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

The amyloid beta (A beta) 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 A beta accumulation in the brain strongly support the notion that inhibiting A beta aggregation will prevent AD. Similarly, genetic studies of frontotemporal dementia with parkinsonism linked to chromosome 17 (FDP-17 MAPT) showing that mutations in the MAPTgene 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 A beta and tau are prime targets for disease modifying therapies in AD. Treatment strategies aimed at preventing the aggregation and accumulation of A beta, 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 A beta or tau. We will also discuss the need for thoughtful prioritization with respect to clinical development of the preclinically validated modifiers of A beta and tau pathology. The current number of candidate therapies targeting A beta 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 A beta have entered clinical trials. (C) 2009 Elsevier Inc. All rights reserved.