Study uncovers new Alzheimer’s genes, links to immune disruption

The largest-ever study of genetics in Alzheimer’s disease patients has identified 42 new genes that appear to be linked to the neurodegenerative disorder.

The new genes takes the total number associated with Alzheimer’s to 75, opening up new avenues for research of ways to diagnose and treat the conditions, and suggest that immunological dysfunction may have a greater role to play than previously thought.

In particular, the findings suggest that disruption to innate immunity – the first line of defence against pathogens – as well as overly aggressive activity of white blood cells in the central nervous system called microglia.

Another revelation is that the tumour necrosis factor alpha-dependent signalling pathway is involved in disease, something that was not known before. Drugs that inhibit TNF are already widely used to treat inflammatory diseases like rheumatoid arthritis, psoriasis and Crohn’s disease.

The study brought together researchers from eight countries – including France, the US, UK and other European nations – and was led by Prof Jean-Charles Lambert, research director at France’s National Institute of Health and Medical Research (Inserm).

The uncovered genes also confirmed the importance of amyloid beta and tau proteins, which have been the focus of much of the drug discovery effort in Alzheimer’s for the last couple of decades, albeit with limited results and just one approved therapy – Biogen’s Aduhelm (aducanumab) – whose efficacy is a topic of considerable debate.

Lambert said the discovered genes are being studied to “give them meaning in relation to our clinical and biological knowledge, and thereby gain a better understanding of the cellular mechanisms and pathological processes at play.”

The study was carried out using the genomes of 100,000 people with Alzheimer’s and 600,000 healthy individuals. While it is known that lifestyle factors like diet, exercise and smoking can have an effect on the risk of developing the disease, there is a strong genetic component, accounting for 60% to 80% of cases.

According to Prof Julie Williams of Cardiff University and the UK Dementia Research Institute, one of the study’s authors, the work is “a major leap forward in our mission to understand Alzheimer’s, and ultimately produce several treatments needed to delay or prevent the disease.”

The researchers also devised a genetic risk score that they reckon will predict which patients with cognitive impairment will go on to develop Alzheimer’s within three years.

“While this tool is not at all intended for use in clinical practice at present, it could be very useful when setting up therapeutic trials in order to categorise participants according to their risk and improve the evaluation of the medications being tested,” said Lambert.

That could be invaluable as drugmakers try to demonstrate the benefit of their amyloid and tau-targeting therapies, which are expected to have the greatest chance of showing efficacy when used very early on in the disease process.

The findings have been published in the journal Nature Genetics.

Commenting on the study, 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.”

She cautioned however that the work also reveals just how complex Alzheimer’s is, with several different mechanisms implicated in the development of the disease.

“It’s going to take a concerted and global effort to develop life-changing treatments, but this seminal study also gives us hope that research will win, and it gives us the opportunity to work on new treatment targets.”

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