Geneticist Professor John Hardy is Chair of Molecular Biology of Neurological Disease at the Institute of Neurology, University College London. After finding mutations in the gene for the protein, amyloid, in a family with early onset disease he proposed a ground-breaking ‘amyloid hypothesis’ for Alzheimer’s disease suggesting that disease was initiated by the build-up of this protein in the brain. The disease progresses when there is an imbalance in the production and the clearance of amyloid. His discoveries of genetic mutations have had a dramatic impact on understanding not only Alzheimer’s disease but more recently in other neurodegenerative diseases including Parkinson’s disease, progressive supranuclear palsy and motor neuron disease. With his collaborators, their development of transgenic mice that mimic these diseases process has provided the foundation of clinical trials for drugs to treat these complex diseases. “Collaborating with clinicians, geneticists and cell biologists is work in progress. Although we have not found a successful treatment yet, I believe we are on the way towards rational, mechanismbased treatments,” said Professor Hardy. His work on Alzheimer’s disease, other dementias and Parkinson’s disease is amongst the most highly cited in neuroscience.

Professor Christian Haass is at the Ludwig-Maximilians-University of Munich and at the German Center for Neurodegenerative Diseases. “My research into Alzheimer’s has focused on the cascade of events starting with amyloid and progressing through the development of plaques and tangles that eventually kill brain cells and destroy memory,” he said. When he started to work on Alzheimer’s disease in 1990, very little was known about the cellular mechanisms involved in this disease. He focused on the generation and metabolism of amyloid, the major component of the disease that signifies plaques. Professor Haass hypothesised that amyloid production may be normal and not necessarily part of a pathological process, which at the time was the widely accepted general opinion in the field. This pivotal finding was highly significant and has since led to the development of therapies to lower amyloid production in patients. Working with John Hardy, Professor Haass has demonstrated how amyloid is generated and how genetic mutations seen in families with very aggressive and rare forms of Alzheimer’s affect its production. Most recently, Professor Haass generated mouse models to investigate inflammation in neurodegenerative disorders, which according to his findings may at least initially play a protective role. He found that genetic mutations alter the function of special immune cells called microglia in the brain that can lead to Alzheimer’s disease. This has stimulated a completely new approach to designing possible new therapies by modulating the activity of microglia.

Professor Michel Goedert is a Programme Leader at the Medical Research Council Laboratory of Molecular Biology in Cambridge and an Honorary Professor at Cambridge University. His work using human brain tissues, transgenic mice, cultured cells and purified proteins was instrumental in the discovery – despite considerable initial scepticism – of the importance of Tau protein for Alzheimer’s disease. When Tau acts abnormally, it assembles into clusters of filaments and becomes insoluble. A pathological pathway leading from soluble to insoluble filamentous Tau is believed to cause neurodegeneration. Different Tau filaments are associated with distinct neurodegenerative diseases, including Pick’s disease and progressive supranuclear palsy, where Tau filaments form in the absence of beta-amyloid deposits outside brain cells. In his more recent studies, he showed that filamentous Tau clusters can propagate along nerve cell pathways through self-seeding. “Eventually – perhaps decades after seed formation – the first disease symptoms appear”, said Professor Goedert. “Therefore, if you can halt propagation, that could lead to ways to prevent and treat disease.”