Five Novel Late-Onset Alzheimer’s Disease Risk Genes Identified in Landmark Genomic Study

VCBeat (WeChat Official Account: vcbeat) has learned that researchers from the International Genomics of Alzheimer’s Project (IGAP) announced on February 28, 2019, that they identified five new risk genes for late-onset Alzheimer’s disease in a gene-level meta-analysis (i.e., a meta-analysis of individual genes across single datasets). Meanwhile, they also confirmed another 20 previously identified genes associated with late-onset Alzheimer’s disease.

Researchers identified these genes by conducting a genome-wide association meta-analysis of data from more than 94,000 individuals, enabling them to link specific biological processes—such as immune response, lipid metabolism, and the metabolism of tau protein and amyloid precursor protein (APP)—to the disease. They noted that variants in APP and amyloid-β (Aβ) influence both early-onset and late-onset Alzheimer’s disease, and that neurofibrillary tangles composed of Aβ and tau proteins are characteristic features of the condition. Furthermore, they added that this may imply that therapies targeting familial genetic disorders could also be suitable for treating Alzheimer’s disease. The study was recently published in the latest issue of Nature Genetics.

To conduct a meta-analysis, the IGAP team, led by Margaret Pericak-Vance of the University of Miami and her colleagues, combined 46 different datasets, yielding a total of 35,274 Alzheimer’s disease cases with clinical and autopsy records, along with 59,163 controls. Through the first two stages of analysis, the researchers identified 21 genome-wide significant loci, 18 of which had been previously recognized. Following third-stage investigation and comprehensive meta-analysis, they identified 13 new loci associated with the risk of late-onset Alzheimer’s disease.

By integrating diverse lines of evidence—including gene annotation, eQTL analysis, gene expression analysis, and pathway analysis—researchers prioritized the candidate genes they identified, quantifying the magnitude of the roles played by IQCK, ACE, ADAM10, ADAMTS1, and WWOX in Alzheimer’s disease risk.

For example, ADAM10, which encodes an α-secretase active in the brain, is part of the APP protein processing pathway. Researchers have pointed out that its overexpression in mice can prevent the production and aggregation of Aβ protein, while two rare ADAM10 variants can increase Aβ protein levels in mouse models of Alzheimer’s disease. WWOZ is a gene associated with high-density lipoprotein cholesterol and triglycerides; it is highly expressed in astrocytes and neurons, and by binding to Tau protein, it prevents excessive Tau phosphorylation, thereby avoiding the formation of neurofibrillary tangles and the aggregation of Aβ protein.

“As we continue to better understand and pinpoint approaches for treating and preventing Alzheimer’s disease, this study helps researchers clarify which genes should be prioritized for investigation,” said Richard Hodes, Director of the National Institute on Aging, in a statement. He also noted that the discovery of novel risk genes will create opportunities for developing new gene-based therapies for Alzheimer’s disease.

(Compiled by Ning Chen)