Chapter 1 : The Creation of a New Disease
Feared more than cancer or heart attack, Alzheimer’s disease has now capture people’s fears and worries. But finding how the disease develops and then progresses has eluded scientists. Going back in time when Dr. Alois Alzheimer observed the new disease provides some evidence and clues to why we have failed to control this disease.
Finding that there were some clamping of neurons, plaques and tangles, in the brain was not a new discovery. But the creation of this new disease relied on other issues at the time. It relied on a belief that certain people are inferior, that politically it was beneficial for the Munich clinic to define this new disease to compete with the Prague clinic, and the belief that old age is a dustbin of medical problems. The motivation for creating this new disease was not only scientific but also political in 1900 Germany.
Alzheimer’s disease stayed dormant until the 1950s when American scientists started looking at diseases of older age and searching for cures. By the 1970’s the zeal of searching for a pill to cure all maladies, including Alzheimer’s disease, blinded researchers and they lost focus on how the disease develops and progresses.
The foundation of the science is however unstable. The initial observations that Alzheimer observed, the plaques and the tangles, were common, not just for Alzheimer’s disease but also for many other diseases including neurosyphilis (Dr. Alzheimer’s speciiality.) The plaques and the tangles did not directly cause the disease as many people had these in their brain but never developed the disease. This is a story of how the most frightening disease in the world was created by a perfect storm. Today we are left with disorganized research and a 100% failure of finding a cure or a way of slowing the disease. The future looks bleak and we can only understand this present situation by looking back in history.
Chapter 1: The Creation of a New Disease
What Alois Alzheimer identified more than a century ago was an early onset dementia that was important, but not for the reasons he and his clinic director Emil Kraepelin presumed. Initially Alzheimer saw a pattern that fit the biological proof in support of the clinical observations—plaques and tangles and early-age of onset. Subsequent researchers fell into the same pattern: a habitual research method of finding proof. We now know that these criteria are not discrete enough to both define and predict Alzheimer’s disease.
And we know this because of the ambivalence of the neurobiology, of how the plaques and tangles relate to the disease. Questions arose from the beginning, which to this day we still cannot answer, because there is a problem with what we are trying to explain. Other than familial Alzheimer’s disease, the remaining paths of the disease are random and cannot be measured reliably.
Clinicians remain dependent on prognostic tools that are unreliable. There remains a healthy discussion about the validity of the diagnosis. Research on the clinical features of Alzheimer’s disease is based on combining many short–term, specific, small, cross-sectional study samples. As a result research is fragmented and confusing. Whether by choice or chance we are told that the salvation to this disease will come from a cure. But this construct contains a falsehood. A similar search for laboratory proof is currently being undertaken for Alzheimer’s disease. But how did this state of disorganization in research come about? To find an answer we have to move away from science and look closer at the politics of the disease.
Chapter 2: Politics
Only tenuous evidence existed that separate Alzheimer’s disease from senile dementia. The current consensus among researchers is that Alzheimer’s disease and senile dementia are indistinguishable in contrast to Alzheimer’s belief.
The imperative to promote a more biological psychiatry was a paradigm-changing endeavor in the 20th century. Alzheimer’s disease played a major role in contributing to psychiatry’s reliance on neurobiology, biology, chemistry and genetics. Because of its prominence, Alzheimer’s disease will likely play a large role in the future of psychiatry. This prediction is being realized with the introduction in 2010 of the NIH-sponsored Research and Domain Criteria (RDoC) which integrates biomarkers, genomics and clinical observations to define both normal and abnormal behavior. Alzheimer’s disease is the proving concept for this new U.S. federally-funded nosology.
The fact that in the 1900s the Munich laboratory competed with the Prague laboratory was also a factor. Even today, biomedical research remains a highly competitive field. Nowadays biomedical research seems particularly prone to fraud because of the level of competition among clinics. Back in the 1900s Kraepelin understood this competition which played a significant role in the scramble to be the first to define Alzheimer’s disease. The belief that some people are different from others because of genetics may have also helped Kraepelin assert the distinction between Alzheimer’s disease and senile dementia. The eugenics argument is rarely mentioned in the literature despite the importance of the philosophy in academic circles at the turn of the 20th century. The fact that most of Kraepelin’s perceived competitors were Jewish—at a time when Jews were considered inferior by some groups—could not have been a small consideration. As an example, Fischer’s obscurity and his early demise in prison because of his Jewish beliefs, is another indication of the strong undercurrent of racist beliefs at the time. Although Fischer’s insights into dementia have now been vindicated his legacy remains obscured. But of all these factors, the central issue was—and still is—ageism. If Alzheimer could not argue that this new disease was not just for older people, there would be no classification of a new disease.
