Alzheimer’s 101

By Zaven S. Khachaturian

The year 2007 marks the beginning of "Alzheimer’s 101," a renewed campaign to conquer all forms of dementia and memory disorders.

As the celebration of the 100-year anniversary of Alzheimer’s research comes to a close, patients with cognitive impairment remain frustrated by the lack of effective interventions. Ever-increasing life expectancy and the pending exponential rise in the prevalence of dementia together underscore the urgency of the public’s concerns about strategies to accelerate the discovery of cures for brain diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s diseases. The public’s impatience with the slow pace of progress in developing therapies for dementia is understandable. We must remember, however, that there are numerous hurdles associated with such progress, whether that progress takes the form of launching a new national initiative of research or redirecting the focus of an already well-established program.

Although research on brain disorders has a long history, the current profusion of knowledge on the neurobiology of these brain disorders was only recently acquired. Only 30 years ago, conventional wisdom regarded Alzheimer’s disease as a hopeless and untreatable condition. In academia, the disease generated little interest in research except for a handful of plucky investigators. Federal expenditures on research were virtually zero. Twenty-five years ago, the clinical infrastructures essential for systematic longitudinal studies of well-characterized patients were not available. Twenty years ago, the concepts of "cure" and "prevention" were inconceivable. Crucial clinical tools such as diagnostic criteria, standardized assessment instruments, cadres of specialized professionals, memory disorder clinics, family support groups, or outreach programs — all of which are taken for granted now — did not exist. Fifteen years ago, information on genes and/or biologic pathways involved in the development of the disease was limited at best. Ten years ago, animal models of the disease did not exist. Five years ago, persons at high risk for the disease could not be identified, and the idea of clinical trials for prevention or for delaying symptoms was only a pipe dream. Hallmark lesions of the disease could not be directly visualized in patients until 2004.

Today, in less than three decades, research has yielded significant progress and propelled the efforts against this disease from obscurity to the forefront of modern biomedical science. The indices of this remarkable transformation are the exponential increase in scholarly publications and the dramatic increases in the numbers of investigators. The genes involved in early-onset Alzheimer’s disease and a risk (susceptibility) gene have been identified. Traditional thinking on brain aging has been reversed on its head with the discovery that healthy aging nerve cells can regenerate. We have learned a great deal about the genetics, synthesis, degradation, aggregation, toxicity, folding, and clearance of abnormal proteins involved in the pathogenesis; we have developed strategies on how to prevent their toxicity. Intensive studies are underway on multiple fronts, from basic science to genetics to drug therapy to caregiving. Several clinical trials with promising leads for disease-modifying compounds are underway. The field is more optimistic than ever about the prospects of discovering more effective treatments and, ultimately, methods for preventing the disease entirely. These positive expectations, however, must be moderated with current realities. Insufficient knowledge about critical therapeutic targets, inadequate funding and resources for research, an array of organizational and administrative impediments, and the very nature of a disease that is unlikely to be amenable to single-drug treatments all combine to make this issue one of the most challenging the mental health field has ever faced.

The progress to date would not have been possible without strategic planning and a commitment for systematic investment in research, capacity building, and infrastructure development. In 1978, the National Institute on Aging (NIA) began to develop the plans for a comprehensive national program of research on "Brain Aging" and "Alzheimer’s disease" at the National Institutes of Heath (NIH). With its limited initial resources, NIA necessarily took a long-term strategic approach and systematically addressed numerous logistical hurdles. The most critical challenges were to recruit the best scientific talent, to identify promising ideas, and to develop critical research resources and infrastructures. The NIA’s experiences during the early formative years of program development might provide valuable guidelines for prospective initiatives to find cures for cognitive impairments. Today, just as it was the case nearly 30 years ago, the need for strategic thinking and planning is paramount.

Neuroscience research is extremely costly and highly technical. Unraveling the mysteries of the brain and halting the insidious wreckage of brain diseases require highly sophisticated research tools and equipment. Many investigators, even at the world’s leading research universities, are seriously constrained by the lack of easy access to essential resources. New instrumentation to permit measurement of biologic processes, not previously ascertainable, is also expensive and often requires highly trained scientists and technicians, which adds additional cost. Although the field has recruited the best scientists in the world, all of them committed to finding life-saving treatments, and although we have made progress in understanding the neurobiology of these diseases, the research enterprise for finding a cure is in jeopardy.

The critical challenge for "Alzheimer’s 101 Campaign" is to formulate a new national strategy, a business plan, to answer a common question: "What is being done to accelerate the discovery of cures for brain diseases?" Although the prospects of delaying the onset of symptoms or preventing disability might now be technically feasible, the more difficult challenge is to translate the basic knowledge on neural repair/regeneration into practical applications. The barriers to the discovery of a cure include not only inadequate funding, the high cost of clinical studies, a lack of adequate resources, and appropriate modeling systems but also the management of discovery programs. The administrative and decision-making structure for supporting research simply cannot meet the needs of the rapidly evolving scientific world. There is a need for a flexible system that supports rapid decision making and can handle unexpected opportunities and breakthroughs.

To this end, the Lou Ruvo Brain Institute (LRBI) is forming partnerships to lead the charge; it will plan and organize our efforts in the "Alzheimer’s 101 Campaign" with a cure as the ultimate goal.* The Institute is dedicated to the conquest of not only Alzheimer’s disease but also Huntington’s, Parkinson’s, amyotrophic lateral sclerosis, and other chronic brain disorders affecting cognitive functions.

The new battlefront is much broader than Alzheimer’s or the heated scientific disputes on the roles of various twisted molecules. The ultimate enemy is the problem that the patients experience and families have to face every day, the loss of memory—a common feature in a number of brain diseases. The goal is to foster the creation of a new paradigm for planning and supporting the organization of worldwide cooperative research networks to develop new technologies for early detection and treatments for various forms of memory impairments. The mission of the LRBI is to add a voice in advocating for increases in the federal budget for research. The Institute aims to (1) develop a national resource to discover new interventions for memory disorders and (2) create a streamlined decision-making process in the selection and support of new ideas.

As the baby boom generation ages and brain diseases become more prevalent, we must confront the pending health care crisis this demographic change will pose. As resources become more difficult to allocate, we must reconsider our national priorities. As part of that exercise, it is now critical to significantly expand research on disorders of the aging brain. Ultimately, investment in brain research is the only cost-effective means to avoid the pending public health catastrophe this country faces. The new model of public-private partnerships the LRBI is creating, in collaboration with Alzheimer’s Association, Hereditary Disease Foundation, and other entities, will provide the strategic vision and leadership that will bring critical knowledge and the essential building blocks for discovering a cure.

* The LRBI is the medical-scientific branch of the Keep Memory Alive foundation, a Nevada-based not-for-profit organization, devoted to promote healthy “vital aging” and enhance the quality of life for a burgeoning number of people with cognitive impairments and dementia.