Revisiting Alzheimer's Disease from a New Perspective: Can "Risk Factors" Play a Key Role?

Alzheimer's disease (AD) has been intensively studied for decades, but why has its common pathological cause remained so enigmatic? Our studies have suggested that plaques and tangles occur spontaneously during aging as a result of a natural decline of energy metabolism and Ca2+ signaling, but not necessarily due to conventional pathogens. This view would lead to an unexpected outcome; that is, natural aging plays a more important role in neurodegeneration than is currently recognized. Does this model over-simplify the disease origin? We know that AD-type neurodegeneration typically occurs at the end stages of life when not only do plaques and tangles appear, but also many other bodily changes as well (bone loss and skin wrinkling, etc). Neurodegeneration differs from the latter changes mainly by "social" consequences, not by "physiological" origin. If neurodegeneration is a natural event, then why do only some people, but not others, develop AD? Obviously, additional factors are required for neurodegeneration to develop into AD. By comparing current models and ruling out other possibilities, we think that several known "risk factors" most likely play a critical role in the late-onset sporadic AD. These risk factors can exert their effects either by providing the conditions for ailing neurons to die (extended longevity and sedentary lifestyle), or by enhancing the individual's "vulnerability" to natural neurodegeneration (low synapse reserve). In this context, late-onset sporadic AD would be similar to many other age-related conditions where perhaps no single pathogen can be held exclusively responsible for most cases; rather, many risk factors are important to allow the initial defect to turn into clinical diseases. Accordingly, these factors should be the primary targets for AD prevention. Yet, some other AD cases, especially the early-onset ones, may be complicated by the concomitant involvement of other diseases in the brain.