Journal of Molecular Neuroscience Copyright © 2002 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/02/19:1–3/$10.75

Introduction

Strategies for Drug Discovery for Cognitive Aging and Alzheimer’s Disease Howard M. Fillit, Alan W. O’Connell, and Lorenzo M. Refolo The Institute for the Study of Aging, New York, NY Received October 1, 2001; Accepted October 16, 2001

showing that modifiable lifestyle risk factors and medical co-morbidities can contribute to cognitive decline in late life, such as physical and mental exercise, education, social engagement and occupational complexity, alcohol, smoking, diabetes, hypertension, and elevated cholesterol. All Alzheimer’s patients develop characteristic neuropathological features including the amyloidcontaining neuritic plaques, tau containing neurofibrillary tangles and the loss of cholinergic neurons in specific regions of the brain associated with cognition. These hallmarks of AD have provided researchers with important clues concerning the key therapeutic targets for AD. Currently, FDA approved therapeutic options for patients with AD are very limited, and focus on improving the cognitive deficits associated with the disease. These treatments, called acetylcholines-terase inhibitors, target acetylcholinesterase, the enzyme that breaks down the key memory-associated neurotransmitter acetylcholine. Deficiency in this neurotransmitter is believed to contribute to the cognitive impairment observed in AD. Unfortunately, these drugs have limited efficacy and probably have no effect on modifying the underlying disease or dementing process. Clearly, in order to more successfully treat and/or prevent AD, we are going to need more effective treatments, particularly with disease-modifying or preventive capabilities. The successful prevention and/or treatment of AD is linked to the development of accurate and convenient early detection methods that can identify AD before significant neuronal degeneration has occurred, particularly those individuals in the population at risk of developing AD. The current inability to detect the disease in its early stages significantly impedes the prospect of developing effective thera-

Alzheimer’s Disease (AD) is a progressive degenerating disease that slowly kills nerve cells, resulting in memory loss, language deterioration, impaired visual-spatial skills, poor judgment, and indifferent attitude. It is the major cause of dementia in middle-to-old age individuals throughout the world. Currently, it is estimated that worldwide there are 40 million people affected by Alzheimer’s disease and it is estimated that by the year 2030 this number will reach in excess of 60 million. In addition to the millions suffering AD, many more millions of individuals suffer lesser degrees of cognitive impairment with aging, such as mild cognitive impairment (MCI) and age-associated memory impairment (AAMI). Increasingly, therapeutic strategies and clinical trials (particularly prevention trials) are moving towards addressing issues of MCI and AAMI. An increasing amount of research is being directed to agents to be developed to prevent the progression of MCI to AD. And although research on AAMI remains somewhat in its infancy, there is a growing recognition that we no longer must accept AAMI as an inevitable part of aging. Agents for AAMI, primarily new cognitive enhancers, may soon be among the many “quality of life” drugs available to older persons to improve their function. Few now believe there is a single cause of AD. The disease is likely the result of a combination of multiple genetic and environmental factors. Mutations in three genes (APP, presenilin 1 and 2) have been identified to play a role in the autosomal dominant form of AD, although this is rare and affects less than 1% of all cases. Polymorphisms in several genes including ApoE and alpha 2-macroglobulin are associated with the more common, sporadic form of AD. However, and perhaps even more important to the general population, is the recent research

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2 pies for treating this devastating disease. In addition, there is a need to develop techniques that can enable physicians and researchers to monitor the effectiveness of therapeutic intervention on disease progression and/or prevention. Such surrogate markers would facilitate clinical trails and regulatory approvals. Ideally, physicians treating AD patients will have at their disposal accurate early detection methods, a range of truly effective therapeutic options to treat and prevent AD and techniques that enable them to monitor the effectiveness of therapeutic intervention on disease progression. A great deal of progress has been made recently in the arena of early detection employing newly developed imaging techniques such as MRI and PET scanning. In recent years much progress has been made in the fight against AD and cognitive aging. Although many questions remain unanswered, we now have a clearer understanding of the possible causes. This progress has presented the research community with a significant increase in the numbers of possible therapeutic targets that may be useful in the treatment and/or prevention of AD and cognitive aging. There is now a real need to direct financial and other resources to help validate these newly identified therapeutic targets and more importantly to use them to develop truly effective therapeutics. The development of new therapeutics and detection methods for AD and cognitive aging is considered high-risk and long-term. This has resulted in those working in the field encountering problems securing the resources necessary to develop new treatments and early detection methods for AD and cognitive aging. The Institute for the Study of Aging (ISOA) is a non-profit foundation, privately funded by the Estee Lauder Trust, that helps provide the resources necessary to capitalize the research progress that has been made and translate it into new and effective treatments for AD and cognitive aging. The Institute, founded in 1998, has a mission to catalyze and fund the discovery and development of the next generation of therapeutic drugs for AD, related dementias, and cognitive aging. In addition, the Institute is engaged in funding the development of early detection and other techniques that will aid physicians in the prevention and monitoring of disease progression. The Institute has currently committed over $16M in funding to 58 programs in academic institutions and the biotechnology industry in the US and worldwide. These programs cover the drug discovery and development continuum from target

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Fillit et al. identification through to clinical evaluation in Phase I/IIa and off-label human trials. The programs target a wide range of established and novel therapeutic approaches, including alternative anti-amyloid and anti-tangle approaches, new antioxidants, neuroprotectants, hormones, anti-cholesterol, antiinflammatories, and novel cognitive enhancers. Significant funding has also been committed to the development of technologies to help in the early detection and monitoring of disease progression. Since its establishment, numerous important research findings have been made by Institute supported scientists. During 2001, for example, the Institute funded the first anti-cholesterol statin trial for AD and also the first gene therapy AD clinical trial. As part of its mission, the Institute aims to disseminate the research findings of its scientists to the research and lay communities as an update its scientific progress. On October 14–15, 2001, the Institute held its Second Annual Investigator ’s meeting, which was attended by 47 of its funded investigators from academia and the biotechnology industry. This was a significant increase from 2000 and reflected the growth and diversification of the Institute’s funding portfolio. At the meeting, the funded investigators discussed their progress in developing new agents for the prevention and treatment of Alzheimer’s disease and cognitive aging. In addition, this unique meeting brought together academic and industry scientists, all of whom are focused on one mission, drug discovery for cognitive aging and Alzheimer’s disease. The meeting facilitated the development of collaborations within the Institutefunded network to facilitate the drug discovery and development process for AD and cognitive aging. The second report of the series Drug Discovery and Development for Alzheimer’s Disease 2001 is being published in the Journal of Molecular Neuroscience in order to achieve even wider dissemination and recognition of the Institute’s investigators research results. In this supplement, Institute-funded investigators have described the advances made by them and their colleagues during 2001 with regard to drug discovery and drug development for cognitive aging and Alzheimer’s disease. We would like to take this opportunity to thank all our funded investigators, scientific advisory board members, and Institute staff for the dedication and expertise that has made these scientific advances towards new treatments for AD and cognitive aging possible. We particularly owe special thanks to Tonya Lee for her efforts in organizing

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Strategies for Drug Discovery the meeting and insuring its efficient and effective conduct. We at the Institute look forward in the coming years to continuing to share our progress in the search for new and effective treatments for AD and

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3 cognitive aging. We remain as ever true to our vision, “that one day in the not-too-distant future, old age will no longer be accompanied by the dreadful fear and indignity of the loss of memory and mind.”

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