Technical Abstract: Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer’s Disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and little information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the senescence-accelerated mouse prone 8 strain (SAMP8 mouse), a model of accelerated aging that is increasingly being validated as a model of sporadic/age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared to control-fed animals. Neither resveratrol nor pterostilbene increased Sirt1 expression or downstream markers of Sirt1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of PPAR alpha expression. Taken together our findings indicate that at equivalent and diet achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased PPAR alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.