The aim of this study was to evaluate the effect of cognitive reserve (CR), in progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and Alzheimer's disease (AD). For this purpose, we followed up 263 patients (154 SCD; 109 MCI) for a mean time of 7years. CR was assessed by the Test di Intelligenza Breve (TIB), functionally equivalent to the National Adult Reading Test. High CR resulted as a protective factor for progression from SCD to MCI. Age at conversion to MCI was delayed 9years on average in SCD with high CR with respect to SCD with low CR. On the contrary, high CR resulted as a risk factor for progression from MCI to AD dementia only in APOE ε4 carriers. Conversion time from MCI to AD dementia was 3years shorter in ε4 carriers with high CR than subjects with low CR and ε4 non-carriers with high CR. Consistent with the CR hypothesis, our results showed that higher levels of CR protect against the earliest clinical manifestations of AD. In line with the previous researches, we found an interaction between CR and APOE in progression from MCI to AD dementia.