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Protofibrils of Amyloid-? are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease.

ABSTRACT: Worldwide, Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid ?-protein (A?) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that A? is responsible for the pathogenesis of AD (i.e., the amyloid hypothesis). Indeed, A? molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. However, while these A? species form amyloid plaques of the type implicated in AD neurodegeneration, recent clinical trials designed to reduce the production of A? and/or the plaque burden have not demonstrated clinical efficacy. In addition, recent studies using synthetic A? peptides, cell culture models, Arctic transgenic mice, and human samples of AD brain tissues have suggested that the pre-fibrillar forms of A?, particularly A? protofibrils, may be the most critical species, compared with extracellular fibrillar forms. We recently reported that protofibrils of A?1-42 disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Therefore, the therapeutic reduction of protofibrils may prevent the progression of AD by ameliorating neuronal damage and cognitive dysfunction through multiple mechanisms.

SUBMITTER: Ono K

PROVIDER: S-EPMC7037706 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease.

Ono Kenjiro K Tsuji Mayumi M

International journal of molecular sciences 20200131 3

Worldwide, Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is responsible for the pathogenesis of AD (i.e., the amyloid hypothesis). Indeed, Aβ molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. ...[more]

PMID: 32023927

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Project description:One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer's disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been successfully applied to actual clinical trial data accrued from the Phase 3 clinical trials of solanezumab.

Dataset Information

Protofibrils of Amyloid-? are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease.

Publications

Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease.

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