Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, ie, amyloid-β 1-42 (Aβ 1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ 1-40, Aβ 1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ 1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ 1-42/Aβ 1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ 1-42/t-tau and Aβ 1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ 1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, r S=− 0.71, p< 0.0001). Survival analysis showed that 81% of MCI with a low Aβ 1-42/p-tau ratio (< 1372) progressed to AD. The best model of logistic regression analysis retained Aβ 1-42 and p-tau (sensitivity 75%, 95% CI: 70–80%; specificity 96%, 95% CI: 94–98%). We can conclude that Aβ 1-42 and p-tau reliably predict conversion to AD in MCI patients.