A unified model of dementias and age‐related neurodegeneration

Abstract

…but ignorance more frequently begets confidence than does knowledge: it is those who know little, and not those who know much, who so positively assert that this or that problem will never be solved by science. Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment,1 there are no proven disease-modifying interventions. Despite huge and growing costs of care,2 a pipeline of candidate drugs,3 >400 registered trials,4 tens of thousands of patients,5 billions of dollars in both US federal6 and pharmaceutical company investment,7, 8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed9 in attempts to prevent, slow, or alter the course of the dementias. This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias.10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015,11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions. The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications. The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. Although there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias.12 Over the past century,13 several models have attained varying degrees of acceptance. Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1). Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors. Until recently, the foremost among such explanations has been amyloid β (Aβ) theory,14-17 in various iterations. Other candidates have been tau tangles,18-20 mitochondrial dysfunction,21, 22 or other etiologies. Despite academic argument, and in line with Alois Alzheimer's original warning about confusing histological findings with causation,13 these models have targeted biomarkers (whether classic biomarkers such as amyloid and tau protein or less common biomarkers such as inflammation,23, 24 or mitochondrial dysfunction), but a comprehensive, systems model explaining causation often remains unclear. Some models assume or imply a single causal agent which, in turn, drives other common pathological findings (and biomarkers) of AD, although this view (which assumes a predominant interacting cause) is seldom explicit. One leading model used by many pharmaceutical firms, for example, has been that AD is caused by Aβ deposition and other markers of AD are secondary, implying that an intervention targeting the primary cause (Aβ) would prove effective in dealing with secondary factors (tau protein changes, and so on). Equally, pharmaceutical interventions targeting other putatively primary causes, such tau proteins, mitochondrial dysfunction, and microglial activation, imply that their primary target lies “upstream” and is causal not only for dementia, but for other, secondary pathological findings and biomarkers (Figure 2). Thus, for example, primary abnormalities in tau protein physiology might result in secondary Aβ plaque formation and other secondary biomarkers. Such models have failed to result in effective interventional human trials and, despite the suspicion that the underlying pathology of AD might well share mechanisms with other dementias, none of these models accounts for potentially shared mechanisms in all dementias, such as Parkinson disease, frontotemporal dementia (FTD), dementias, dementias, dementia, primary age-related and so on to as models to for age-related in of an model for both age-related human dementias and in a in our clinical in human trials. a comprehensive to effective interventions. In AD, there has been a that a more fundamental the The is often to although there is no on the that result in This of model (Figure be by a single fundamental amyloid tau mitochondrial and A more general model would all dementias, an underlying and shared in specific dementias. The fundamental is with clinical on its with and which between (Figure it would age-related human dementias and age-related in The of human trials on is that in in This that although age-related is common in both and the of such the underlying mechanisms of such effective as age-related human dementias may share a fundamental on its with and between so the age-related in may share a fundamental the of which on its with and between (Figure Although the fundamental may be example, between and and between will not only result in findings (eg, the of Aβ plaque or the of tau but will result in to these example, is a shared in and dementia in that the would share findings in of the (eg, amyloid and tau protein or the of the most common (eg, and the to the of an underlying from models to human trials. 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