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Neurodegeneration in late life is a very complex phenomenon, and its complexity strains against the nice neat clinical definitions of disease found in the textbooks. Different patients with Alzheimer’s disease can exhibit quite different mixes of various forms of pathology, developing at different paces and times: aggregates of amyloid-β, tau, and α-synuclein; vascular degeneration; markers of neuroinflammation; metabolic disruption similar to that of diabetes, and so forth. One case of Alzheimer’s might be different enough from another to require a different designation. Thus researchers talk about defining subtypes of Alzheimer’s disease, or that individual patients have Alzheimer’s that is exacerbated by a comorbidity arising from other neurodegenerative processes.
Another way of looking at this is to categorize mechanisms that contribute to Alzheimer’s. To what degree is a given set of mechanisms important in a given patient? A sizable amount of work has gone into investigation of processes and feedback loops other than the primary amyloid cascade hypothesis of the condition. It is an open question as to where all of these contributing aspects of the condition fit into a chain of cause and consequence, or whether the ordering of that chain is similar from patient to patient. Alzheimer’s disease may well be a collection of distinct conditions that all happen to wind up in a similar end state.
The authors of this paper draw the gloomy conclusion that this complexity, and continued failures in the development of therapies based on the amyloid cascade hypothesis, imply that there are no silver bullets. I would argue otherwise, and say that instead comparatively simple points of intervention have not yet been developed fully. Senolytic therapies that clear senescent glial cells from the brain seem quite effective in animal models, for example. The approach of restoring lost drainage of cerebrospinal fluid, to clear out aggregates from the brain, also looks promising. There will be others. The complexity of aging emerges from simpler root causes, and there will always be some clever way to intervene at a point of maximum leverage.
Alzheimer’s disease (AD) is among the most ominous of modern health epidemics. AD is not alone in its ascent. Other chronic diseases, particularly Parkinson’s disease (PD), a neurodegenerative disorder associated with the build-up of α-synuclein protein and death of dopaminergic neurons, and type 2 diabetes mellitus (T2DM) are increasing in prevalence at similarly alarming rates. Although AD, PD, and T2DM share common risk factors, chief among these being age, there is more to their relationship. Evidence suggests that the pathophysiological mechanisms underlying AD, PD, and T2DM interact synergistically.
In addition to the well-known amyloid cascade hypothesis of AD, other hypotheses have been proposed that include: (1) the Wnt/Glycogen Synthase Kinase 3β (GSK3β) hypothesis, (2) the α-synuclein hypothesis, and (3) the type 3 diabetes hypothesis. Dsfunctional Wnt-signaling can contribute to the development of AD and its two pathological hallmarks, Aβ plaques and p-tau tangles. The canonical PD-associated protein α-synuclein may be locked in pathological positive feedback loops with Aβ and tau. Finally, insulin resistance in the brain, “type 3 diabetes,” may contribute to development and exacerbation of AD. Each model interacts with the others. These interrelationships, make it clear that the pathology of AD is not a linear cascade, nor a simple feedback loop, but rather a network of cross-talking models and overlapping vicious cycles.
Given the cooperative and reinforced nature of this complex network, it is no surprise that the prototypical monotherapeutic approach to AD has reliably failed. Certainly, drugs that target key nodes within the network, such as GSK3β inhibitors or AKT activators, have shown promise in animal models, and this important work affords us valuable mechanistic insights. However, these pre-clinical successes generally have not translated into clinical success, at least not with the same degree of efficacy. This is likely because animal models harboring distinct AD-causing mutations and dysfunctions in particular linear pathways do not accurately recapitulate the complex pathologies underlying sporadic human AD. In brief, we are proposing that the single-target silver-bullet approach to AD drug discovery is doomed to fail and that we may only be able to treat or prevent AD by developing new multifaceted treatment options.