One of the most common questions newly diagnosed patients ask is: “What’s in my future?” That question harbors the fear of an ultimately fatal disease, as the “script” associated with Parkinson’s is that of a progressive disease that leads to loss of independence, confinement to a wheelchair and, ultimately, an early death.

The year was 2015. Members of the Movement Disorders Society were abuzz with interest over the publication of a new set of criteria for the diagnosis of Parkinson’s disease. Discussions around the world centered on how to put the changes in perspective. How different were the new criteria compared to the one we had relied on for most of the prior two decades? How would it impact research? Could it be useful in sending us down a new path that might finally culminate in disease-modifying therapies?

An editorial perfectly timed as we approached the final work on this book was published in the October 2019 issue of Lancet Neurology. With the title, “Re-aligning scientific and lay narratives of Alzheimer’s disease,” several Alzheimer’s investigators pointed out a discrepancy between the narratives circulated among Alzheimer’s patient advocates and those in academic circles. The advocates’ narrative centers around the belief that each case of Alzheimer’s is its own unique disease; the scientific narrative, while acknowledging the heterogeneity, is based on a “theory of everything,” the overarching path to Alzheimer’s that can be generally applied to all cases.

That second narrative, in part because of the esteemed researchers that tell it, attracts the lion’s share of funding. It portrays neuroscience as being on the brink of treatments to slow down Alzheimer’s. All that is needed is larger, more resource-intensive studies into what is being done to address everyone’s Alzheimer’s disease.

Like other fields of medicine, neurodegenerative disorders will move from reductionism, in which any evidence about aspects of a disease inform about a global disease, to systems biology, in which genetic and biological signals prevail as anchors on how diseases are subtyped, diagnosed and treated. The recognition that the manner in which a disease expresses does not predict an underlying biology will allow us to move to a biology-first approach to studying diseases of brain aging.

As Brain Fables was going through the final stages of publishing we became aware of Dr. Kariem Ezzat’s work on the physics of amyloids. In his laboratory at the Karolinska Institute, in Stockholm, he and his team have been examining what happens to proteins as they transform from their soluble to insoluble state (that is, go from being dissolved in the liquids in and around cells to becoming solid objects). Their experiments showed that as the normally soluble protein encounters an abnormal surface, such as a nanoparticle or a virus, referred to as a “nucleating factor”, it is forced to aggregate, becoming solid or insoluble; and turns into an amyloid. Many proteins help preserve the integrity of neurons in a soluble state.

Aggregated brain proteins are enshrined in a century-old model of disease, the clinico-pathology model. The clinico part includes the diversity of symptoms and signs that are the expression of many types of abnormalities of brain aging: stooped posture, memory difficulties, problems with urination, depression. The pathology part is what we assume brings it all together. If a brain after death is seeded by plaques containing beta-amyloid and neurons filled with tangles of tau, these clinical signs can be safely assumed to belong to one disease: Alzheimer’s.

Throughout this book there has been one theme permeating each chapter: Parkinson’s and Alzheimer’s are not two distinct diseases but a spectrum of disorders. The stories created for each are as compelling as they are fictitious. There is no such thing as Parkinson’s disease. There is not such thing as Alzheimer’s disease. These are but powerful ideas. The time has come to accept that any mechanistic discoveries related to a form of Parkinson’s, especially the genetic ones, such as those due to GBA mutations, are potential targets for therapeutic development for only those subtypes. No treatment revolving around one mechanistic discovery can be expected to slow the progression of diseases as complex and multifaceted as Parkinson’s or Alzheimer’s, let alone “cure” them.

Neurology journals have been flooded with review articles on biomarkers and “precision medicine.” Many start with the standard disclaimer that a major challenge for the development of biomarkers is the numerous biological processes responsible for Parkinson’s and Alzheimer’s diseases. One such disclaimer goes like this: “ … [finding a biomarker or a drug to work on all Parkinson’s patients] is wrong because (1) Parkinson’s disease is not a single disease, and (2) no two individuals have the same biological makeup.” So far so good. However, the very next paragraph starts with: “Now let us summarize the work done to date on validating biomarkers of progression for Parkinson’s disease.” No further mention is made of which disease these efforts pertain to. (Presumably all!) These articles invariably surrendered to the luring power of sophisticated analytic methodologies to overcome the shortcomings mentioned in the disclaimer.

A decade ago one of my colleagues was asked at a conference, “When will we have a cure for Parkinson’s disease?”

“It could happen at any time,” he replied. “It could happen next year. It could happen in 10 years. It could happen tomorrow.”

My colleague’s optimism was well-founded. Talented researchers were hard at work in laboratories throughout the world, and money was pouring in from governments, the pharmaceutical industry, and foundations large and small. The Michael J. Fox Foundation had become a muscular force that was determined to take down this progressive, degenerative disease.

Levodopa is the closest thing we have to a miracle in modern medicine. When people with Parkinson’s disease start treatment with this molecule and its dose is titrated to an optimal level, many symptoms vanish – at least for the duration of its therapeutic action. The effect on the overall function of a patient affected by Parkinson’s symptoms is so marked that “response to levodopa” was enshrined as part of the clinical diagnosis of Parkinson’s disease. Lack of or poor response to levodopa raises the concern that the patient might not have Parkinson’s disease at all.

In Chapter 4 we reviewed the findings of an important study that demonstrated an ostensible paradox: when we divide patients into subtypes, based on mild, intermediate, and “diffuse malignant” levels of severity, the brain pathology at autopsy does not vary between groups in either severity or distribution. In this chapter, we will examine an even more difficult paradox: the proteins that get identified at autopsy to confirm a diagnosis may have nothing to do with why neurons die.

After taking the patient’s history and completing a full examination, Dr. Smith summarizes his findings: “Based on my experience and the diagnostic criteria available, you have Disease X. We could support this diagnosis by Test Y, although my clinical impression should suffice. Because the progression of Disease X varies among patients, it is impossible to predict the speed of such progression for you. I suggest we start Treatment Z soon.”

In Sapiens, Yuval Noah Harari argues that humankind’s greatest invention is our ability to create and believe fictions. While all other animals communicate realities with which they interact, humans create a separate layer of subjective, interpretative realities. The fiction most universally embraced today is money. “Dollar bills have absolutely no value except in our collective imagination, but everybody believes in the dollar bill,” says Harari.