Cytoskeletal modulators and pleiotropic strategies for Alzheimer drug discovery

The Alzheimer's Association Research Roundtable, a consortium of Association senior scientists and leaders from pharmaceutical, biotech, and imaging companies, met to discuss strategies for developing novel therapeutics for the treatment of Alzheimer's disease (AD). The goal of the meeting was to address, primarily, strategies that do not hinge on directly modulating levels of β‐amyloid. The identification of β‐amyloid as the major constituent of senile plaques and the subsequent discovery that familial AD can be caused by mutations in either the β‐amyloid precursor protein or presenilins, proteases that cleaves β‐amyloid from its precursor, has spawned numerous therapeutic strategies for treating AD. These include passive and active vaccines for clearing β‐amyloid from the brain and the development of small molecule inhibitors of β‐ and γ‐secretases that can attenuate the production of β‐amyloid. But the field recognizes that there is more to AD than β‐amyloid alone. What role do neurofibrillary tangles play in the disease, for example, and how are they influenced by β‐amyloid? What lies upstream of β‐amyloid production in the sporadic AD brain, and how do apolipoproteins and cholesterol influence disease progression? Are there environmental or behavioral factors that contribute to the initiation or progression of sporadic AD? Because of the complexity of AD, the field is continually looking to other therapeutic strategies that may complement or substitute for therapies that target β‐amyloid. This roundtable meeting was charged with discussing and evaluating some of those strategies.