After these have been ‘switched off’ by A?? they cannot be ‘switched on’ again just by removing the A??. moreover This process seems to be mediated via a histone deacetylase, HDAC2, which the authors have shown to be activated in brain tissue from both transgenic mouse models, where it reduced synaptic density and memory function, and human AD sufferers. They went on to show that inhibiting HDAC2 restored synaptic plasticity and improved some aspects of memory, although it did not boost the number of surviving neurons in the mice. The pathway is a complex one that also involves the glucocorticoid receptor, GR1. The implied possibility of reversing pathology, in contrast to slowing decline, is an exciting one but needs further evaluation.

HDAC inhibitors are already used or being explored in a number of conditions, for example, oncology, and some pharmaceutical companies are exploring their potential in AD. However, we also need to understand whether such drugs might affect other important but unrelated aspects of genetic function. Roles of epigenetic mechanisms in aging and AD are likely to be a strong focus of future translational research. Towards Alzheimer’s disease prevention Over the past few years the challenges of disease modification in symptomatic patients have become increasingly apparent. Preclinical studies almost invariably show GSK-3 diminishing efficacy with increasing pathology at initiation of treatment. There have been several failed phase III clinical trials with disease modifying agents, though many of these agents were suboptimal with respect to potency, therapeutic window, or brain penetrance.

Moreover, even phase II studies with more optimal disease modifying agents fail to show evidence for significant efficacy. Thus, a clinical highlight of the past year has been a renewed emphasis on designing and implementing more appropriate clinical trial methodology for www.selleckchem.com/products/azd9291.html evaluating disease-modifying treatment in AD. Editorials and reviews have emphasized that disease-modifying treatment in established AD at the stage of dementia may be too late – the greatest benefit could come from preventing the chain of events that leads to neurodegeneration and irreversible structural changes in the brain [14-17]. Biomarkers exist that are able to identify AD pathology, particularly amyloid deposition, long before cognitive decline begins, and sensitive cognitive tests and paradigms using functional magnetic resonance imaging are showing alterations even during what has been termed ‘preclinical AD’ [16] and the ‘asymptomatic at risk’ individual [18] and new diagnostic research criteria have been proposed by two working groups. Treatment trials are at an advanced level of planning in two groups of people at risk for AD.