We evaluated the effect of Acetyl-cholinesterase-inhibitors (AChEIs) on cognitive decline and overall survival in a large sample of older patients with late onset Alzheimer's disease (LOAD), vascular dementia (VD) or Lewy body disease (LBD) from a real world setting. Patients with dementia enrolled between 2005 and 2020 by the "Alzheimer's Disease Research Centers" were analysed; the mean follow-up period was 7.9 years. A 1:1 propensity score matching was performed generating a cohort of 1.572 patients (786 treated AChEIs + and 786 not treated AChEIs- with AChEIs. The MMSE score was almost stable during the first 6 years of follow up in AChEIs + and then declined, while in AChEIs- it progressively declined so that at the end of follow-up (13.6 years) the average decrease in MMSE was 10.8 points in AChEIs- compared with 5.4 points in AChEIs + (p < 0.001). This trend was driven by LOAD (Δ-MMSE:-10.8 vs. -5.7 points; p < 0.001), although a similar effect was observed in VD (Δ-MMSE:-11.6 vs. -8.8; p < 0.001). No effect on cognitive status was found in LBD. At multivariate Cox regression analysis (adjusted for age, gender, dependency level and depression) a strong association between AChEIs therapy and lower all-cause mortality was observed (H.R.:0.59; 95%CI: 0.53-0.66); this was confirmed also in analyses separately conducted in LOAD, VD and LBD. Among older people with dementia, treatment with AChEIs was associated with a slower cognitive decline and with reduced mortality, after a mean follow-up of almost eight years. Our data support the effectiveness of AChEIs in older patients affected by these types of dementia.