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Neurology Today:
doi: 10.1097/01.NT.0000368761.13949.29
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A Critical Reconsideration of Alzheimer Disease

FILLEY, CHRISTOPHER M. MD

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Dr. Filley is professor of neurology and psychiatry and director of the Behavioral Neurology Section at the University of Colorado-Denver School of Medicine.

Treating Dementia: Do We Have A Pill For It? Edited by Jesse F. Ballenger, Constantine G. Lyketsos Peter J. Whitehouse, Peter V. Rabins, Jason H.T. Karlawish. 280 Pages. Johns Hopkins University Press 2009.

Alzheimer disease (AD) is one of society's most urgent medical problems. Not only is this devastating disorder diagnosed frighteningly more often each year, it also remains stubbornly refractory to efforts to find its cause and cure, and the anticipated burdens to individuals and society become ever more ominous. In the last few decades, a handful of AD therapies have been introduced, with at best modest clinical benefits; the inadequacy of these medications is widely acknowledged. In this context, it is not surprising that conventional approaches to the problem will be critically examined. This book raises fundamental questions not just about how AD is treated, but indeed whether in fact it can be considered a disease at all.

Treating Dementia: Do We Have A Pill For It? focuses on AD, the most common dementia in older people, and other dementias are mentioned only in passing. This emphasis is deliberate, as the primary subject is the vast and diverse enterprise dealing with AD and the many stakeholders involved.

The book is a multi-authored text that in some ways resembles the many volumes one can peruse at a neurology meeting devoted to one or another neuroscientific topic. But this one is different. From the first few pages, it is evident that a major goal will be to examine the very idea of AD by considering how it actually came into being and what influences continue to shape its understanding today.

Representing the orthodox view of AD and its neurobiology, Donald L. Price, MD, Johns Hopkins University (JHU) professor of pathology, neurology, and neuroscience and colleagues present an authoritative chapter on well-known basic science findings that have recently structured the AD field: the cholinergic hypothesis, N-methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity, and the amyloid cascade hypothesis. These three lines of inquiry have all led to current or potential treatments, and satisfy to a considerable extent the need for a biomedical model. Here is what can be called the molecular approach to AD, demonstrating that progress on some neurobiological aspects of the disease has indeed been substantial.

Yet uncertainty is growing about all of this in view of the feeble efficacy of cholinesterase inhibitors and NMDA-antagonism, and, most recently, the apparent failure of amyloid-directed immunotherapy to meaningfully improve cognition. Commenting on the disappointment engendered by such results, Peter V. Rabins, MD, JHU Richman Family Professor for Alzheimer's and Related Disease and co-director of Division of Geriatric Psychiatry and Neuropsychiatry, in the final chapter, finds it “unconscionable” that cures for AD are regularly and erroneously predicted within five years, while appropriately cautioning against the nihilism that can develop in the face of so many negative results.

The pharmaceutical industry comes under heavy fire. A recurrent theme is that the usefulness of AD medications – from tacrine to memantine – is far more apparent in the rhetoric of marketing than in clinical practice. Drugs with significant cost and potential toxicity are heavily promoted despite their limited efficacy. Direct consumer advertising of drugs only adds to the problem, fostering public desire to take AD drugs for which the medical profession has little enthusiasm.

In a particularly trenchant chapter JHU geriatricians John Gilstad, MD, and Thomas Finucane, MD, point out that nearly all data supporting the use of currently approved AD drugs have been gathered by industry-sponsored research and that drug company promotional efforts even seep into the medical literature. While industry misconduct is not specifically alleged, financial motivations are interpreted as influencing the persuasive language of papers reporting clinical trial results. These authors conclude with the arresting statement that “in 10 years we will be embarrassed that we were manipulated by drug companies into channeling so many billions of dollars to the drug companies and away from these tragically ill patients and their valiant and sometimes desperate caregivers.”

Still, other authors in Treating Dementia concede that the AD drugs have mild efficacy in some people some of the time. The value of hope is often invoked, and many clinicians will no doubt endorse the potential utility of offering medication that, after all, has been discovered as a result of basic science research, clinically tested for many years, and approved by the United States government. A practicing JHU academic psychiatrist, Allen A. Anderson, MD, declares in his chapter that “any treatment benefit, no matter how trivial or short-acting, is a blessing.” The problem is whether this benefit is clinically meaningful, and thus whether the medications merit so much societal expenditure. Perhaps the money would be better spent on more humanistic efforts to improve quality of life.

Representing patients, caregivers are also given their due. In her exceptionally well written chapter “Managing Dad,” writer Judith Levine elaborates the view that for her “hope will not be found in chemicals, but in relationships and communities.” Those caring for people with AD constitute a large, often less visible group, sometimes called the second victims, who must witness the inexorable cognitive and emotional decline while drugs do little good. Are marginally effective pills better than a caring community, a stable living situation, and regular exercise?

Figure. DR. CHRISTOP...
Figure. DR. CHRISTOP...
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What readers will likely find most controversial is the question of whether AD is even a disease. In the chapter, “Can We Fix This With a Pill?,” Case Western University Neurology Professor Peter J. Whitehouse, MD, PhD, steps squarely into this debate, suggesting that AD may be a form of cognitive aging. While not completely dismissing the biomedical model of AD, he has clearly become skeptical, finding this claim “more political than scientific.” In this sense, AD has been artificially conceptualized in an effort to medicalize the process of cognitive aging. He uses mild cognitive impairment as another, more current example of how a “disease” can be socially constructed. This critique represents a remarkable shift in his perspective, as he was indeed a major contributor to the basic science leading to the development of the cholinergic hypothesis three decades ago.

As a whole, Treating Dementia considers the medical response to AD as a continuum ranging from basic scientific and pharmaceutical company research to comprehensive patient-centered care. Naturally, one hopes that both imperatives can be met, so that we can pursue not just the etiology and pathogenesis of dementia in older people but also how to optimally treat its sufferers and help their families until more effective methods become available. Perhaps the medicalization of AD compromises efforts to better care for people in need, but it is also likely that something is terribly wrong with the brains of people with what we have come to know as AD.

The challenge of AD is to attack the problem at all levels — from bench to bedside — and integrate the information into an ever more satisfying synthesis. Many other diseases have proven distressingly mysterious until their origins were elucidated and their treatments established. This provocative book serves the important purpose of obliging the reader to reconsider basic notions about AD, most notably the extravagant claims of the pharmaceutical industry.

Hope must be maintained, but so should realistic expectations, without drug company hype and with proper respect for the perplexing neurobiology of the disease. There is much to learn about how to treat AD, and the complex systems of medical care, scientific research, and drug development must collaborate effectively to accomplish the task. While many points in this book will doubtless prove contentious, AD is an impressively difficult medical problem, and reconsidering fundamental assumptions has a humbling and, in the end, salutary effect.

©2010 American Academy of Neurology

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