RESUMO
The field of Alzheimer's disease (AD) research critically lacks an all-inclusive etiology theory that would integrate existing hypotheses and explain the heterogeneity of disease trajectory and pathologies observed in each individual patient. Here, we propose a novel comprehensive theory that we named: the multipathology convergence to chronic neuronal stress. Our new theory reconsiders long-standing dogmas advanced by previous incomplete theories. Firstly, while it is undeniable that amyloid beta (Aß) is involved in AD, in the seminal stage of the disease Aß is unlikely pathogenic. Instead, we hypothesize that the root cause of AD is neuronal stress in the central nervous system (CNS), and Aß is expressed as part of the physiological response to protect CNS neurons from stress. If there is no return to homeostasis, then Aß becomes overexpressed, and this includes the generation of longer forms that are more toxic and prone to oligomerization. Secondly, AD etiology is plausibly not strictly compartmentalized within the CNS but may also result from the dysfunction of other physiological systems in the entire body. This view implies that AD may not have a single cause, but rather needs to be considered as a spectrum of multiple chronic pathological modalities converging to the persistent stressing of CNS neurons. These chronic pathological modalities, which include cardiovascular disease, metabolic disorders, and CNS structural changes, often start individually, and over time combine with other chronic modalities to incrementally escalate the amount of stress applied to CNS neurons. We present the case for considering Aß as a marker of neuronal stress in response to hypoxic, toxic, and starvation events, rather than solely a marker of AD. We also detail numerous human chronic conditions that can lead to neuronal stress in the CNS, making the link with co-morbidities encountered in daily clinical AD practice. Finally, we explain how our theory could be leveraged to improve clinical care for AD and related dementia in personalized medicine paradigms in the near future.