Abstract: It is believed that overproduction and deposition of amyloid-β (Aβ) plaques in the hippocampus and cortex region of the brain cause neuronal dysfunction leading to cognitive impairments in Alzheimer’s disease (AD). Until now, there has been no effective treatment to reduce plaque load from the brain. Recent studies have shown that regular treadmill exercise lowers plaques from the brain of a mouse model of AD. Out of three proteolytic enzymes or secretases, while α-secretase activates the non-amyloidogenic pathway of amyloid precursor protein (APP) cleavage to inhibit Aβ plaque production, β- and γ-secretases indulge the APP cleavage in the amyloidogenic pathway for the formation of Aβ plaques. Accordingly, it is nice to see that treadmill run increases α-secretase and decreases β- and γ-secretases in AD mice. Interestingly, in normalaged mice as well, a treadmill run increases α-secretase and decreases β- and γ-secretases, indicating that in normal subjects as well, a treadmill run may keep the formation of Aβ plaques at bay. The prototype role of peroxisome proliferator-activated receptor α (PPARα), a nuclear hormone receptor, is to regulate energy homeostasis via catabolism of fatty acids. However, it has been shown that the success of treadmill run depends on PPARα as the treadmill remains ineffective in increasing α-secretase and reducing plaque burden in AD mice lacking PPARα. Here, we discuss about this drug-free safe approach and associated PPARα-dependent mechanisms for the inhibition of plaque pathogenesis.