Aberrations in protein folding, processing, and/or degradation are common features of neurodegenerative diseases, such as Alzheimer's disease (AD). Sodium 4-phenylbutyrate (PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. PBA acts as a chemical chaperone reducing the load of mutant or unfolded proteins during cellular stress. Previously, we reported that 5-week administration of PBA reinstated memory loss and dendritic spine densities in the Tg2576 mouse model of AD. In this study we reported that chronic administration of PBA, starting before the onset of disease symptoms (6 month-old) prevents age-related memory deficits in Tg2576 mice. The amelioration of the memory impairment is associated to a decrease in amyloid beta pathology and the glial fibrillary acidic protein (GFAP), suggesting that inflammation was reduced in PBA-treated animals. Together, the beneficial effects of PBA make it a promising agent for the prevention of AD.