A major international research study has more than doubled the number of genetic regions associated with Alzheimer’s disease. The results reveal novel insights into the pathological processes involved in the disease, and open up new avenues for therapeutic research.
Alzheimer's disease is the most common form of dementia and thought to contribute to 60-70% of the 55 million cases of dementia worldwide (World Health Organization). Currently, there is no cure for Alzheimer’s disease, however the disease is known to have a strong genetic component. Greater understanding of how these genetic risk factors interact with the environment to cause disease could therefore offer novel therapeutic targets to slow cognitive decline.
As part of an international collaboration involving researchers from Europe, the USA and Australia, Oxford Population Health has contributed to the largest genetic study to date on patients with Alzheimer’s disease. The results, published today in Nature Genetics, bring valuable new insights into the biological mechanisms driving the disease, and open up new avenues for treatment and diagnosis.
The researchers performed a genome-wide association study (GWAS), an approach which analyses the entire genome of thousands or tens of thousands of people, whether healthy or sick, to identify genetic risk factors associated with specific aspects of the disease. The study used samples in the European Alzheimer & Dementia Biobank, which includes 20,464 clinically diagnosed cases of Alzheimer’s disease and 22,244 controls from 15 European countries, as well as data from the UK Biobank, which were analysed by the Oxford Population Health Team.
Using this method, the scientists were able to identify 75 regions (loci) of the genome associated with Alzheimer's, 42 of which had never previously been associated with the disease. These regions were further characterised to explore the cellular mechanisms and pathological processes for the disease.
The results confirmed the role of two pathological brain phenomena already associated with Alzheimer’s disease: the accumulation of amyloid-beta plaques, and neurofibrillary tangles of Tau protein. Many of the novel genes were found to be implicated in amyloid peptide production and Tau protein function.
However, the loci also implicated new processes in the pathology of Alzheimer’s. These include dysfunctions in the innate immune system, and the action of microglia that normally eliminate toxic substances in the central nervous system. For the first time, this study provides genomic evidence that the tumor necrosis factor alpha (TNF-alpha)-dependent signalling pathway is involved in the disease.
Besides adding to our understanding of the origins of Alzheimer’s disease, the results were used to devise a novel genetic risk score which could be applied within clinical care in the near future. The risk score predicts which patients with cognitive impairment will, within three years of the first symptoms, go on to develop Alzheimer's disease. The risk score could also enable clinical trials to test therapeutic treatments for people genetically at high risk of Alzheimer’s disease, but who have not yet developed the condition.
Professor Cornelia van Duijn (Oxford Population Health), one of the leading co-authors on the study, said: ‘This study has expanded our current understanding of Alzheimer’s disease, and opened up new avenues for translational genomics and personalised medicine. The fact that both amyloid and Tau emerge as key pathways underscores the need to move forward with trials of antibody-based therapies. The discovery of the potential involvement of the TNF-alpha pathway also presents the possibility of re-purposing existing drugs that target this pathway.’
‘In addition, the new genetic risk score means that we can conduct clinical studies that specifically test early-stage interventions that aim to treat the underlying genetically-determined disease pathways. If we can show anti-neurodegenerative effects at a 'younger age' in those genetically at high risk, we can move the field forward towards effective, early-stage interventions.’