Sally Hunter deserves our gratitude for her blog post detailing the uncertainty we have about the molecular and immunological characteristics of the Aβ proteins at the center of the dominant so-called amyloid cascade hypothesis of Alzheimer’s disease. What is most refreshing is her attempt to see the molecular phenomena embedded within a systems biology perspective, as well as pointing to broader (and indispensable) contexts such as public health and epidemiology. She deserves further plaudits for her persistence in getting her message across and effectively aligning her concerns with a growing body of other wisely skeptical voices. She focuses on the need for more complex models at a molecular level. If more space were available she could have expanded on how little we know about the normal function of the Aβ related proteins in healthy brain function.
The amyloid cascade hypothesis is not merely a scientific hypothesis, it is more often used as a political statement. It is illuminating to compare this alleged hypothesis to the so-called cholinergic hypothesis that was dominant for a period before Alzheimer’s became more the subject of molecular biological and genetic focus. Is the cholinergic hypothesis true? We are told hypotheses need to be tested by trying to reject the null: can it be rejected and, if so, using what criteria? Clearly, there are loss of cholinergic neurons and nicotinic receptors in several types of dementia. The preclinical and clinical evidence that cholinergic systems are involved in memory and attention is strong. And cholinomimetic drugs were approved by the FDA on the basis of well-designed studies, although we can argue in retrospect that their effectiveness in clinical practice is minimal.
It appears that the amyloid hypothesis suffers from similar problems. How could we reject the hypothesis? In the clinical diagnostics and drug trials space with which we are familiar there have been repeated failures over the past decade. Now the claim is often made that we just need to apply our therapies earlier (now in people with so-called elevated risk as demonstrated on an amyloid PET scan) and study their effects for longer durations and with higher doses. Money has been wasted on poorly designed evaluations of the imaging methodology itself. Hundreds of millions of dollars were allocated by the Centers for Medicare and Medicaid Services to try to determine whether the experts who advocated for the investment could evaluate in an unblinded nonrandomized situation whether they found the test useful. Not to mention that the scans are often difficult to interpret—even in the hands of “experts”. Individuals who received the scans were only told that their risks were either elevated or not. Reasonably, they might ask “how elevated”? One might expect quite different reactions from people whose scans are said to be either positive (elevated) or negative, by neglecting that the imaging measures of amyloid actually exist on a continuum rather than being a binary. People receiving these scans tend to believe it is a “test” for Alzheimer’s (it is not—it is a test for amyloid) and hence have unrealistic sense of the importance of the scan.
Our fear is that the political pressure to get an outcome from the amyloid hypothesis, i.e., prove it is true and the enormous financial and time investment worthwhile, is so great that it is, as others like the late Mark Smith have suggested, “too big to fail”. If we are not careful, we will let the FDA yield to pressure to approve drugs on the basis of un-validated biomarkers. The tearful and angry marketing message that creates fear that our healthcare system will be overwhelmed by Alzheimer’s disease and related disorders may be used to try to justify doing something even if it is close to nothing (and an expensive nothing at that!). For example, the Alzheimer’s Association advocates the development of medications to end or cure Alzheimer’s and extrapolates hundreds of billions of dollars of cost saving, while at the same time using modeling with the drug priced at zero [1,2].
Fortunately, we are now finding that there are many interventions that can improve quality of life for people with dementia including behavioral, educational and arts-based approaches. Do we really only have to only “care today” expecting to “cure tomorrow”? Or should we recognize that regardless of what we do medically, improving our care for each other is more important than pursuing illusory goals of cure.
And now we are talking about drugs to prevent Alzheimer’s disease and there is much hype in this field of prevention that we need to critically evaluate. Yet, there is enough evidence to support so-called lifestyle and community interventions that developing policies to enhance such programs appears reasonable, even in the absence of large-scale randomized controlled studies. Dietary modifications, physical exercise, meaningful cognitive activities, and social engagement all likely contribute to improved brain health and resistance to age-related cognitive loss. These are not specific for heterogeneous groups of conditions like Alzheimer’s disease or even dementia more generally but rather are good for a variety of age-related conditions including those involving the heart.
The problem with these kinds of interventions is mainly that they do not glitter in the way that efforts to cure diseases bedazzle us. These often promised but rarely delivered biomedical approaches produce a glitter which is ultimately fool’s gold and the real “gold” goes to those in the Alzheimer’s field who make irresponsible promises while ignoring genuine opportunities to address the individual and social challenge of dementia at a local, state, and national level. The amyloid hypothesis is ultimately about politics; it’s about false hope and it’s about irresponsible behaviors and profit motivated corruption of values that should be central to our research efforts. We need to understand more deeply the consequences of economic and political forces to commodify and financialize the brain and the rest of our lives (i.e., neoliberalism). Appreciating the social determinants of health and enhancing our collective commitment to one another are essential to addressing the real challenges of Alzheimer’s. In those processes we also have the opportunity to learn important lessons about what it means to grow old and in fact to be a human being within an interdependent community in increasingly vulnerable ecosystems.
Peter J. Whitehouse and Danny George
 Alzheimer’s Association (2015) Changing the Trajectory of Alzheimer’s Disease: How a treatment by 2025 saves lives and dollars. http://www.alz.org/documentscustom/trajectory.pdf
 Whitehouse PJ, George DR (2016) A Tale of Two Reports: What Recent Publications from the Alzheimer's Association and Institute of Medicine say about the State of the Field. J Alzheimers Dis 49, 21-25.