Life Sciences Division

Identification of two new factors driving genetic susceptibility to Alzheimer’s disease

CEA

There are over 850,000 sufferers of Alzheimer’s disease in France, making it the leading cause of memory loss and impaired intellectual functioning in the elderly — and a major public health issue. A team of French and European researchers has recently identified two new factors of genetic susceptibility associated with the pathogenesis of Alzheimer’s disease.

This research was led by the Inserm’s “public health and molecular epidemiology of ageing-related disease” research unit (UMR 744) in tight collaboration with the CEA’s National Genotyping Centre — Genomics Institute, the Fondation Jean Dausset-CEPH human polymorphism study centre, and a European consortium networking 25 teams. These findings represent some of the first scientific results made possible through funding from the National Foundation for Scientific Cooperation, which coordinates the research strand of the government’s program to combat Alzheimer’s and related disease, launched in February 2008.

Taking age, family history, and a genetic susceptibility factor — the ε4 allele coding for apolipoprotein E (APOE) — out of the equation, the causal factors behind Alzheimer’s disease remain unknown. A research drive sponsored by the National Foundation for Scientific Cooperation harnessing French researchers with a European research consortium has produced one of the first large-scale pangenomic* studies worldwide to focus on Alzheimer’s disease. This pioneering study analyzed genome data from over 20,000 individuals, including 6,000 who presented confirmed cases of Alzheimer’s disease. The study was able to identify two new genetic susceptibility factors for Alzheimer’s disease, opening up new perspectives for the development of diagnostic tools and therapeutic strategies.

These findings were first published on 6 September 2009, in Nature Genetics online.

Like many chronic diseases, the onset of Alzheimer’s disease is linked to a complex series of interactions between factors of genetic predisposition and environmental risk factors. The genes for familial forms of Alzheimer’s disease, which are early-onset (before 60 years old) and relatively rare (less than 3% of all-form Alzheimer’s), have already been identified. However, the remaining ‘sporadic’ forms still have no confirmed genetic predisposition factors other than the ε4 allele of the apolipoprotein E gene.

This study was designed to identify other genetic predisposition factors for sporadic AD. The research teams ran a two-phase genome analysis on over 20,000 subjects.

Phase 1 consisted in cross-comparing 500,000 genetic variants distributed across the full genome of 2,032 confirmed French cases of AD and 5,328 non-AD controls. The population was taken from a vast patient cohort for ageing research, the Etude des Trois Cités. This phase shortlisted 11 human genome regions as candidates for AD pathogenesis. The second step then consisted in running an independent analysis on each of these 11 regions, comparing 3,978 AD patients and 3,297 controls in collections from Belgium, Finland, Italy and Spain.

It was through this study step that two new genes predisposing for AD were identified: one is the clusterine gene (CLU), also called as apolipoprotein J, with a locus on chromosome 8, and the other is the 3b/4b component of complement receptor 1 (CR1), with a locus on chromosome 1. It is still not clear what role these two new genes play in the onset of AD, but previous research suggests they may be involved in eliminating a major component of amyloid plaques: β amyloid peptide.
 
The research group now plans to study the mechanisms of action of these two new targets. This research opens up solid perspectives for novel diagnostic and therapeutic strategies that should ultimately speed up progress in the fight against Alzheimer’s disease.