Targeting Abeta and tau in Alzheimer's disease, an early interim report.

The amyloid beta (Abeta) and tau proteins, which misfold, aggregate, and accumulate in the Alzheimer's disease (AD) brain, are implicated as central factors in a complex neurodegenerative cascade. Studies of mutations that cause early onset AD and promote Abeta accumulation in the brain strongly support the notion that inhibiting Abeta aggregation will prevent AD. Similarly, genetic studies of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17 MAPT) showing that mutations in the MAPT gene encoding tau lead to abnormal tau accumulation and neurodegeneration. Such genetic studies clearly show that tau dysfunction and aggregation can be central to neurodegeneration, however, most likely in a secondary fashion in relation to AD. Additional pathologic, biochemical, and modeling studies further support the concept that Abeta and tau are prime targets for disease modifying therapies in AD. Treatment strategies aimed at preventing the aggregation and accumulation of Abeta, tau, or both proteins should therefore be theoretically possible, assuming that treatment can be initiated before either irreversible damage is present or downstream, self-sustaining, pathological cascades have been initiated. Herein, we will review recent advances and also potential setbacks with respect to the myriad of therapeutic strategies that are designed to slow down, prevent, or clear the accumulation of either "pathological" Abeta or tau. We will also discuss the need for thoughtful prioritization with respect to clinical development of the preclinically validated modifiers of Abeta and tau pathology. The current number of candidate therapies targeting Abeta is becoming so large that a triage process is clearly needed to insure that resources are invested in a way such that the best candidates for disease modifying therapy are rapidly moved toward clinical trials. Finally, we will discuss the challenges for an appropriate "triage" after potential disease modifying therapies targeting tau and Abeta have entered clinical trials. Copyright (c) 2009 Elsevier Inc. All rights reserved.