Therapeutics and Mild Cognitive Impairment: Current Status and Future Directions

To date, most AD treatments have been based on the hypothesis that amyloid is causally responsible for nerve cell damage, which in turn leads to biochemical defects and, ultimately, to clinically apparent dementia (Fig. 1). In the 1970s, it was noted that mental status test scores of patients with AD correlated with choline acetyltransferase levels. As a result, the earliest neurotransmitter-based treatments for AD were designed to augment neurotransmission of the cholinergic system. Several acetylcholinesterase inhibitors (AChEIs) have been developed and marketed for use in patients with AD. These compounds produce measurable but small improvements on tests of cognitive function as well as on ratings of clinicians’ global impressions in patients with mild, moderate, and even severe dementia. The magnitude of these benefits is small, however, and AChEIs do not alter the course of neurodegeneration. The duration of the beneficial effects associated with AChEI treatment is unknown, and it is not clear when treatment should be stopped. Other unanswered questions include whether AChEI treatment delays nursing home placement and whether the drugs are effective in patients with the earliest forms of AD. Another major goal of AD treatment trials is to slow the rate of decline or delay time to end points. One of the first studies to address some of these issues was a double-blind, placebo-controlled trial of 341 patients with moderate AD (Sano et al., 1997). Subjects were randomized to receive placebo, the monoamine oxidase inhibitor selegiline, vitamin E (alpha-tocopherol), or the combination of selegiline and vitamin E. The primary end point of this 2-year study was a composite end point that included death, institutionalization, loss of activities of daily living, and change on the clinical dementia rating (CDR) scale from 2 to 3 (indicating moderate to severe dementia). Patients in each of the treatment groups were delayed in the time to reaching the end point compared with those in the placebo arm. Vitamin E produced the largest effect, selegiline the second largest. The group receiving combination therapy was affected the least, suggesting the absence of an additive effect. None of the treatments was associated with slowing of cognitive decline. In addition, vitamin E was associated with a 25% decrease in institutionalization and less deterioration in activities of daily living (Sano et al., 1997). Current treatment of AD reflects these findings. Therapy for AD usually begins with vitamin E (1,000 IU) administered twice daily, with addition of an AChEI and monitoring with mental status testing, global function, and activities of daily living. The mechanism by which vitamin E produces its beneficial effects is unknown. Estrogen is one of several other agents under investigation for prevention and treatment of AD. Estrogen receptors are present on cholinergic basal forebrain neurons and increase choline acetyltransferase levels. Epidemiologic studies suggest a protective effect of estrogen, and some small clinical trials have suggested an improvement in cognition. Of the four clinical trials of estrogen published during the past 4 years, however, most have yielded negative findings in women with AD. Address correspondence and reprint requests to Dr. Leon J. Thal, Department of Neuroscience, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, U.S.A. ; e-mail: lthal@ucsd.edu Alzheimer Disease and Associated Disorders Vol. 17, Suppl. 2, pp. S69–S71 © 2003 Lippincott Williams & Wilkins, Inc., Philadelphia