An international team of scientists working on the largest ever genome-wide study looking for genes linked to Alzheimer’s have discovered two new genes, CLU and PICALM, are related to the disease, a finding that is being described as a “leap forward” for dementia research, especially because the last time a gene was found to be linked to the common form of Alzheimer’s disease was in 1993.

The study, which was described by Welsh First Minister Rhodri Morgan as a “real feather in the cap of Welsh science”, was led by the University of Cardiff in Wales, UK, and involved 80 researchers from the UK, Ireland, France, Germany, Belgium, Greece and the US, was published in the online issue of Nature Genetics on 6 September.

Until this study only one gene, APOE4, had been linked to Alzheimer’s disease. Now, with the discovery of CLU and PICALM, scientists expect to pursue new avenues for developing treatments for the disease.

The only other genes that have been connected to Alzheimer’s disease are in extremely rare familial forms of the disease, which is inherited in fewer than 1 case in every 100.

Sir Leszek Borysiewicz, of the UK’s Medical Research Council (MRC) praised the discovery as:

“A huge step towards achieving an earlier diagnosis of Alzheimer’s.”

Rebecca Wood, Chief Executive of the Alzheimer’s Research Trust, which part-funded the study, said:

“These findings are a leap forward for dementia research.”

“At a time when we are yet to find ways of halting this devastating condition, this development is likely to spark off numerous new ideas, collaborations and more in the race for a cure,” she added.

Senior investigator professor Julie Williams, who is Chief Scientific Adviser to the Alzheimer’s Research Trust told the media that CLU and PICALM reveal new genetic pathways that lead to Alzheimer’s.

The CLU gene codes for a protein called clusterin which normally protects the brain in several ways. Variations in CLU could remove the protective benefit of clusterin, and this could be a potential route to Alzheimer’s, a disease whose features include the build up of amyloid protein plaques around brain cells.

Co-author Dr John C. Morris, of Washington University in St Louis, Missouri, US, said that previous research at the University’s Alzheimer’s Disease Research Center (ADRC), of which he is the director, suggests that in mice the CLU gene may be involved in the formation of amyloid deposits in the brain.

PICALM affects synapses, the connections between brain cells and plays a role in the transport of molecules into and within nerve cells, which helps to form memories and other important brain functions, said Williams.

“We know that the health of synapses is closely related to memory performance in Alzheimer’s disease, thus changes in genes which affect synapses are likely to have a direct effect on disease development,” she added.

For the study, Williams and colleagues conducted a genome-wide association (GWA) study that pooled DNA samples from more than 19,000 older European and US residents. 7,000 of the donors had Alzheimer’s, while the others had no clinical symptoms of the disease.

The samples came from brain and blood tissue made available and analyzed by dozens of laboratories in the UK, Ireland, Germany, Belgium, Greece and the US.

By looking at more than 600,000 common DNA markers, the investigators found the two new genes were linked to higher risk of Alzheimer’s; they also confirmed the importance of APOE4.

Co-author Dr Alison M. Goate, a professor of neurology at Washington University, said this study was the first to provide significant evidence of new genetic risk factors for the most common form of Alzheimer’s. In 1991, Goate led a team in England that that identified the first early-onset Alzheimer’s mutation in the APP gene on chromosome 21.

Goate said that the two new genes are significant but their effect appears to be much smaller than that of APOE.

“Using statistical methods, we’ve been able to estimate the amount of risk attributable to APOE at about 19 or 20 percent. The newly identified genes each come in under 10 percent, so it appears they have a much smaller effect,” said Goate.

However, the effect might be small but it is not insignificant, she added, explaining that while it isn’t yet clear how these new genes influence Alzheimer’s risk, levels of clusterin tend to rise when brain tissue is injured or becomes inflamed. Some researchers have found increased levels of clusterin in the brain and spinal fluid of patients with Alzheimer’s, said Goate.

The researchers also found 13 other genes that should be investigated further for possible links with Alzheimer’s risk, so there may be more discoveries yet to come.

In fact the Cardiff-led team shared their data with another French-led team who found convincing evidence that there may also be a third gene linked to Alzheimer’s that is called CRI. Their paper appears in the same issue of Nature Genetics.

The study was funded by the Wellcome Trust, Medical Research Council, Alzheimer’s Research Trust, the Welsh Assembly Government and other bodies.

“Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease .”
Denise Harold, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Marian L Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S Brown, Peter A Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A David Smith, Seth Love, Patrick G Kehoe, John Hardy, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schürmann, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison M Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter P De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E Shaw, Magda Tsolaki, Andrew B Singleton, Rita Guerreiro, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, Minerva M Carrasquillo, V Shane Pankratz, Steven G Younkin, Peter A Holmans, Michael O’Donovan, Michael J Owen & Julie Williams.
Nature Genetics, Published online 6 September 2009.

Sources: Alzheimer’s Research Trust, Washington University School of Medicine.

Written by: Catharine Paddock, PhD