Diseases of old age are not news. For most of the past century, it was assumed that old age is a stage of dying and therefore associated with decrepitude. Older adults were meant to have diseases and die. No medical interest exists to subvert such inevitability. The reason why Alzheimer’s disease gained traction is because, for the first time, the disease was affecting younger people. The importance of these prejudices are present with us today.
The birth of Alzheimer’s disease as we know it today, was more than simply a new clinical observation it also had political overtones. It reflected the stereotypes of the time. In 2011, the NIA changed the definition of Alzheimer’s disease to allow the pharmaceutical industry to experiment with a clinical disease before it becomes diagnosed (pre-clincial). But this is creating costly and divergent research. After a century of research we are still unclear about the diseases that come under Alzheimer’s diseases and sadly, we are not closer to understand what causes Alzheimer’s disease or its many variants.
Chapter 3: Disorganized research
Several major sources of confusion remain in Alzheimer’s disease research. The primary confounder comes from the fact that we do not know what Alzheimer’s disease is, and even if we did, we cannot reliably diagnose it, either clinically or neurobiologically. Even if we accept the NIA’s pre-clinical stage of Alzheimer’s disease, the validity and reliability of pre-clinical data is poor at best, and contradictory at worst.
The varied causes of cognitive diseases are not well understood. Gaining knowledge about chemical, neurological and biological pathways and processes does not directly contribute to our understanding of behavioral or clinical disorders. After more than a hundred years of research, there remains a lack of understanding of whether one disease has different expressions—Alzheimer’s disease, Lewy Body Dementia, Vascular dementia—or whether different disease processes lead to the same pathway of expression—Alzheimer’s disease caused by physical trauma, bacteria, virus or vascular disease. Therefore, it is difficult to make distinct and accurate diagnoses.
The concept that Alzheimer’s disease is not a disease but a syndrome provides an impetus for more research by examining the process of the disease, rather than investing all research efforts in finding a cure. The cause/s of the disease are still unknown. Correlational studies might imply causation but this is psychology, not science. Researchers need to admit that the results are puzzling because we are working from an incomplete theory—one that we need to update.
The second source of confusion comes from the great variance among older adults—heteroscidasticity. Even among identical twins, this drift can result in one twin getting Alzheimer’s while the other escapes. This relates to epigenetic changes that influence both brain plasticity and neurogenesis. This variance, that increases among individuals as they age, will continue to dilute the linear association between a specific neuropathology and its expression, especially among older adults.
Although researchers look for genetic markers that will eliminate all these epigenetic or environmental factors, so far The Alzheimer’s forum has identified more than 1,395 studies working on 695 genes that account for up to 0.5 percent of Alzheimer’s disease. If 695 genes account for half of one percent of Alzheimer’s disease, then even if researchers can identify and manipulate all of these genes the disease will not be cured. This criticism, that genetic studies cannot explain all the variance of Alzheimer’s disease, can be applied to the search for biomarkers, both biological and chemical. The only challenge to the current expression of biological determinism is the fact that there is no competing paradigm to guide research.
The deduction is that confusion becomes a ploy, not a failure or an expression of incompetence. Confusion as a method allows a small research group connected with the NIA to dictate and continuously change the meaning of the disease. Regardless of the intention, the result is obvious. Confusion and uncertainty have created great fear. This confusion unfortunately spills over into clinical practice as well, affecting patients, their families and their rights as citizens. Alzheimer’s disease is over-registered and over-diagnosed with consequential wasted health care costs and undue stress to the family. Perhaps the confusion is that we did not understand that our fear of Alzheimer’s disease has become a neurobiolgical playground where we have feverishly worked ourselves into a research cul de sac.
