Identifying Genetic Risk for Late-onset Alzheimer's Disease: The GERAD Consortium

Alzheimer?s disease (AD) is the most common form of dementia whose numbers will double in the next generation resulting in over one million sufferers in the UK alone. It is vital we understand the causes of AD quickly to allow the development of preventative and therapeutic interventions. We have good evidence that genes play significant roles in AD development and that there are several remaining to be found. This research study will use new technological advances to test the influence of every human gene on the risk of developing AD. The success of this approach depends on using very large samples of AD cases and controls. This study is the largest genome-wide association study (GWAS) of AD world-wide and is anticipated to identify 20 new risk genes and disease pathways AD risk genes pinpoint primary biological processes which trigger disease development.

Alzheimer‘s disease (AD) is a common, heritable, genetically complex disorder. Genome-wide association studies (GWAS) have succeeded in identifying over 400 genetic variants contributing to complex phenotypes, in less than two years. Recently, our consortium performed a GWAS in 16,000 AD and control samples, which succeeded in identifying two new susceptibility genes (CLU: p= 8.5 x10-10, odds ratio (OR) = 0.86 & PICALM: p= 1.3 x10-9, OR = 0.86), provided strong evidence for the existence of several more (13 variants observed p 1 x 10-5 , 4 expected by chance: p= 7.5 x 10-6)and confirmed a third susceptibility gene CR1. We will undertake a powerful GWAS (+55,000 individuals) of AD, aiming to identify 10 new susceptibility genes contributing to disease risk, modifying age at onset or contributing to copy number variation. Findings will be screened for AD susceptibility pathways and tested for relationships with clinical symptoms. This proposal will produce a definitive study of common genetic risk in AD and will deliver around 20 new susceptibility genes, CNVs and pathways in 2 years. Identifying new susceptibility genes will pinpoint primary causal pathways to disease and provide the basis for future preventative and therapeutic interventions, contribute to early susceptibility testing and increase UK research capacity.