These authors equally contributed to this article.
New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs
Article first published online: 12 MAR 2012
© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 73, Issue 4, pages 504–517, April 2012
How to Cite
Salomone, S., Caraci, F., Leggio, G. M., Fedotova, J. and Drago, F. (2012), New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs. British Journal of Clinical Pharmacology, 73: 504–517. doi: 10.1111/j.1365-2125.2011.04134.x
This review has been presented by Prof. Filippo Drago in the invited EPHAR Lecture in St. Petersburg, 5 April 2011.
- Issue published online: 12 MAR 2012
- Article first published online: 12 MAR 2012
- Accepted manuscript online: 28 OCT 2011 08:55AM EST
- Received; 25 July 2011; Accepted; 11 October 2011; Accepted Article Published Online; 28 October 2011
- Alzheimer's disease;
- clinical trials;
- disease modifying drug;
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.