| Citation | Peter St George-Hyslop has pioneered the systematic use of reverse genetic approaches to Alzheimer's Disease (AD). He was one of the first to reveal that AD was etiologically heterogeneous. He contributed to the discovery of several causative genes, including most notably those encoding the presenilins (PS1 and PS2), which he was the first to identify. Using genetic, cellular and biochemical methods, he has shown that these genes cause AD via a metabolic pathway that generates neurotoxic Ab and that cerebral Ab deposition is the earliest pathological feature of AD in presymptomatic gene carriers. His recent demonstration that anti-Ab immunization inhibits both cerebral Ab deposition and cognitive deficits in a mouse model of AD supports a central role of Ab in the pathogenesis of AD, and gives hope that modulating Ab might be therapeutically useful. His work has profoundly altered clinical and basic research paradigms on AD, is already being applied clinically, and is a cornerstone for the development of new treatments. For instance, the presenilins are molecular targets for the rational design of inhibitors of Ab production. |