Alzheimer disease pharmacologic treatment and treatment research

Abstract

Purpose of review: This article reviews marketed pharmacologic treatments for Alzheimer disease as well as their efficacy, effectiveness, adverse effects, and issues involved in their use, including duration of treatment, adverse events, and controversies. Current experimental drug development, including challenges to developing successful drugs for Alzheimer disease, are also reviewed and assessed.

Recent findings: Cholinesterase inhibitors and memantine are the available pharmacologic treatment options. They show limited clinical effects over the shorter term for some patients, mild to moderate cholinergic adverse effects in a minority of patients, and potentially underappreciated toxicity over the longer term. No subsequent experimental drug in development has been successful thus far; there has not been a new drug marketed for Alzheimer disease since 2003.

Summary: Cholinesterase inhibitors and memantine are marketed for the treatment of Alzheimer disease. Drug development programs aimed at new targets, including the amyloid-β cascade, have been unsuccessful thus far despite their designs to detect very small or minimal clinical effects from the experimental drugs. Marked advances in preclinical science nevertheless support a basis for considerable optimism that effective interventions will be found soon.

Figure 2-1.

Cholinesterase inhibitors, optimum dose versus placebo. The figure shows the mean drug-placebo difference on the ADAS-Cog from several clinical trials along with 95% confidence interval widths displayed as horizontal lines. The overall mean effect is −2.37 points with 95% confidence intervals of −2.73 to −2.03. ADAS-Cog = Alzheimer Disease Assessment Scale—Cognitive Subscale; ITT-LOCF = intention to treat last observation carried forward; ChEI = cholinesterase inhibitors; SD = standard deviation; IV, Fixed = inverse variance, fixed effect; CI = confidence interval; Chi² = Chi squared; df = degrees of freedom; Z = Z score. Reprinted with permission from Birks J, Cochrane Database Syst Rev. © 2006, John Wiley & Sons, Inc. onlinelibrary.wiley.com/doi/10.1002/14651858.CD005593/abstract.

Figure 2-2.

Comparison of the identical effect of donepezil from a clinical trial compared to placebo, with standard deviation (SD) bars (left) reflecting the distribution of outcomes and standard error of the mean (SEM) limits (right) reflecting the precision of the outcomes. The narrow standard error bar indicates the relatively high precision and strong statistically significant drug-placebo estimate of the difference. The SD limits show how, despite the statistical significance, substantial overlap occurs in outcomes between patients treated with donepezil and patients treated with placebo, such that very few individuals can be seen to benefit on ADAS-Cog scores. Even the patients who improve to the greatest extent (eg, those outside the 1 SD limit) are still in the moderately severe dementia range. ADAS-Cog = Alzheimer Disease Assessment Scale—Cognitive Subscale; AD = Alzheimer disease. Reprinted from Lindner MD, et al, Academic Press. © 2008, with permission from Elsevier.