Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.
Jones L., Holmans PA., Hamshere ML., Harold D., Moskvina V., Ivanov D., Pocklington A., Abraham R., Hollingworth P., Sims R., Gerrish A., Pahwa JS., Jones N., Stretton A., Morgan AR., Lovestone S., Powell J., Proitsi P., Lupton MK., Brayne C., Rubinsztein DC., Gill M., Lawlor B., Lynch A., Morgan K., Brown KS., Passmore PA., Craig D., McGuinness B., Todd S., Holmes C., Mann D., Smith AD., Love S., Kehoe PG., Mead S., Fox N., Rossor M., Collinge J., Maier W., Jessen F., Schürmann B., Heun R., Kölsch H., van den Bussche H., Heuser I., Peters O., Kornhuber J., Wiltfang J., Dichgans M., Frölich L., Hampel H., Hüll M., Rujescu D., Goate AM., Kauwe JSK., Cruchaga C., Nowotny P., Morris JC., Mayo K., Livingston G., Bass NJ., Gurling H., McQuillin A., Gwilliam R., Deloukas P., Al-Chalabi A., Shaw CE., Singleton AB., Guerreiro R., Mühleisen TW., Nöthen MM., Moebus S., Jöckel K-H., Klopp N., Wichmann H-E., Rüther E., Carrasquillo MM., Pankratz VS., Younkin SG., Hardy J., O'Donovan MC., Owen MJ., Williams J.
BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.