Chapter 4: Research cul de sac
The inductive method of observing a disease to learn what people have in common creates a false syllogism—a fallacy. Just because everyone with dementia has the neuropathology, we cannot logically argue that everyone with the neuropathology will have dementia. Because science should also be based on a deductive model, where theory directs the line of investigation, researchers need to conduct more theory-driven hypothesis testing. A mounting body of evidence does not support the theoretical construct that a linear causal pathway exists between a biomarker, causing MCI that then matures into a dementing illness. Infact a systematic review of the literature agues for broad use of techniques to counter MCI. Partly for this reason, we see very little deductive reasoning in research on Alzheimer’s disease, although it is evident in neurobiological studies. The two worlds of neuroscience and clinical services that are evident in Alzheimer’s disease remain distinct, separate and divorced.
The lack of validity, across a whole spectrum of issues in Alzheimer’s disease research is a negative statement. The anomalies point to the necessity of expanding the concept of biomarkers to explain how they might be moderated or mediated by other, as of yet unexplored factors. It could be that the plaques and tangles are like scarring on a wound—indicative of a trauma but serving as a protective feature. Clearing the scab will not change the underlying trauma and might even be detrimental to the healing process. We are leading to potential situations where despite being competent and having normal memory and behavior, a patient might still be diagnosed with dementia. Such is the mission of the Research Domain Criteria. We need to resist this biological determinism mode of thinking, which is becoming more and more prevalent, and which has negative repercussions on our relationship with our medical and legal institutions. Alzheimer’s disease is playing a major role in persuading researchers to adopt such a system of biological determinism.
The relationship between Alzheimer’s disease and changes in the normal aging processes need to be distinguished. One possible clue could be the speed of attrition. Even though we still do not know enough about normal aging processes, sudden attrition might be indicative more of disease pathology. A longitudinal perspective is crucial for elucidating such a distinction. Despite all the ambiguity surrounding the disease, we see the disease as very real and very frightening. We remain fixated on it because it feeds a very personal and intimate fear. We accept a fanciful process of causation because it is safe to assume that we know how to approach the problem and possibly find a cure. But if we reinterpret the philosophy behind our fear of Alzheimer’s disease we might arrive at some basic understanding that might help in defining a new, badly-needed research paradigm.
Chapter 5: Philosophy of Alzheimer’s disease
People need a consistent, stable sense of self throughout their lifetimes, including when they self-project into future situations. This is the essence of being, of Dasein. A purely neurobiological model of cognition cannot explain some basic anomalies in research. For example, a woman misdiagnosed with Alzheimer’s disease nevertheless makes herself believe that she has the disease; men who pretend to be 20 years younger become younger; and clusters of people who have very long lives age well without Alzheimer’s disease but these clusters are found only in small geographic areas. All these events can help us understand the dynamics of our reality, our being. This is the study of ontology. Such preoccupations have also received validation from neurological studies. The next frontier involves accepting a broader definition of being—of Dasein—that includes others, the environment and our geography. It is not biological determinism, because the biology/genetics is determined by the environment and our interpretation of that environment. We own the biology as well as the environment.
There is a cultural condition of the fear of Alzheimer’s disease. That there is an element of self–limitation, of a self-fulfilling prophecy and it may be time to question our own mindsets. Older adults report that their fear of Alzheimer’s disease has increased from the second most feared disease to the most feared disease. Fear of dementia is now so strong that there is a new term: “Dementiaphobia”. This alone represents significant condition of our Dasein—both in terms of what we care about (gaining ownership of beliefs and ideas), the Facticity (we have no control over whether we get Alzheimer’s disease), and also in our personal projections of the future (the likelihood that we are going to get Alzheimer’s disease).
In this context, fear has already limited our ability to deal with negative cognitive episodes. This is a constant in our lives. Many opportunities exist to misinterpret cognitive decline as both long-term and Alzheimer’s disease-related. Fear is nuanced. A family member suffering Alzheimer’s disease creates a template for us to follow, a mindset, especially if we provide care for them. There is significant deterioration in the health of caregivers when compared to a similar group of non-caregivers. Caregiving becomes more stressful the longer one does it. The stress does not stop when the care recipient dies. Also seen in the “widowhood effect”—where the surviving spouse dies soon after their partner—exemplifies how intimate relationships define what is important in life. Death following spousal death among older adults has been estimated at between 30 percent and 90 percent in the short term, and around 15 percent in the long term.
Not only are we led to believe that Alzheimer’s disease is random without any control, caring for a loved one with Alzheimer’s disease magnifies this as a likelihood in our future. This association might contribute more to familial dementia then genetic factors. Because we learn by experience we are sensitized to look for “signs” of the disease that we then use to promote the likelihood that we will get the disease. “We have nothing to fear but fear itself” is the new watchword for Alzheimer’s disease.
