Objective

Alzheimer’s disease is the leading form of age related dementia. In an ever aging population the impact of AD is likely to become “a healthcare burden of epidemic proportions”. It is over 25 years since Selkoe and Hardy formulated the “Amyloid Hypothesis of Alzheimer’s Disease” based on the original pathological observations of Alois Alzheimer and a wealth of genetic evidence focused around the amyloid precursor protein (APP). Drug discovery approaches have thus focused on targeting the aberrant forms of beta amyloid (A) proteins, using antibodies to A or inhibiting the processing enzymes ( and  secretase) responsible for the production of thepeptide. To date  secretase inhibitors have failed, antibody approaches have been unsuccessful (although a number are still under evaluation) and  secretase inhibitors are in phase III AD trials. This lack of success has somewhat precipitated a refocusing away from amyloid and onto more novel areas of AD drug discovery. In this regard, new genetic findings have highlighted key areas, such as neuroinflammation, proteostasis and mitochondria dysfunction, which may be producing functional vulnerabilities and these are the areas which will require significant disease understanding to identify and “validate” suitable targets for the next drug discovery efforts in AD