New insights into underlying causes of Alzheimer’s disease

An international team of researchers has identified some striking new insights into the underlying causes of Alzheimer’s disease, including five new genes that increase risk for the disease.

The International Genomic Alzheimer’s Project (IGAP), which is a collaboration of four consortia, including the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD) consortia led by Cardiff University, analysed data from more than 94,000 individuals with Alzheimer’s disease.

“This work emphasizes the need for collaborative science,” said Dr Rebecca Sims, a Principal Investigator at the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University.

“Large sample sizes provide us with the power we need to detect new links to the causes of Alzheimer’s disease.”

This unprecedented project, funded in part by the Medical Research Council (MRC) and Wellcome Trust, scrutinized more genetic data than any other study of Alzheimer’s disease to date. Collaborative data sharing enabled the scientists to discover five novel genetic variants or changes that influence the risk for Alzheimer’s disease.

Cardiff University’s Professor Peter Holmans spearheaded the analysis that examined the functions of the five genes newly associated with Alzheimer’s disease—IQCK, ACE, ADAM10, ADAMTS1 and WWOX, in conjunction with the functions of other genes to identify the biological pathways where the genes implicated in Alzheimer’s disease risk are clustering.

This work yielded two important and novel results. Firstly, genes involved in breaking down amyloid precursor proteins (including ACE and ADAM10) are implicated in the aetiology of late-onset Alzheimer’s disease. This reveals a link between early-onset and late-onset Alzheimer’s disease, and suggests that some therapies developed for early-onset disease may also work for late-onset disease.

Second major finding

The second major finding is that certain changes in genes that bind to a protein called “tau” may affect disease development at an earlier stage than previously thought.

These findings support the idea that groups of genes linked to specific biological processes work in tandem to control functions that affect disease development. For example, amyloid processing, tau binding, lipid transport, inflammation, and immune response appear to be controlled by ‘genetic hubs’.

The study also revealed that rare variants, those variants that are at a frequency of less than one percent in a population, likely play an important role in Alzheimer’s disease. The researchers discovered this by showing that common risk variants, changes found in more than one percent of the population, and rare risk variants for Alzheimer’s disease tend to be found in the same genes and hubs.

While several rare variants have been previously linked to increased risk of the disease, this is the first study to show that many more rare risk variants exist, and they are most likely to be found in the same genes and hubs that contain common risk variants.

Identifying and confirming these rare risk variants will be a significant step forward for the creation of personalized screening strategies and better-informed drug development for Alzheimer’s disease.

“This is an exciting time to be studying Alzheimer’s disease,” said Professor Julie Williams, Associate Director of the UK Dementia Research Institute, who heads the GERAD consortium.

“It is now clear that Alzheimer’s disease is triggered by multiple components and that at least some of them need to go wrong to trigger disease development. This study shows that some of these components involve our immune systems, how we process lipids such as cholesterol in the brain and how the brain rids itself of unwanted material such as amyloid plaques and the integrity of the communication systems observed within brain cells.

“Identifying genes that influence disease is changing how we think about the underlying biology and is the initial step to translation to clinical care.”

The study ‘Genetic meta-analysis of diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing’ is published in Nature Genetics.