Chapter 6: Complexity Theory of Dementias
The brain is the most complex organ in the universe. Nothing else is more complex. The simple theory that two misfolded proteins by themselves create a breakdown of thinking is not accurate. Theories based on the Amyloid Cascade hypothesis are incomplete. Emerging evidence points to a more complex process. There are many possible causes of dementia. The initial injury might or might not progress. The neurological disease might or might not affect cognition.
These considerations are valid and have been left out of the new research agenda. Our conventional reliance on genetic causes is similarly simplistic. Accepting the evidence that external injury (viral, bacterial, biological, chemical, environmental, behavioral) can initiate dementia reframes the disease as a public health issue. In this case, we can alleviate or minimize some of these causes. We are already doing this with head trauma in sports with new protocols for diagnosis and treatment. Other injuries that are shown to contribute to dementias should be similarly addressed. By addressing potential traumas, perhaps we could eventually prevent most of the initial causes of the disease. Such an approach opens the door to positive, creative prevention. Adjusting the focus to include the study of multiple causes also brings the disease squarely into the public health field.
A central puzzle of dementias is the penumbra. Also, a feature of stroke, the penumbra or shadow that accompanies the surrounding dead tissue in the brain might explain why some stroke victims experience the growth of the penumbra that eventually leads to dementia. The process of penumbra raises radical scientific questions about the progression of dementias and whether or not the neuropathology can be contained.
Perfusion (blood circulation) and the role of vascular conditions play a major role in dementias. Emphasizing the roles of an active lifestyle, healthy diet, and awareness of vascular issues moves the discussion further into the public health realm. Within Complexity Theory, the concept of the brain functioning as a machine is incorrect. Even dementia patients learn new things, and they sometimes forget things then remember them, or have episodes of clarity. How can we explain this fluctuation through neuronal death? Appreciating that parts of the brain can continue to grow, switch capacity from left to right and back to front, and vice versa, and acknowledging that cognition might be an assimilation of different systems within the same brain, will help researchers ask more incisive questions about the role of the brain.
Acknowledging that the brain is always changing, neurons and glial cells constantly die and get replaced, where more than 30,000 proteins constantly misfold and get degraded, where constant injuries to the brain are accommodated, where memories are constantly re-imaged and prioritized, where cognitive functions are shifted from one area of the brain to another, all of these events define the daily functioning of our brain. The question that needs to be asked is why does this constant maintenance stops or becomes overwhelmed?
Science will benefit from a resurgence of sociological and philosophical discussion about the role of cognition in the mind, the distinction between mind and brain, and the concept of self. All these broad discussions have been rejected in preference for the more simplistic explanation. So far, after a century of confusion, it is time to stop repeating the same mistakes in the hope of coming up with new results. We need a new methodology that might provide different results.
Chapter 7: Synthesis
A more inclusive approach allows diverse literature to be included rather than ignored. The body as a sovereign entity a self-willed, independent, exclusive and free agent is an illusion. Ample evidence now shows that our body—meaning our brain and body—not only respond to external activity but also mirrors these activities. External influences—of which we are unaware most of the time—affect how we think, behave and feel. Social constructs, memes, and stereotypes affect us because we internalize and operationalize them within us. There is no impermeable barrier between our external environment and our body; an illusion of the mind creates this duality. No better example exposes this illusion than dementias and aging. The crescendo of fear of dementias affects us. We often live trapped in a world where fear dictates our future. Fear of dementia as represented by Alzheimer’s disease now represents perhaps the penultimate disease meme of the 21st century. To combat this we need to expand our study of dementias to include social and psychological factors, otherwise, we will remain in our current research cul de sac. We need to shift from a hypercognitive model to a caring model. Care might lead to a cure.
Chapter 8: Epilogue
This is as far as science can take us. Criticism of dementia research dictates a number of changes that need to be made at the Federal level to promote a healthier and more inclusive scientific debate. Scientists need to be very sure of what they are studying and to emphasize the validity and reliability of their subject matter. Such recommendations are necessarily abstract, nuanced, and academic. But on a more personal level, I can identify the basic parameters of the data and conjecture how I see this Complexity Theory apply at an individual level. This is not prescriptive in any way but the start of a discussion away from the neurobiology.
Recommendation for self-help
Summary and Class Discussion Points