Highlights from the 8th Annual International Alzheimer’s Disease Meeting
September 1, 2002 5 minutes read
Conference Coverage
Source: Neurobiol Aging. 2002;23(1S):S1-S606.
More than 2000 dementia-related studies were presented at the 8th International Conference on Alzheimer’s Disease and Related Disorders (ICADRD), held in Stockholm, Sweden, July 20-25, 2002. Several items of potential interest to neurologists bear mention.
If there were such a title, cholesterol would probably have been voted "Molecule of the Year" at the 2002 ICADRD meeting, based on the sheer number of presentations concerning the cholesterol-lowering statins as a potential means of treating Alzheimer’s disease (AD).
Two years ago, 2 retrospective epidemiologic studies suggested that use of statins might reduce the risk of AD as much as 40-79% (Wolozin B, et al. Arch Neurol. 2000;57:1439; Jick H. Lancet. 2000;356:1627). Two new epidemiologic studies presented at the ICADRD lend further support to this idea. A retrospective study from Boston University carried out on 2378 individuals from Alzheimer-affected families, including 547 African Americans, found reduced risk of AD among statin users regardless of their APOE genotype, race, or the brand of statin prescribed. Another study examined 4740 residents of Cache County, Utah, older than 65 years and found that statin use was associated with a reduced prevalence of dementia but had no statistically significant effect on AD incidence. In addition, use of statins that penetrated the blood brain barrier was associated with less risk reduction than use of agents that did not enter the brain, such as atorvastatin (Lipitor®). This is the first substantive study to find that statin use inversely correlated with the prevalence, but not incidence, of AD, and the first to indicate possible differences among available statins in lowering risk of AD. Other presentations at the ICADRD provided evidence that cholesterol can influence the pathophysiology of AD and suggested mechanisms whereby statins might exert their protective effects. While these developments are encouraging, prospective verification of AD risk reduction by statins has yet to be carried out. However tempting this may seem, it is premature to consider prescribing statins for the sole purpose of preventing or treating dementia until prospective tests are completed.
Another topic that received considerable attention at the ICADRD meeting was the identification of prognostically relevant subgroups among patients with mild cognitive impairment (MCI). Patients with MCI have memory or other cognitive impairments that are greater than most people their age, but are not sufficiently impaired functionally to be considered demented. MCI patients are at increased risk for development of dementia, with an estimated 10-15% progressing to diseases such as AD each year. Several studies have now indicated that the MCI population is heterogeneous, and not all patients with MCI have the same level of risk for developing AD. The emerging consensus is that most patients with MCI will go on to develop dementia within 10 years, but not all will develop AD. It is now recognized that subgroups of MCI patients can be distinguished that have the highest likelihood of developing AD. Unfortunately, there is still a great deal of variability across studies in defining these MCI subtypes. "Amnestic MCI" and "MCI-AD" are 2 such characterizations of MCI patients that attempt to identify a greater likelihood of developing AD based on the characteristics of the cognitive impairments. Definitional issues and the difficulties involved in testing for the relatively subtle cognitive deficits associated with MCI are likely to limit the clinical application of the MCI construct for the time being. Once these issues have been overcome in the future, identification of MCI and its subtypes is likely to become an important part of the strategies used for the early detection and prevention of AD.
Acetylcholinesterase inhibitors were the subject of some discussion at the ICADRD conference. Head-to-head comparisons of the available agents revealed distinctions among donepezil, rivastigmine, and galantamine in terms of their ease of use and tolerability, but less clear differences in their efficacy. Broadened use of these agents in treating other forms of dementia can be anticipated based on the results of studies using galantamine and donepezil in patients with vascular dementia and mixed dementias. The results reported at the ICADRD suggested short-term (6 month) symptomatic benefits in treating patients with vascular dementia. The long-term benefits have yet to be determined, and as yet, none of the cholinesterase inhibitors have received FDA approval for this indication.
Acetylcholinesterase inhibitors are the mainstay of therapy for AD throughout the world, but several new classes of medicines are under development. Among the latter group, the selective NMDA antagonist Memantine shows promise, both in terms of its efficacy in treating severe dementia and its track record of tolerability. Memantine has been approved for treatment of dementia in Germany for over a decade, and it is currently in Phase 3 clinical trials in the United States. The glutaminergic mechanism of action of memantine is distinct from that of other currently approved treatments. At least one study presented at the ICADRD suggested that memantine can be safely administered in combination with acetylcholinesterase inhibitors. Barring unexpected results in ongoing clinical trials, memantine appears to have reasonable prospects for future approval in the United States as a symptomatic treatment for AD.
Looking to the future, one of the most exciting developments in AD therapeutics is the advent of techniques for manipulating beta-amyloid production and deposition in the brain. The use of immunotherapy against amyloid suffered a setback this past year when several patients in the Elan AN1792 trial developed brain inflammation. Nevertheless, immunotherapy is still considered to be a viable approach, although modifications to the active immunization strategy used by the Elan trial will be needed. Another interesting approach involves the development of small molecules that can sequester amyloid in the periphery, thereby creating a gradient for movement of amyloid out of the brain. Animal studies suggest the feasibility of this approach, and clinical trials are anticipated in the near future. The development of inhibitors targeting the amyloid-producing secretase enzymes is also moving forward, although no efficacy data from human trials have been formally presented as yet. With the multiplicity of agents designed to alter amyloid burden now in the pipeline, new brain imaging methods are needed to measure amyloid burden in living brain. Techniques currently under development use radioligands or MRI contrast labels to bind plaques in human brain. While it may be several years before amyloid imaging and amyloid-based treatments become part of routine clinical practice, these developments suggest that a new era in AD diagnosis and treatment is now getting underway. —Norman R. Relkin
Dr. Relkin, Associate Professor of Clinical Neurology and Neuroscience, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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