The largest genetic study of Alzheimer’s to date has provided compelling evidence linking the disease to disruption in the brain’s immune system.
The study, using the genomes of 100,000 people with Alzheimer’s and 600,000 healthy people, identified 75 genes linked to an increased risk of the disease, including 42 that had not previously been implicated.
The findings suggest degeneration in the brains of dementia patients could be spurred on by “over-aggressive” activity in the brain’s immune cells, called microglia.
Prof Julie Williams, the director of the UK Dementia Research Institute at Cardiff University and a co-author of the study, said the findings could help reignite efforts to find an effective treatment.
“This is an enormous clue to what’s going wrong,” she said. “Eight or nine years ago we weren’t working on the immune system. The genetics has refocused 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 would, within three years of first showing symptoms, go on to develop Alzheimer’s.
The score is not intended for clinical use at the moment, but could be used when recruiting people for clinical trials of drugs aimed at treating the disease in the earliest stages.
Alzheimer’s disease is the most common cause of dementia, which affects more than 850,000 people in the UK. Despite the huge burden of the disease, there have been no new drugs for it in the past two decades, with the exception of Aducanumab, controversially licensed in the US but unavailable in Europe and the UK.
Previous research has shown that while lifestyle factors such as smoking, exercise, and diet influence Alzheimer’s risk, 60%-80% of the disease risk is based on genetics. However, Williams said, drug development was heavily influenced by the study of families with rare genetic mutations causing early-onset Alzheimer’s.
The latest work highlights different sets of genes seen in more common forms of Alzheimer’s, including a role for the immune system. “If [at the outset] we’d seen the genetics of common disease, we would’ve said this is an immune disease,” said Williams. “It’s not the same disease.”
Risk genes highlighted in the study include ones that affect how efficiently the brain’s immune cells, microglia, clear away tissue that is distressed. In people at risk, these housekeeper cells appeared to be working too aggressively.
A similar pattern was found for genes that control how readily synapses, which connect neurons, send out an “eat me” signal when in distress. The high-risk variants appeared to lower the threshold for synapses sending out distress signals, causing the brain to purge connections at a quicker rate.
“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, fit with previous results pointing to a role for the immune system. People with diabetes, which affects the immune system, are at considerably higher risk, for instance, and once dementia has been diagnosed infections can trigger more rapid cognitive decline.
Dr. Susan Kohlhaas, the director of research at Alzheimer’s Research UK, said: “Creating an extensive list of Alzheimer’s disease risk genes is like having the edge pieces of a puzzle put together, and while this work doesn’t give us the full picture, it provides a valuable framework for future developments. The research also, however, tells us just how complex Alzheimer’s is, with several different mechanisms implicated in the development of the disease.”
Prof Tara Spires-Jones, the deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, who was not involved in the work, said the findings were important for the field. “The new genes provide hints about why people develop Alzheimer’s that will be followed up in future studies to try and better understand the disease and develop treatments,” she said.