In the news

To identify new common susceptibility loci associated with Alzheimer’s disease. 

The researchers undertook a three-stage genetic association study based largely on individuals of European descent and combined all data in a meta-analysis. Stage 1 involved a meta-analysis of four genome-wide association study datasets involving 6,688 patients and 13,685 controls, with stages 2 and 3 involving genotyping in over 13,000 patients and 26,000 controls. A final meta-analysis was conducted including data from nearly 20,000 patients and 40,000 controls.

The meta-analysis in stage 1 identified 61 associated SNPs of which 12 (10 novel and 2 previously implicated) were taken forward for replication in stage 2. Five were again associated in stage 2 and three showed further evidence of replication in the stage 3 samples. Data from all three stages combined in a meta-analysis showed association for five genes (ABCA7, MS4A6A, MS4A4E, CR1 and BIN1). The researchers also combined their data with data from the Alzheimer’s disease genetic consortium (in an accompanying paper in Nature Genetics) in a meta-analysis and found association with 3 further genes (CD2AP, CD33 and EPHA1).

The study, taken together with the results from the Alzheimer’s disease genetic consortium, shows compelling evidence for five new Alzheimer’s disease susceptibility loci (counting MS4A6A and MS4A4E as one), as well as evidence for two previously implicated loci, CR1 and BIN1, at genome-wide statistical significance levels. These genes have functions in the immune system, cell membrane, or are involved in lipid processing and could play roles in disease pathogenesis and as such should help to focus future research. 

This well conducted study from a large European-American consortium highlights the benefits of collaborative work in identifying novel common variants, each of which confers a small increase in Alzheimer’s disease risk. Although genes involved the immune system and the way in which the brain processes cholesterol and fats have been implicated previously, a process called endocytosis has strongly been implicated for the first time. A better understanding of the disease process may allow the development of effective treatment, although a vast amount of work is still required before clinical benefits can be realised.