CHAPTER 22 Multitargeted Drugs for Treatment of Alzheimer’s Disease ANDREA CAVALLI and MARIA LAURA BOLOGNESI 22.1 INTRODUCTION Neurodegenerative diseases have been an especially difficult field for drug discovery [1]. Owing to the huge complexity of the nervous system and the poor understanding of most diseases, most drugs currently available are the result of a pathology-centered approach, rather than a truly comprehensive strategy [2]. This approach has helped deliver therapies that cannot be categorized as disease-modifying. Basically, they achieve successful palliation through different neurotransmitter replacements. But despite the variety of neurodegenerative disorders, there seem to be some remarkable parallels between them in terms of their underlying pathogenic factors. Many of the genes and pathways altered in one neurological disease are also commonly dysre- gulated in others, even if they do not share the same pathophysiology, age of onset, or outcome. As a result, the therapeutic strategy for one neurodegenerative disease may be effective for the others [3]. Among the neurodegenerative diseases, Alzheimer’s disease (AD) is the most common and the most devastating form of dementia in the elderly. The mechanisms that underlie neuronal dysfunction and eventual cell death in AD remain unknown, although theories abound, ranging from protein misfolding and toxic aggregation to oxidative stress, inflammation, and apoptosis. Molecular genetic studies in familial forms of the disease have proposed a causative role for amyloid precursor protein (APP) and presenilin (PS1 and PS2) mutations. But AD is a prototypical example of a complex syndrome where genetic predisposition interacts with environmental factors. To this end, the presence of the apoE allele, which has been identified as a strong genetic risk factor for late-onset AD, is not necessary for development of the disease [4]. Proof is therefore lacking for this hypothesis, and the expected validation of genetic knowledge-based treatment strategies has yet to arrive. Polypharmacology in Drug Discovery, First Edition. Edited by Jens-Uwe Peters. Ó 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc. 441