Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder resulting in cognitive impairment, loss of executive functions and progressive dementia. AD is the most common cause of dementia and incidence is increasing, probably due to a rapidly ageing population. Despite research efforts and a substantial unmet medical need, no effective cure has been identi fied and treatment remains symptomatic. In this review, I assess the current status of AD research and examine future approaches for the development of a potential disease-modifying treatment. Research has focused primarily on amyloid pathology, after a correlation was discovered between mutations in several genes associated with amyloid processing and AD. The Amyloid Cascade Hypothesis suggests that increased amyloid beta (Aβ) aggregation is the major cause of AD, triggering the toxic events that lead to progressive neurodegeneration. However, no drug candidate targeting the cascade has yet produced a successful treatment. It is now speculated that treatment requires early targeting of Aβ, when pathology remains reversible, and clinical trials are focusing on assessing Aβ compounds in pro-dromal AD. Lack of an effective A β-focused treatment has resulted in the consideration of hyperphosphorylated neurofibrillary tangles of tau (NFT), another major pathologi cal hallmark of AD. Studies have repeatedly demonstrated a strong correlation between NFT build up and cognitive decline, and recent studies have identified a number of tau genetic markers associated with AD. Compounds preventing the hyper phosphorylation of tau may therefore halt disease progression; however, the failure of previous tauopathy trials in progressive supranuclear palsy (PSP) has highlighted potential set-backs. The importance of tau as an independent cause of AD, and therefore a target for treatment, may be clarified by ongoing tau-focused clinical studies. Although A β and tau are both highly relevant, their relationship in causing AD remains unknown. Amyloid- and tau-targeting treatments may individually prove effective, however the convergent progression of A β and tau pathology suggests combination therapy may eventually be required, particularly in late stages of disease when both are abundant. While ongoing work focuses on single target therapies, a dual Aβ and tau targeting approach may be more likely to produce a breakthrough.
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