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Alzheimer's Disease GWAS Meta-Analysis Leads to New Susceptibility Loci, Risk Score

NEW YORK – A genome-wide association study meta-analysis by members of an international team has uncovered dozens of Alzheimer's disease (AD) risk loci, including 42 sites not previously linked to the neurological condition, while providing the basis for a genetic risk score (GRS) for the disease.

"By applying a GRS derived from all the genome-wide significant variants discovered in this study, we identified an association with the risk of incident AD in prospective population-based cohorts and with the risk of progression over time from [mild cognitive impairment] to AD," co-senior and co-corresponding author Jean-Charles Lambert, a research director at INSERM in Lille, France, and an investigator at the University of Lille, and his coauthors wrote in Nature Genetics on Monday.

The researchers flagged 75 AD-associated loci through a two-stage GWAS meta-analysis that included more than 111,300 AD cases and nearly 677,700 unaffected controls, including 42 new risk loci. By digging into the variants in this collection, they confirmed links between AD risk and microglia cell function, amyloid-beta peptide pathways, and Tau protein pathways, while highlighting 31 genes with newly detected AD-related loci for further analyses.

"[W]e characterized these regions in order to give them meaning in relation to our clinical and biological knowledge, and thereby gain a better understanding of the cellular mechanisms and pathological processes at play," Lambert said in a statement.

Along with immune system-related genes and genetic variants at loci implicated in Parkinson's disease and other neurodegenerative conditions in the past, the team's pathway and gene prioritization analyses unearthed variants in and around components of the linear ubiquitin chain assembly complex, particularly when it came to regulation of the tumor necrosis factor (TNF) alpha pathway.

The linear ubiquitin chain assembly complex has been implicated in everything from inflammasome and microglial activation to autophagy and TNF-alpha signaling, the investigators explained. They noted that TNF-alpha signaling-related variants outside of the linear ubiquitin chain assembly complex turned up in the broader AD risk variant set.

By bringing together more than 80 genetic risk variants for AD and related dementias from the GWAS meta-analysis, meanwhile, the team developed a GRS that appeared to boost AD risk prediction over previous models and can complement risk insights based on age and APOE status.

"In population-based cohorts with clinically diagnosed AD cases, the GRS was significantly associated with conversion to AD; this was shown in a fixed-effect meta-analysis," the authors reported. "Likewise, the GRS was significantly associated with AD conversion in patients with [mild cognitive impairment]."

Lambert cautioned that the GRS "is not at all intended for use in clinical practice at present," but suggested that it "could be very useful when setting up therapeutic trials in order to categorize participants according to their risk and improve the evaluation of the medications being tested."