Targeting tau and Aβ amyloid pathways shows promise in curing Alzheimer’s disease
The tau and Aβ amyloid pathways have emerged as possible novel targets in treating Alzheimer’s disease (AD), according to studies discussed at the recently concluded Hong Kong Pharmacy Conference.
“The tau aggregation inhibitor TRx0014, at a dosage of 138 mg/day, demonstrated a significant treatment benefit vs placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale test [5.42 points; p=0.047] in patients with moderate AD,” said Dr Andrew Lung-Tat Chan of the Divisions of Geriatrics and Neurology, Queen Elizabeth Hospital, Hong Kong. [Biomed Res Int 2016;2016:3245935]
“More recently, a phase I trial showed favourable safety profile and immunogenicity of the tau vaccine, AADvac1. Further trials are needed to establish proof of its clinical efficacy,” he said. [Lancet Neurol 2017;16:123-134]
Accumulation of phosphorylated tau protein with resultant microtubule dysfunction and neuronal degeneration is believed to be one of the pathophysiological mechanisms of AD.
Another mechanism, which was recently explained with genetic evidence, is Aβ amyloid accumulation. “Aducanumab, an amyloid-based passive immunotherapeutic agent, was found to reduce Aβ plaque measurements and slow cognitive decline in individuals with mild AD dementia,” said Chan. [Nat Rev Dis Primers 2015;1:1-18]
“Amyloid-based passive immunotherapy using solanezumab, bapineuzumab or crenezumab, however, did not show clinical benefits,” he pointed out. [Expert Rev Neurother 2015;15:83-105]
AD drug development is gaining momentum despite a low overall success rate of 0.4 percent and a lack of new drugs being approved since 2003. [Alzheimers Res Ther 2014 3;6:37] To date, 24 agents are being evaluated in 36 phase III AD trials, with 76 percent of the agents being amyloid-related. Another 45 agents are being evaluated in 52 phase II clinical trials, while 24 agents are in phase I development. [Alzheimers Dement TRCI 2016;2:222-232]
“The challenges in drug development for AD stem from a lack of validated diagnostic criteria and markers that are useful for setting clinical endpoints and efficacy standards. The long, symptom-free prodromal phase of AD results in enrollment of patients with already advanced disease into clinical trials,” said Chan. [Annu Rev Med 2017;68:413-430]
“However, the field is optimistic due to better understanding of genetic risk factors and the Aβ amyloid and tau pathways, which may provide insights about molecular pathophysiology and potential drug targets to propel drug research programmes,” he added.
Meanwhile, cholinesterase inhibitors such as donepezil, galantamine and rivastagmine are at times used in AD treatment because many symptoms can be explained by its deficiency. Studies of these agents showed small but significant improvements in cognition and global status. [Neuropharmacology 2014;76:27-50]
“Combination of cholinesterase inhibitors with the N-methyl D-aspartate receptor antagonist memantine showed small effects on cognition [standardized mean difference (SMD), -0.25], global scores [SMD, -0.20], behaviour and mood [SMD, -0.17], but is not commonly recommended,” said Chan. [BMJ Open 2012;2:e000917]
“Every source of compounds, including academic institutions and pharmaceutical companies, should contribute to AD drug development and there is a need to diversify therapeutic approaches,” he emphasized.