The discovery of several new genes linked to late-onset Alzheimer’s disease widens the portal into the causes of the disease and offers new ways for identifying those at risk and finding proteins and pathways for drug development, according to authors of two large studies published in Nature Genetics this week.

The new genes reveal that processes other than accumulation of amyloid protein, so far the only genetic knowledge we have of Alzheimer’s, are involved in the disease.

In the largest study of its kind, the Alzheimer Disease Genetics Consortium (ADGC), identified common variants in four genes, MS4A4/MS4A6E, CD2AP, CD33 and EPHA1, associated with late onset Alzheimer’s disease.

Each of the genes adds to the risk of developing the most common form of Alzheimer’s, which accounts for the vast majority of cases and occurs in older people over the age of 65.

Until recently, only four genes linked to late-onset Alzheimer’s disease had been confirmed, with apolipoprotein E-e4 (APOE-e4) having the largest impact on risk. These genes are involved with the development of amyloid protein plaques in the brain.

But the four new genes relate to inflammatory processes, lipid metabolism, and the movement of molecules within cells, explained Dr Richard Mayeux, a lead scientist in the ADGC and Chairman of the Department of Neurology of Columbia University Medical Center in New York.

He told the press that:

“A significant aspect of our research is that these genes clarify three new pathways.”

Add these to what we already know and:

“… we may now have four pathways that are critically related to the disease and that could really make a difference in how we study and potentially prevent and treat it,” said Mayeux.

The genome-wide association study (GWAS) was conducted by the ADGC and led by the University of Pennsylvania School of Medicine, the University of Miami, Boston University School of Medicine and Columbia University. It was supported by the National Institute on Aging, part of the National Institutes of Health in the US.

Altogether 44 research centers collaborated in the study, led by Dr Gerard D. Schellenberg from the University of Pennsylvania.

The consortium analysed the genomes of more than 11,000 people with Alzheimer’s and almost the same number of elderly people who were dementia-free.

This data was joined by additional, confirming data from three other consortia, bringing the total of people studied to more than 54,000.

Work from this study also contributed to the discovery of another gene, reported in the same issue of the journal.

In that study, senior author Dr Julie Williams a professor at Cardiff University’s MRC Centre for Neuropsychiatric Genetics and Genomics in the UK, and colleagues followed up previous GWAS work from the GERAD+ consortium that examined 20,000 people with Alzheimer’s and 40,000 well individuals.

They identified common variants at ABCA7 and MS4A6A/MS4A4E associated with Alzheimer’s disease, plus evidence to support several additional susceptibility loci.

Williams said in a statement that:

“Through our on-going research we are finding genes that increase a person’s risk of developing Alzheimer’s disease, allowing us to pinpoint what may be going wrong, biologically, in the brain.”

Their study was funded by the Wellcome Trust, Medical Research Council, Alzheimer’s Research UK and the Welsh Assembly Government.

She said that the exciting thing about these new discoveries is the genes appear to be clustering in patterns.

“So several genes are implicating the immune system, for example – and it’s telling us there’s something different about the immune system of people who go on to develop Alzheimer’s disease. So their immune response or inflammatory response within the brain is different in Alzheimer’s disease,” explained Williams.

But perhaps the most exciting part of discovering these new genes, is a cluster of four that relate to a new area of research called endocytosis, the way a cell imports big molecules and processes them in a very specific way.

“We now have four genes that implicate this very precise process and it offers a very big clue that this process is playing a strong role in the development of Alzheimer’s disease,” said Williams.

Schellenberg said while this work represented years and years of effort by many scientists, it is only beginning to define “how genes influence memory and intellectual function as we age”.

“We’re all tremendously excited by our progress so far, but much remains to be done, both in understanding the genetics and in defining how these genes influence the disease process,” he added.

The researchers want their work to achieve two things: find out what causes Alzheimer’s so as to help develop effective drugs, and predict who is at risk, which will be important as preventive measures become available.

Finding out more about the genes involved in the disease will help uncover the steps that begin in the brain long before the symptoms of Alzheimer’s, memory loss and cognitive decline, begin to show, and eventually, help researchers understand the processes that lead to the destruction of large parts of the brain.

Williams also described these efforts as just the beginning of piecing together “the jigsaw”, and there was still a long way to go before we can start using this information to find people at risk or develop new drugs, although she expressed hope at what they might promise:

“If we were able to remove the detrimental effects of these genes through treatments, we hope we can help reduce the proportion of people developing Alzheimer’s in the long-term,” said Williams.

Plans are already under way for an even bigger study, under the auspices of the newly formed International Genomics of Alzheimer’s Project, which met for the first time in Paris in November 2010. The project is funded by the Alzheimer’s Association in the US and the Fondation Plan Alzheimer in France.

“Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease.”

Adam C Naj, Gyungah Jun, Gary W Beecham, Li-San Wang, Badri Narayan Vardarajan, Jacqueline Buros, Paul J Gallins, Joseph D Buxbaum, Gail P Jarvik, Paul K Crane, Eric B Larson, Thomas D Bird, Bradley F Boeve, Neill R Graff-Radford, Philip L De Jager, Denis Evans, Julie A Schneider, Minerva M Carrasquillo, Nilufer Ertekin-Taner, Steven G Younkin, Carlos Cruchaga, John S K Kauwe, Petra Nowotny, Patricia Kramer, John Hardy, et al.

Nature Genetics, Published online 03 April 2011.

DOI:10.1038/ng.801

“Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease.”

Paul Hollingworth, Denise Harold, Rebecca Sims, Amy Gerrish, Jean-Charles Lambert, Minerva M Carrasquillo, Richard Abraham, Marian L Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Nicola Jones, Alexandra Stretton, Charlene Thomas, Alex Richards, Dobril Ivanov, Caroline Widdowson, Jade Chapman, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, et al.

Nature Genetics, Published online: 03 April 2011.

DOI:10.1038/ng.803

Additional sources: Columbia University Medical Center, Cardiff University (3 Apr 2011).

Written by: Catharine Paddock, PhD