Is Simpler Always Better? The Case for Going Beyond the Amyloid Hypothesis in Alzheimer’s Disease

In a recent review, the authors presented an inventory of published hypotheses on the etiology of Alzheimer’s disease (AD) in the last four decades [1]. The lack of a common definition of what “Alzheimer’s Disease” means is the first major hurdle in the search for the ultimate etiology of this disorder. Indeed, as stated by the authors, one of the basic problems of the field is the lack of a universally accepted definition; there are at least 3 dimensions to consider in the definition of AD: 1) the clinical syndrome, 2) the neuropathological features, and more recently, 3) a definition based on in vivo biomarkers such as cerebrospinal fluid amyloid-β, tau, and p-tau. The presence of biomarkers is regarded by some as equivalent to the disease itself and by others as a risk factor for the development of the disease, which is the reasonable option in regard to the uncertainty of the natural history of cognitive performance in the presence of these biomarkers [2]. If we start from the clinical syndrome, which is the most useful definition where potential patients are concerned, postmortem hallmarks of the most frequent pathological entities are not sufficient to explain the variability of cognitive performance [3]. This includes amyloid and tau, but also other prevalent features of known diseases (Lewy bodies, hippocampal sclerosis, TDP-43, micro-infarcts, etc.), which are most often present in various associations in different individuals, producing a bewildering array of individual combinations [4]. In addition, associations between the clinical phenotype of dementia and the main pathological hallmarks of AD (amyloid plaques and neurofibrillary tangles) become less significant as patients get older [5]. Seldom do we encounter such discussions in recent publications; the lack of conceptual clarity between the clinical definition of cognitive decline and the biomarker definition of AD are important barriers to the development and widespread acceptance of a unifying theory.

One of the striking findings originating from this review is the persisting dominance of the amyloid hypothesis publications, even in 2010–2020 interval, and this remains difficult to explain in view of the very modest progress despite the enormous efforts invested in the therapeutic trials based on this dominant hypothesis. The authors allude to potential non-scientific reasons for this state of affairs: the allure of a single factor hypothesis and the potential of very high reward if proven correct [1].

Another potential explanation for the persistence of the amyloid hypothesis is the sunk-cost fallacy, whereas so much unrecoverable costs have been invested in the past, that the cost of abandoning the hypothesis is simply too great to consider, thus motivating the perpetuation of the same framework.

AD is acknowledged by most researchers to be a complex syndrome involving many different processes and comorbidities [6]. Despite this mundane statement, this review shows that fully three quarters of hypotheses for the etiology of AD are single-factor hypotheses; in addition to amyloid, most try to explain the syndrome in terms of a unique etiological domain such as vascular factors, metabolism, mitochondrial dysfunction, infections, and inflammation to name a few [1]. How does one explain this? One possible explanation is found in the famous citation from Einstein: “It can scarcely be denied that the supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience.” Traditional teaching of medicine has similarly recommended that one should always strive to attain the simpler, so-called “unicist” explanation to analyze a clinical problem, and this reasoning still has value in everyday clinical practice, and perhaps this also influences attempts to explain AD. In this case however, it appears that the simplest explanation is not likely the best one. When studying AD, a problem that involves the slow longitudinal dynamic dysfunction of networks of interconnected neurons across decades, with considerable inter-individual heterogeneity, a single-factor hypothesis is unlikely to represent the best correlate of the phenomenon, despite the undeniable attractiveness of a single-factor hypothesis.

Another implication of the fact that the majority of cases of AD dementia are caused by multiples etiologies, is that it will be challenging (to say the least) for clinicians in practice to assess the contribution of all these putative different pathological processes to the cognitive impairment of a given individual. We are on the path towards identifying more and more biomarkers in our patients, but this approach will likely reach its feasibility limits soon. Rather than aiming to identify all contributing pathological processes in a particular individual in order to intervene on each one, which will likely be very expensive and not feasible at scale [7], a more promising approach would be to foster brain and cognitive resilience, which are likely processes that can help an individual to fend off or delay the clinical impact of many different pathological processes or cumulative disorders [8].

As the authors state, a unifying theory of the etiology of AD has failed to emerge. The scoping review presented in this issue draws a picture of all major theoretical frameworks that are orienting research efforts into this disorder. Based on their work, the authors propose three criteria that a new unifying theory of AD should meet, and these overlap with some of Bradford Hill’s viewpoints on causality [9]. A new, unifying theory of the etiology of AD should try to fulfill a maximum number of Hill’s viewpoints, to strengthen claims of causality and rally support from the research community. The hypothesis that will most reliably represent the biological processes that lead to AD dementia will necessarily have to be more complex than the dominant amyloid hypothesis, and thus, will face the risk of being less attractive than a single factor hypothesis.

This review can hopefully constitute a starting point for researchers to look forward to a complex multifactorial framework to explain AD and come to terms with the fact that there will likely be no “silver bullet” for it. For this to happen, we must develop a theory with wider scope and better correlation with empirical data. Of course, this theory should include amyloid as a factor, but probably not as a central one.

A “holistic framework that could reframe the debate in simpler lines” is certainly desirable. In my view, such a framework might be provided by the stream of research stemming from the neuroplasticity hypothesis, which sounds like another single-factor hypothesis, but allows for a better integration in a final common pathway of the multiple risk factors and other hypotheses presented in this review [10, 11]. Other multi-factorial propositions have also been published in the last few years, but were unfortunately not included in the scoping review [12, 13]. There are still major unmet needs in the care of affected individuals, until we develop what will probably need to be a multifaceted approach to prevent, delay or avoid this multifaceted, complex, and devastating disorder.