affects people older than 65 years of age. There is an increasingly emerging need to identify specific markers of dementia for interventions before disease progression. Irisin is a myokine produced during exercise with multiple effects on various organs, including a neuroprotective role on brain. Here, we investigated the involvement of irisin in patients with dementia biologically classified according to the Amyloid-β-Tau-Neurodegeneration classification system. Serum and cerebrospinal fluid (CSF) levels of irisin were measured using ELISA assay in patients with Subjective Memory Complaint (SMC=20), Mild Cognitive Impairment (MCI=44), and Alzheimer’s Dementia (AD=82) to evaluate possible association with neuropsychological markers of AD. After enrollment of 146 subjects, a neuropsychological examination was performed using 18 tests including the Mini Mental State Examination (MMSE). Our results demonstrated that patients with AD had significantly reduced levels of irisin in both CSF and serum compared with SMC (p < 0.0001 and p= 0.0037, respectively). Positive correlations between irisin concentration in CSF and the MMSE were observed (p<0.0001). Interestingly, scores obtained from psychometric tests in memory, attention, executive, visuospatial, and language domains correlate positively with both CSF and serum irisin levels. These findings suggest that irisin may play a role in the cognitive decline associated with AD. Further investigation based on these results could lead to identify irisin as a biomarker for early detection of AD and it be a potential candidate of irisin-based therapy development for the prevention and treatment of AD.