Potential therapeutic strategies for Alzheimer's disease targeting or beyond β-amyloid: insights from clinical trials

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with two hallmarks: β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer's disease.

Figure 1

β-amyloid hypothesis based therapeutic targets. APP, after sequentially being cleaved by BACE1 and γ-secretase, gives rise to a neuron toxic molecule Aβ42. This peptide can exist as monomers or aggregates into oligomers and plagues. The assembly of Aβ42 triggers downstream effects and induces tau phosphorylation. BACE1 inhibitors and GSI/GSM aim to prohibit the production of pathological Aβ, and vaccines or Aβ antibodies promote clearance mechanism. As for tau, GSK-3β inhibitors and other antiaggregates are potential therapeutics targeting on blocking tau hyperphosphorylation or aggregation.