Alzheimer's research & therapy
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The oligomer cascade hypothesis, which states that oligomers are the initiating pathologic agents in Alzheimer's disease, has all but supplanted the amyloid cascade hypothesis, which suggested that fibers were the key etiologic agents in Alzheimer's disease. We review here the results of in vivo, in vitro and in silico studies of amyloid β-protein oligomers, and discuss important caveats that should be considered in the evaluation of these results. ⋯ These multiple orthogonal approaches have revealed much about the molecular and cell biology of amyloid β-protein. However, as informative as these approaches have been, the amyloid β-protein oligomer system remains enigmatic.
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Alzheimers Res Ther · Jan 2013
Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy.
Memantine and cholinesterase inhibitors potentially offer additional benefits in Alzheimer's disease (AD) when used together. This study assessed the efficacy and safety of combination treatment with memantine added to stable donepezil in patients with moderate to severe AD, and in a subset with moderate AD. ⋯ These results support and extend previous evidence that combination treatment with memantine added to stable donepezil in patients with moderate AD, and in those with moderate to severe AD, is associated with significant benefits in reducing 24-week decline in cognition, function and global status. Combination treatment produces substantially reduced rates of marked clinical worsening, has good safety and tolerability, and generates effect sizes that are both statistically significant and clinically meaningful.
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Alzheimers Res Ther · Jan 2013
Should interventions to treat or prevent Alzheimer's disease be tested in a population or as targeted treatment of highly selected study participants?
Symptomatic treatments for Alzheimer's disease should retain a place in the advanced stages of disease since their actions on these symptoms, even if not modifying the course of disease, are critical for improving patients' comfort and reducing the burden felt by caregivers, especially those facing behavioral disorders. In mild or prodromal stages, the opportunity to act on specific pathophysiological targets should be considered. These targeted and tailored therapies have the greatest chance to be active in the early stages of disease, in the context of heterogeneous pathological mechanisms to be specified by reliable and accessible biomarkers. Finally, interventional approaches in large populations seem particularly appropriate for prevention strategies.
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Alzheimers Res Ther · Apr 2011
What can we learn from study of Alzheimer's disease in patients with Down syndrome for early-onset Alzheimer's disease in the general population?
The clinical and scientific study of dementia in adults with Down syndrome led to the development of the amyloid hypothesis as a fundamental concept in Alzheimer's disease pathogenesis. The journey started with the discovery of the structure and metabolic processing of β-amyloid brain deposits associated with Alzheimer's dementia in adults with Down syndrome, and then the prediction and confirmation of the amyloid precursor protein gene on chromosome 21. The processes and genes responsible for tau hyperphosphorylation contributing to toxic brain deposits were additionally identified. ⋯ Nearly 200 genetic causes of early-onset types of Alzheimer's disease have since been identified. Only a minority of these causes are on chromosome 21, although the aetiology of excess amyloid production remains fundamental to their pathogenesis. Knowledge of the pathogenic mechanisms of Alzheimer's disease in predisposed families and in people with Down syndrome is a step closer to prevention or cure of this devastating disease.