New Genes Found Raise Alzheimer’s Disease Risk

In LOAD, patients typically experience their first symptoms at around the age of 65, and most people who develop Alzheimer's tend to have the late-onset form of the condition.

A very large international team of scientists led by those at Cardiff University (Cardiff, UK) conducted a three-stage case-control study of 85,133 study participants. To begin with, the team genotyped 34,174 samples using a whole-exome microarray. Then, using de novo genotyping and genotype imputation, they examined 35,962 independent samples and tested the genetic variations that they had identified in patients with LOAD in the first stage.

In the third stage, the scientists examined a further 14,997 samples in an effort to find which of the associations identified in the second stage were the most significant. In the first stage, they identified more than 200,000 variants. Then, they examined these further, looking for common and rare variants. After excluding variants that were already known to be associated with Alzheimer's disease, the teams were left with 43 candidate variants, which they further investigated in the second stage.

The investigators narrowed the candidates down to two genes that were not previously believed to have links with Alzheimer's disease. They also found a new mutation in a third gene, which was already known to be implicated in LOAD. They observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in Phospholipase C Gamma 2 (PLCG2); a risk variant in ABI Family Member 3 (ABI3); and a new genome-wide significant variant in Triggering Receptor Expressed On Myeloid Cells 2 (TREM2), a known susceptibility gene for Alzheimer's disease.

The authors concluded that these protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Rebecca Sims, PhD, the first author of the study, said, “In addition to identifying two genes that affect the risk of developing Alzheimer's disease, our new study reveals a number of other genes and proteins that form a network likely to be important in its development.” The study was published on July 17, 2017, in the journal Nature Genetics.

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