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Alzheimer's Disease Meta-Analysis Identifies Five New Risk Genes

NEW YORK (GenomeWeb) – Researchers affiliated with the International Genomic Alzheimer's Project (IGAP) have uncovered five new late-onset Alzheimer's disease risk genes in a genetic meta-analysis. They likewise confirmed 20 other genes previously linked to late-onset Alzheimer's risk.

The researchers identified the genes through a genome-wide association meta-analysis using data from more than 94,000 people, which also enabled them to tie certain biological processes like immune response, lipid metabolism, tau binding proteins, and amyloid precursor protein metabolism to disease. This, they noted, suggests that variants affecting APP and Aβ processing play roles in both early- and late-onset Alzheimer's. Amyloid plaques of Aβ protein and neurofibrillary tangles of tau protein are disease hallmarks.

"The size of this study provides additional clarity on the genes to prioritize as we continue to better understand and target ways to treat and prevent Alzheimer's," Richard Hodes, director of the National Institute on Aging, which in part funded the work, said in a statement. The study was published today in Nature Genetics.

For their meta-analysis, the IGAP team, led by the University of Miami's Margaret Pericak-Vance and her colleagues, combined 46 different datasets to yield an overall set of 35,274 clinical and autopsy-documented Alzheimer's cases and 59,163 controls to interrogate. Through the first two stages of their multi-stage analysis, the researchers uncovered 21 loci reaching genome-wide significance, 18 of which had previously been identified. After the third stage of their investigation and an overall meta-analysis, they identified 13 novel loci associated with risk of late-onset Alzheimer's.

By weaving together various line of evidence — gene annotation, eQTL analyses, gene expression analysis, and pathway analyses — the researchers prioritized candidate genes at the novel signals they found, implicating the IQCK, ACE, ADAM10, ADAMTS1, and WWOX genes in Alzheimer's risk.

ADAM10, for instance, encodes an alpha secretase that is active in the brain and is part of the non-amyloidogenic pathway of APP. Its overexpression in mice, the researchers noted, can prevent the production and aggregation of Aβ, and two rare ADAM10 variants increased Aβ levels in a mouse model of Alzheimer's.

Meanwhile, WWOZ, which is a high-density-lipoprotein cholesterol and triglyceride-associated gene, is highly expressed in astrocytes and neurons, and binds tau, where it may regulate tau hyper-phosphorylation, the formation of neurofibrillaries, and aggregation of Aβ.

At the same time, the researchers confirmed the links between 20 previously implicated genes and Alzheimer's disease risk. Those genes, the researchers noted, are themselves involved in APP metabolism and are expressed in brain tissues, immune-related tissues, and obesity-related tissues.

In their pathway analyses, the researchers found that the common variants they identified were often involved in APP metabolism or Aβ formation, tau protein binding, lipid metabolism, and immune response. This, they noted, indicates that variants affecting APP and Aβ processing are not only linked to early-onset Alzheimer's disease, but also to late-onset Alzheimer's disease. Further, they added that it could mean that therapies developed for the familial form of the disease might also be suitable to treat the common form of the disease.

Pathway analysis showing that tau is involved in late-onset Alzheimer's supports recent evidence that tau may play an early pathological role in the disease and confirms that therapies targeting tangle formation or degradation could potentially affect late-onset disease, Pericak-Vance and her colleagues noted in their paper.

Their analysis of risk genes and disease-linked pathways also indicated an enrichment of rare variants in late-onset Alzheimer's disease risk and suggested there might be additional rare variants to find if larger samples are studied.