Current and Future Treatments for Alzheimer Disease

摘要: EDITORIAL Current and Future Treatments for Alzheimer Disease Gary W. Small, M.D., Susan Greenfield, Ph.D. ore than a century ago, Alois de- scribed the results of brain autopsy he performed on middle-aged woman who had devel- oped rapidly progressive cognitive decline. The amyloid plaques tau tangles that noted in patient’s neocortex other regions were thought to explain her condition. Initially, disease was considered rare presenile dementia; then, late 1960s neuropathologists showed present brains older persons suffered from dementia.Alzheimer strikes approximately 10% people 65 years or 45% those 85 older. 1 Its incidence prevalence double every 5 after age 60 years. Over million suffer U.S., worldwide estimates approach 44 million. Due part graying world population, is expected triple by 2050. In response daunting numbers currently af- flicted looming future sufferers, scientists have attempted uncover causes, contrib- uting factors, treatments. Investigations identified mutations (presenilin pre- cursor protein [APP] mutations), common genetic risks such as apolipoprotein E-4 (APOE-4) allele, nongenetic factors contribute risk. Biomarkers better define phenotype advanced our knowledge provided potential tools can focus treatment research. Initial drug research aimed boost acetyl- choline, because cholinergic deficits known symptoms. U.S. Food Drug Ad- ministration (FDA) has approved four cholinesterase M inhibitors (tacrine [Cognex], donepezil [Aricept], rivastigmine [Exelon], galantamine [Razadyne]) one N-methyl d-aspartate (NMDA)-receptor an- tagonist (memantine [Namenda]) disease. These drugs demonstrated benefits cognition, behavior, function, but their modest effect sizes temporary leave room improvement. At 2015 Alzheimer’s Associa- tion International Conference, many experts expressed optimism about ongoing research, although no disease-modifying symptomatic treat- ment with moderate large size yet been discovered. WHY SO MANY DRUGS HAVE FAILED To understand why so failed be effective treating disease, we need con- sider underlying neuronal mechanisms mode action, then determine whether could indeed clini- cal effects. hypothesis, which provides rationale inhibitors, posits primary problem deficit acetylcholine, caused death neurons. Cholinergic cell cannot root however, populations noncholinergic neurons (e.g., containing monoamines) 2 are additionally prone neuro- degeneration. Moreover, any merely in- creases availability dwindling transmitter will Received August 26, 2015; revised 29, accepted 31, 2015. From Department Psychiatry Biobehavioral Sciences, Semel Institute Neuroscience Human Behavior (GWS), UCLA Longevity Center, David Geffen School Medicine, University California, Los Angeles, CA; Pharmacology (SG), Oxford, UK Send correspondence reprint requests Institute, 760 Westwood Plaza, CA 90024. e-mail: gsmall@mednet.ucla.edu. © American Association Geriatric Psychiatry. Published Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jagp.2015.08.006 Am J Geriatr 23:11, November