Antioxidant Treatment in Alzheimer’s Disease Current State Yossi Gilgun-Sherki, Eldad Melamed, and Daniel Offen* Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center-Beilinson Campus, The Sackler School of Medicine, Tel Aviv University, Petach Tikva 49100, Israel Received February 10, 2003; Accepted February 12, 2003 Abstract Accumulating data from experimental and human studies indicate that oxidative stress (OS) plays a major role in the pathogenesis of Alzheimer’s disease (AD). The production of reactive oxygen species (ROS), which leads to OS, can occur very early, even before the appearance of symptoms and molecular events (β-amyloid plaques and neurofibrillary tangles), leading to tissue damage via several different cellular molecular path- ways. ROS can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., RNA, DNA), causing cell death by modes of necrosis or apoptosis. The damage can become more widespread because of the weakened cellular antioxidant defense systems. Therefore, treatment with antioxidants might theoretically act to prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several studies preformed to date examined whether dietary intake of several antioxidants, mainly vit- amins, might prevent or reduce the progression of AD. Although a few of the antioxidants showed some effi- cacy in these trials, no answer is yet available as to whether antioxidants are truly protective against AD. Reasons for these results might include, in part, blood–brain barrier (BBB) permeability, inappropriate timing of admin- istration, or suboptimal drug levels at the target site in the central nervous system. Thus, antioxidant cocktails or antioxidants combined with other drugs may have more successful synergistic effects. Further, well-designed intervention, as well as observational investigations based on large cohorts studied over a long period of time with several methods for assessing antioxidant exposure, including relation to BBB penetration, are needed to test this hypothesis. Index Entries: Alzheimer’s disease (AD); reactive oxygen species (ROS); oxygen stress (OS); antioxidants; blood brain barrier (BBB). Journal of Molecular Neuroscience Copyright © 2003 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/03/21:1–11/$25.00 Journal of Molecular Neuroscience 1 Volume 21, 2003 *Author to whom all correspondence and reprint requests should be addressed. E-mail: doffen@post.tau.ac.il REVIEW ARTICLE Introduction Alzheimer’s Disease Alzheimer disease (AD) is the most common neu- rodegenerative disorder of the elderly, and it is con- sidered to be the leading cause of death in the United States, after certain cancers and cardiovascular dis- ease. Clinically, it is characterized by progressive memory loss, decline in language skills, and demen- tia, which is an acquired cognitive and behavioral impairment of sufficient severity to interfere signif- icantly with social and occupational functioning. At present, the disorder afflicts ~5 million people in the United States and >30 million people worldwide. A larger number of individuals have lesser levels of cognitive impairment, which frequently evolve into a full-blown dementia, thereby increasing the number of affected persons (Clark, 2000). Prevalence of this disorder is expected to increase substantially in this century, as the disorder preferentially affects