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

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.

Figure 1

Main steps of sequential cleavage of amyloid precursor protein (APP), leading to generation of β amyloid (Aβ) and/or other products. In A, dashed arrows indicate the cleavage sites for α-, β- and γ-secretase. In B, ectodomain shedding of APP by α-secretase gives a soluble extracellular APP fragment (APPsα) and a 83 amino acid, membrane-bound, carboxy terminus fragment (C83/CTFα). Subsequent intramembrane proteolytic cleavage of C83/CTFα by γ-secretase (in C) releases a short extracellular p3-peptide (p3) and a cytosolic APP intracellular domain (AICD). In D, ectodomain shedding of APP by β-secretase gives a soluble extracellular APP fragment (APPsβ) and a 99 amino acid, membrane-bound, carboxy terminus fragment (C99/CTFβ). Subsequent intramembrane proteolytic cleavage of C99/CTFβ by γ-secretase (in E) releases extracellular Aβ and a cytosolic APP intracellular domain (AICD). In F, Aβ oligomerization and deposition lead to neurodegeneration, both directly and through tau hyperphosphorylation. In dashed boxes, disease modifying drugs that interfere with each particular step. See text for more information and references