Scientific Truth or False Hope? Understanding Alzheimer's Disease from an Aging Perspective

Abstract

In this paper, we argue that the current official definition for Alzheimer's disease is misleading, since it defines senile dementia (SD), a long-known incurable senile/geriatric condition, as a discrete/curable disease. This overly optimistic definition was incepted in the 1970s amid the public's fear of the upcoming SD crisis and desperate hope for a cure. Scientifically, however, it has overturned Alois Alzheimer's age-based concept for disease classification-the essence of modern Geriatric Medicine and the National Institute of Aging. Thus, the current definition for SD, though socially and politically appealing, would be scientifically flawed. As an authoritative study guideline, it has caused profound and far-reaching confusions in research by misleading attention to the presumptive pathogenic/erroneous factors as drug targets for "silver bullets". Such well-intentioned studies would generate numerous data, but render SD a scientific and logical enigma. In this context we discuss: 1) why and how senile conditions including SD differ from discrete diseases by origin, thus also by study paradigm and intervention strategy; 2) why senile conditions may not be explained by abnormal/pathogenic factors, but logically should be explained by "normal" elements in life, perhaps advanced aging plus risk factors; and 3) why the "amyloid-β toxicity" controversy, a simple scientific issue, has lasted for so long. Finally, we ask: can scientific inquiry preserve its integrity and objectivity under social pressure? It appears that these fundamental questions warrant serious attention if the scientific nature of SD is to be eventually understood.

What to Look for Beyond “Pathogenic” Factors in Senile Dementia? A Functional Deficiency of Ca2+ Signaling

“…In light of this knowledge, together with our overall model for SD [3,4], we propose that a functional deficiency of Ca 2+ signaling, among a myriad of age-related changes, is the underpinning of cognitive decline during aging ( Fig. 2A).…”

“…This has prompted us to undertake an independent analysis of the SD features and realize that the current definition for SD by the National Institute on Aging (NIA) is the starting point of the problem [3,4]. Our main viewpoints are as follow:…”

“…1B). However, since the pace of aging varies among individuals and is significantly influenced by brain reserve, lifestyle, and other risk factors, the descending trajectory will divert in the population, allowing brain death to occur at quite different ages among individualsmuch as old cars will die at different years [3,[21][22][23] ( Fig. 2A).…”

“…Of great importance is that the two opposing "Ca 2+ hypotheses" can be directly tested: to see whether a long-term use of calcium antagonists will enhance, or impede, learning and memory in old animals. Needless to say, this test will carry not only the hope to create a much-needed animal model for SD (late-onset sporadic AD), but also the danger to become another never-ending controversy (like "toxic" amyloid-␤; where science is entangled with social interests) [3].…”

Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes

“…Alternative theories of AD pathogenesis have also been postulated. For instance, different groups consider AD to be a combination of multiple disorders of diverse etiology [135], a by-product of normal aging [136, 137], or initiated by faulty immune activation [138]. Others have described AD as a metabolic disorder similar to diabetes, and even coined the term Type 3 Diabetes to highlight their shared molecular and cellular disturbances, such as insulin resistance, oxidative stress, and glycogen synthase kinase 3β activation [139].…”