94,437 individuals who had been diagnosed with late-onset Alzheimer’s disease participated in a genome-wide association study that identified variants in five new genes that put people at risk for Alzheimer’s disease. The data also confirmed 20 other genes that had been previously implicated in Alzheimer’s disease.
The last large-scale genome-wide association study (GWAS) was published five years ago and included approximately 75,000 individuals. This study identified 20 genetic risk loci. At the time, 11 of the newly identified loci had never before been implicated in conferring risk for Alzheimer’s disease. In January of 2019, an international team of scientists published an updated Alzheimer’s disease GWAS that was published in Nature Genetics. This time the study included genetic data from over 635,000 individuals. This dramatic increase in the number of subjects allowed for the identification of nine novel Alzheimer’s disease risk loci.
In some ways, this latest GWAS study allowed for the confirmation of the involvement of genes identified in the previous study in Alzheimer’s disease while also identifying novel targets and de-emphasizing some of the suggested hits from the previous paper. An interesting, newly identified risk gene for Alzheimer’s disease is APH1B. Along with presenilins, APH1B makes up the gamma-secretase complex which is responsible for cleaving amyloid precursor protein to form a smaller protein, amyloid b, that is more toxic due to its propensity to form plaques in the brain.
Genome-wide association studies are useful in identifying gene variants that turn up often in patients with a specific disease. What is harder to identify are the rare gene variants. The international team of scientists increased their sample size to genomic data from more than 94,000 individuals in order to identify these rare genetic variants in five additional genes: IQCK, ACE, ADAM10, ADAMTS1, and WWOX that are associated with late onset Alzheimer’s disease.
Another huge advance from this paper is the identification of the groups of genes that work together to influence risk and disease progression. Many of the genes identified play a role in the formation of beta-amyloid plaques, tau accumulation, and the immune system.
By themselves, each of these newly discovered variants contribute only a small amount of increased risk. That being said, this study advances the biological pathways that are involved in the onset and progression of the disease.
A huge component of this study to keep in mind is the dramatic similarity between genes implicated in early-onset and late-onset Alzheimer’s disease. This aspect of the study suggests that treatments developed for people with the early onset form might also help those with the more common late-onset of the disease.
This new research paper is ground breaking for those interested in finding a way to predict who will get Alzheimer’s disease later in life. The goal of this research is to understand how the complex biological, environmental, and lifestyle factors interact to contribute to Alzheimer’s.