My research concentrates on understanding the molecular and cellular events that take place in the brain and especially the role of tau, in Alzheimer's disease, together with the genetics and proteomics of late onset Alzheimer's disease. This work is sponsored by the Wellcome Trust, the Medical research Council, The Alzheimer's Research Trust, the Alzheimer's Society and Research into Ageing.

Pathogenesis of Alzheimer's disease and the role of Glycogen Synthase Kinase-3 in the brain
In Alzheimer's disease, the neuronal protein tau is more highly phosphorylated than in normal brain. Searching for the enzyme responsible for this phosphorylation led our group, and others, to the enzyme glycogen synthase kinase-3 (GSK-3). It is clear now that GSK-3 is not the only tau-kinase but it is perhaps the predominant kinase and we have shown that it is altered in Alzheimer's disease and that it regulates long term potentiation (the closest model we have at a cellular level of memory). In cells we have shown that GSK-3 regulates tau binding to and stabilisation of microtubules and in Drosophila altering tau phosphorylation through GSK-3 inhibition restored axonal transport – a property of neurons essential for their normal function. All of this suggests that inhibition of GSK-3 might be a possible therapeutic option in Alzheimer's disease. '

We are now concentrating on understanding the regulation of GSK-3 in the brain. Our evidence suggests that GSK-3 regulation is altered in Alzheimer’s disease and possibly also in other neuropsychiatric conditions such as schizophrenia.

Biomarkers of Alzheimer's disease
A biomarker, or test, for Alzheimer's disease is urgently sought. Biomarkers are used elsewhere in medicine for improved diagnosis, for pre-symptomatic diagnosis, for risk evaluation, to monitor disease progression or the results of therapy. There are no fully confirmed biomarkers for AD although neuroimaging comes the closest and is widely used in both clinical practice and in research. For biochemical markers there is best evidence for CSF (spinal fluid) assays for tau protein or amyloid – both known to be involved in AD.

We have concentrated instead on trying to find a blood-based biomarker for AD. Using a candidate based approach and using proteomics we have found a range of changes in the blood of people with AD. This demonstrates that a blood based approach is feasible and we have confirmed some of these changes in large numbers of patients. We are now using these and related methods to find biomarkers that might be used in clinical trials and in clinical practice.

This research includes AddNeuroMed, one of the two related InnoMed projects that are pilots for the Innovative Medicines Initiative (IMI). Further details of IMI and AddNeuroMed can be found here.

Genetics of Alzheimer's disease and other disorders
Together with John Powell at the IoP and collaborators in Cardiff I have been involved with large collaborative studies seeking to find genetic susceptibility factors for Alzheimer's disease. Together this group has published many papers including a sibling-pair study finding a region on chromosome 10 linked to AD and a number of possible association findings including the first report of an association with Angiotensin Converting Enzyme. The IoP group has also reported associations of genetic factors with behavioural symptoms in AD and, in studies linking with our interest in intracellular signalling (see above), associations of genes involved in regulation of GSK-3 via wnt and insulin signalling with both Alzheimer's and Schizophrenia.

My group
Many students, post-doctoral researchers and fellows have contributed to this work over the years. My current group are, in no particular order Richard Killick, Claudie Hooper, Graham Cocks, Anna Kinsey, Mirsada Causevic, Nicola Archer, Catherine Tunnard, Nicola Dunlop, Andreas Guntert, Madhav Thambisetty, Paul Hopkins and Ricardo Sainz Fuertes. Recent and much valued colleagues include Rejith Dayanadan, Amritpal Mudher, Eirini Meimaridou, Danae Liolitsa, Fiona Kerr, Abdul Hye and many others.