Increased fructose consumption is among bad nutritional habits that contribute to in￾creased incidence of neurodegenerative diseases. We proposed that coffee, the most popular beverage worldwide, may protect against the progression of Alzheimer’s dis￾ease (AD). We investigated the protective potential of decaffeinated green coffee bean extract (GCBE) and the possible potentiation of pioglitazone (PIO) effects by decaffeinated GCBE in fructose-induced AD in rats. Twenty-four rats [12-untreated and 12-pre-treated (for 4 weeks) with GCBE] consumed drinking water supple￾mented with 10% fructose for 18 weeks. Twelve of these rats (6-GCBE-untreated and 6-GCBE-pre-treated) were treated orally with PIO starting on the 13th week for 6 weeks. Prophylactic administration of GCBE attenuated oxidative damage (increased cortical reduced glutathione and superoxide dismutase activity), while decreased malondialdehyde. It retarded the activation of acetylcholine esterase, in￾creased acetylcholine level in the cortex of fructose-induced AD. It also impeded the upregulation of beta-secretase-1and the accumulation of Aβ plaques that were induced by fructose drinking. With PIO therapy, GCBE showed better effects allevi￾ating oxidative stress and Aβ extracellular plaques formation, while improving cholin￾ergic activity, learning, and memory ability. In conclusions, the consumption of GCBE may protect against the development of AD and delay the progression of AD when given with PIO.