The study, using the genomes of 100,000 people with Alzheimer’s and 600,000 healthy people, identified 75 genes associated with an increased risk of the disease, including 42 that had not previously been implicated. The findings suggest that degeneration in the brain of patients with dementia could be caused by “overactive” activity in the cells of the brain’s immune system, called microglia. Professor Julie Williams, director of the UK Institute for Dementia Research at the University of Cardiff and co-author of the study, said the findings could help rekindle efforts to find an effective cure. “This is a huge indication of what is going wrong,” he said. “Eight or nine years ago we did not work for the immune system. “Our genetics has reoriented us.” The study, the largest of its kind to date, also allowed scientists to devise a genetic risk score that could predict which patients with cognitive impairment could, within three years of the onset of symptoms, develop Alzheimer’s. The rating is not intended for clinical use at this time, but could be used when recruiting individuals for clinical trials of drugs aimed at treating the disease in its early stages. Alzheimer’s disease is the most common cause of dementia, affecting more than 850,000 people in the UK. Despite the huge burden of the disease, there are no new drugs for the last two decades, with the exception of Aducanumab, which has a controversial license in the US but is not available in Europe and the UK. Previous research has shown that while lifestyle factors such as smoking, exercise and diet affect Alzheimer’s risk, 60% -80% of disease risk is based on genetics. However, Williams said, drug development has been greatly influenced by the study of families with rare genetic mutations that cause early onset Alzheimer’s disease. Recent work highlights different sets of genes that occur in more common forms of Alzheimer’s disease, including a role for the immune system. “If [at the outset] “We had seen the genetics of the common disease, we would say it is an immune disease,” Williams said. “It’s not the same disease.” The risk genes identified in the study include those that affect how effectively the brain’s immune cells, the microglia, remove the damaged tissue. In people at risk, these housekeeping cells appeared to function very aggressively. A similar pattern has been found for genes that control how easily synapses, which connect neurons, send a “eat me” signal when they are in discomfort. High-risk variants appeared to lower the threshold for synapses that send out distress signals, causing the brain to clear connections faster. “I’m pretty optimistic that there are treatments that will work for some of the systems we’re looking at,” Williams said. The findings, published in the journal Nature Genetics, are consistent with previous results showing a role for the immune system. People with diabetes, which affects the immune system, are at significantly higher risk, for example, and when dementia is diagnosed, infections can cause a faster cognitive decline. Dr Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “Creating an extensive list of genes at risk for Alzheimer’s disease is like putting together the pieces of a puzzle, and while this work does not give us the full picture. provides a valuable framework for future developments. “Research, however, tells us how complex Alzheimer’s disease is, with several different mechanisms involved in the development of the disease.” Professor Tara Spires-Jones, deputy director of the Center for Brain Science Discovery at the University of Edinburgh, who did not participate in the study, said the findings were important to the industry. “The new genes provide clues as to why people are developing Alzheimer’s that will be followed up in future studies to try to better understand the disease and develop treatments,” he said.
