Mechanism of neurodegeneration through tau and therapy for Alzheimer's disease

Abstract

In Alzheimer's disease (AD), β-amyloid deposition and neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau fibrils, are considered to be major pathologic features. Evidence from the genetic studies of familial AD has given rise to the β-amyloid hypothesis in which β-amyloid is proposed as the cause of AD; thus, the reduction of β-amyloid has been viewed as a potential therapeutic target for AD.1 However, most studies targeting β-amyloid have failed in phase III clinical trial, as discussed extensively elsewhere.2 A major explanation for such failures may be that such therapies have been tested in patients with early- to mid-stage AD, when disease progression is already relatively advanced. In fact, when first AD symptoms are reported or detected, it seems that damage is irreversible and not amenable to slowing down or blockade. Accordingly, researchers are attempting to identify very early stages of disease, that may be therapeutically targetable; that is, they are now seeking an early window of therapeutic opportunity. Even so, this approach depends on differentiating between the trigger and the bullet in AD and their relationship to β-amyloid. At the same time, researchers are becoming aware that an alternative target for halting clinical progression, even in early to moderate AD, may be necessary.