The lack of progress towards effective therapies for Alzheimer's disease based on clearance of amyloid-β, and the relentless focus on that goal for the past two decades, has led to a great deal of alternative theorizing about the mechanisms driving the condition. Some of those theories are less well thought of than others, such as the opinion that rising use of common painkillers is the root cause of Alzheimer's. The paper here provides another example of a view of Alzheimer's disease that probably won't gain much traction in the present environment, but is nonetheless an interesting read. The sheer complexity of the aging brain still allows a great deal of room to interpret the same data in many different ways. The only real proof lies in developing a therapy that does actually produce meaningful results in humans. We can hope that first generation senolytics turn out to be that therapy, but time will tell.
Numerous studies have been attempted to link Alzheimer's disease (AD)-related molecules to the pathogenesis of AD: APOE ε4-associated mechanisms such as amyloid-β (Aβ) clearance and aggregation, cerebral energy metabolism, neuroinflammation, neurovascular function, and synaptic plasticity, and presenilin-related ones such as Aβ production, calcium homeostasis, and neurogenesis. Such heterogeneous and multiple mechanistic pathways may work cumulatively over a lifetime to increase an individual's risk of AD. Nonetheless, the pathogenesis hypothesis needs to make logical connections with several confirmed findings, that is, the existence of both amyloid plaques (APs) and neurofibrillary tangles (NFTs), anatomical characteristics of neurodegeneration. The amyloid hypothesis has long been at the center of discussions. Aβ is believed to be toxic to neurons and have various mechanisms of action.
As an alternative to the Aβ hypothesis, in this paper, I propose that excessive (or aberrant) and maladaptive synaptic plasticity is the cause of AD. Previously, plasticity failure was proposed as a cause of AD. In that hypothesis, AD results if the demand for plastic remodeling exceeds the biological capacity to fulfill it: Familial Alzheimer's disease (FAD)-causing mutations of APP increase the demand for plastic remodeling by shifting the balance of its processing toward more toxic form of Aβ. Another example is the malignant synaptic growth hypothesis, which suggests that AD develops if the positive feedback mechanism during synaptic modification is dysregulated. The authors suggest that Aβ prevents neurons from malignant synaptic growth by impairing the function of plasticity-related synaptic molecules and that FAD-linked mutations produce types of Aβ which have a weaker neuroprotective effect against it. Further, network abnormalities have also been discussed as potential mechanisms of cognitive dysfunction in AD. In these papers, Aβ is considered to be a central molecule causing network abnormalities.
In contrast to the previous discussions, the hypothesis proposed here states that excessive/aberrant synaptic plasticity is a root cause for cognitive dysfunction in AD and that cognitive dysfunction is developed through maladaptive neuronal connections, hyperexcitability of neuronal network and abnormal process of synaptic remodeling. APP is a key player in synaptic plasticity, and in FAD, the mutant APP or presenilin leads to aberrant plasticity through altered APP metabolism and function, which initially manifest as neuronal network abnormalities.
Decades of research do not necessarily support only the amyloid hypothesis, but also can be utilized to hypothesize excessive/aberrant and maladaptive synaptic plasticity as the cause of AD. If this hypothesis is correct, an important goal aimed at delaying the onset of AD and slowing or halting the disease progression is to find ways to adaptively regulate synaptic remodeling without interfering with necessary changes. This requires an understanding of the fundamental mechanism of synapse dynamics, and the characteristics of the stage of synaptic plasticity (formation, maturation, or elimination) at which a person developing AD is affected. Because of heterogeneity between individuals, identifying the stage of synaptic plasticity at which individuals are prone to error is a prerequisite for providing each person the appropriate intervention.
Link: https://doi.org/10.3...agi.2022.913693
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