Why has Alzheimer's disease (AD) remained a conundrum today? The main reason is the stagnation in understanding the origins of plaques and tangles. While they are widely thought to be the products of the "aberrant" pathways, we believe that plaques and tangles result from natural aging. From this new perspective, we have proposed that age-related inefficiency of α-secretase is the underpinning for Aβ overproduction. This view contrasts sharply with the current doctrine that Aβ overproduction is the product of the "overactivated" β- and γ-secretases. Following this doctrine, it has been claimed that the two secretases are "positively identified" and that their inhibitors have "successfully reduced Aβ levels." But, why have these studies not led to the understanding of AD or successful clinical trials? And if so, where did they go off course in reasoning? These questions may touch the basics of biological science and must be answered. In this paper, I dissected several prevailing assumptions and some influential reports with an attempt to trace the origins of the conundrum. This work led me to an original model for Aβ overproduction and also to a serious question: given the universal knowledge that boosting α-secretase reduces Aβ, a straightforward highway for intervention, then why is there such an obsession on "inhibiting β- and γ-secretases," a much more costly and twisting road even if possible? This issue requires the attention of policymakers and all researchers. I therefore call for a game change in AD study.
Keywords: Alzheimer’s; amyloid; calcium; presenilin; tau.