Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of DS is complex and includes development of Alzheimer disease (AD). The accumulation of amyloid beta (Aβ)-peptide in DS brain can be observed as early as 8–12 years of age. Interestingly, the incidence of dementia typically does not increase until adults with DS are over the age 50 years. Within this context, it has been suggested that DS may serve as a model for the study the early molecular events in the pathogenesis and progression of AD neuropathology. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of AD-like dementia. In particular we focused our work on the evaluation of PI3K/Akt/mTOR axis in the frontal cortex from DS subjects (under the age of 40 ) and DS with AD compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis control several key pathways involved in DS neuropathology and progression to AD and, if aberrantly regulated, affect Aβ deposition and tau phosphorylation.