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Leon Thal and the therapeutic age of Alzheimer's disease

By Paul S. Aisen

University of California, San Diego (San Diego, CA, USA)

Alzheimer's disease (AD) is not a degenerative condition of the aging brain about which nothing can be done (although such nihilism was accepted for three quarters of a century after Alois Alzheimer's first report); AD is a specific and treatable disease. Many, many individuals have made important contributions to this sea change, but many in the field would agree that one person, Leon Thal, did more than any other to bring us into the therapeutic age of AD.

Leon was among a group of forward thinking scientists who embraced the cholinergic hypothesis of AD during the late 1970s and early 1980s. He was among the first to translate the hypothesis into clinical intervention, conducting both animal and human studies. His early clinical trials in AD started with a negative study of choline, followed by positive studies of physostigmine plus lecithin and then physostigmine alone. He went on to investigate tacrine in rodents and was a leader, with Ken Davis, of the first large-scale multicenter trial of tacrine in AD, a study that used an interesting enrichment design to demonstrate the cognitive benefits of cholinesterase inhibition and was perhaps the pivotal study to launch the therapeutic age. As Leon commented on acceptance of the 2004 Potamkin Prize for Research in Pick's, Alzheimer's, and Related Disorders, “The importance of this trial was that a drug was demonstrated to enhance cognition in AD and a regulatory pathway for approval of such agents was established. All subsequent cholinesterase and memantine marketed have followed this same regulatory pathway.” Approval of tacrine by the Food and Drug Administration occurred in 1993, and much of the pharmaceutical industry joined the effort to develop safe and effective AD treatments.

From the collaborative group that conducted the first large tacrine trial, with the encouragement of National Institute on Aging visionaries, the Alzheimer's Disease Cooperative Study (ADCS) was born in 1991. Co-authors of the tacrine study article, including Lon Schneider, Peter Whitehouse, John Morris, Claudia Kawas, David Knopman, and Rachelle Doody, became some of the central figures in the establishment and growth of the ADCS. The mission of this organization is to advance the clinical testing of drugs for AD patients by performing functions that individual academic centers and the pharmaceutical industry are unable or unwilling to do. The philosophy for the choice of drugs tested by the ADCS is to serve the public need to develop promising new treatments for AD. Leon Thal was the founder and Director of the ADCS.

Those of us who have attended the ADCS meetings during the past 16 years and worked on the trials are quite certain that there is no other person who could have created this consortium. The drive, humor, intelligence, perseverance, fairness, diplomacy, wit, and kindness required for this colossal task existed together in one person only. The ADCS brought together this country's leading AD clinical investigators to consider the myriad problems slowing AD therapeutic research and established the network that has played a huge role in advancing the field and paving the road to the breakthrough disease-modifying treatments that are now close.

What are the contributions of the ADCS to the field of AD therapeutics? The ADCS brings together, three times each year, this country's leading academic AD trialists to consider developments in the field, suggest approaches to current roadblocks, consider new directions in assessment methodology and analysis, and discuss ethical issues in AD drug development. With each National Institutes of Health (NIH) funding cycle, the ADCS implements therapeutic trials and instrument development studies selected in a multi-tiered review process to represent the most essential projects for public funding.

In its first grant cycle, the ADCS launched a large multicenter trial, led by Mary Sano, of two antioxidants, vitamin E and selegiline, for the treatment of moderate stage AD . This trial demonstrated a modest beneficial effect of each of these interventions in slowing clinical progression. These findings had a huge impact on management of AD and provided evidence that oxidative stress in the brain is an appropriate target for therapeutic research.

The ADCS has a strong record of accomplishment in the development, characterization, and refinement of AD assessment tools, an effort led by Steve Ferris. The ADCS is now the leading source of standard outcome measures, including the cognitive portion of the Alzheimer's Disease Assessment Scale (the most widely used primary outcome measure in the field), for both academic and industry investigators. In addition to refinement of the ADAS-cog, the ADCS has developed assessments of activities of daily living, global clinical change, and pharmacoeconomics, among others. The ADCS Data Core, led by Ron Thomas, working with the organization's project leaders (including Mary Sano and Pierre Tariot, for example), have also contributed to novel analytical methods and clinical targets, such as the use of composite clinical end points for survival analysis, and prophylaxis against behavioral disturbance in AD. Notably, the ADCS study of donepezil and vitamin E in mild cognitive impairment (MCI), directed by Ron Petersen and Michael Grundman, established standards for trials in this population and for the first time showed evidence of response to treatment.

One task of the ADCS had been to test hypotheses generated by epidemiologic studies. Two examples of such ideas are the beneficial effects of estrogen and anti-inflammatory drugs on the pathobiology of AD. In a series of trials, the ADCS clearly demonstrated the lack of efficacy of estrogen and both steroid and nonsteroidal anti-inflammatory drugs in AD treatment. Although clinical trials only test specific treatment regimens in strictly defined populations, these studies have altered perceptions of these theories and have had a significant impact on public health.

Leon saw the importance of collaborations between NIH-funded investigators and industry. Industry, federal regulators, and academic scientists differ in their roles and aims, but they share the mission of delivering better treatment options to the public. Shared expertise and collaborative efforts further the aims of all. The successful joint venture between the ADCS and Pfizer in the MCI trial has led to a number of other fruitful collaborations with large and small companies. A particularly important example of academic-industry partnership is the Alzheimer's Disease Neuroimaging Initiative (ADNI). This huge project, led by Mike Weiner at the University of California San Francisco, is co-funded by the National Institute on Aging and a consortium of pharmaceutical companies. ADNI is a multicenter clinical study using multiple neuroimaging modalities, along with cognitive, behavioral, and biochemical assessments, to characterize the utility of various biomarkers in tracking individuals with AD or MCI as well as cognitively normal older individuals. ADNI is the most ambitious private-public collaboration in the field and has demonstrated the feasibility of real-time posting of study results with open data sharing. Leon was pivotal in the design, implementation, and direction of ADNI, working closely with Mike Weiner, Ron Petersen, and the many other leaders of the project. The ADCS provides the infrastructure to support ADNI.

It is not easy to envision the field of AD therapeutics without Leon's wide-ranging contributions. He was an outstanding teacher; he encouraged and assisted investigators at all levels, from students to established leaders. Many entered the field under his guidance and inspiration; he was certainly the father of AD clinical trialists. Leon was the shepherd to all of us; where would we be if he had not led the way? Millions worldwide have benefited from his efforts. But more, the next generation of AD therapeutics, effective disease-modifying agents, will arrive soon and will represent Leon Thal's greatest legacy.