New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs

Authors

  • Salvatore Salomone,

    1. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry
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    • These authors equally contributed to this article.

  • Filippo Caraci,

    1. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry
    2. Department of Formative Processes, University of Catania, Catania, Italy
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    • These authors equally contributed to this article.

  • Gian Marco Leggio,

    1. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry
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  • Julia Fedotova,

    1. I.P. Pavlov Institute of Physiology of the Russian Academy of Science Laboratory of Neuroendocrinology, St Petersburg, Russia
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  • Filippo Drago

    Corresponding author
    1. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry
      Dr Filippo Drago MD, PhD, Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Tel.: +39 09 5738 4236, Fax: +39 09 5738 4238. E-mail: fdrago@tin.it
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  • This review has been presented by Prof. Filippo Drago in the invited EPHAR Lecture in St. Petersburg, 5 April 2011.

Dr Filippo Drago MD, PhD, Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Tel.: +39 09 5738 4236, Fax: +39 09 5738 4238. E-mail: fdrago@tin.it

Abstract

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop ‘disease modifying drugs’ hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.

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