Dozens Of New Genetic Risk Factors For Alzheimer’s Disease Identified
By Deborah Borfitz
May 18, 2022 | A meta-analysis of new and previous genome-wide association studies (GWAS) has identified 75 genetic risk factors for Alzheimer’s disease (AD), 42 of which weren’t previously implicated. The investigation confirms the importance of two pathological brain phenomena that are currently pursued therapeutic targets—the accumulation of amyloid-beta peptides and the modification of the protein tau—and strengthens the case for having microglial cells join the hit list, according to Jean-Charles Lambert, research director at Inserm (National Institute of Health and Medical Research) based in Lille, France.
The study also shows for the first time that the tumor necrosis factor alpha (TNF-alpha)-dependent signaling pathway is involved in the disease, he adds. It is noteworthy that two of the three proteins composing the linear ubiquitin chain assembly complex (LUBAC), a major regulator of the TNF-mediated signaling pathway, are encoded by two new tier 1 prioritized genes (SHARPIN and RBCK1). The complex’s function is also directly regulated by another tier 1 prioritized gene (OTULIN).
Genes were prioritized based on their likelihood of being the true risk gene responsible for signals of AD and related dementias, as recently reported in Nature Genetics (DOI: 10.1038/s41588-022-01024-z). Researchers also introduced a genetic risk score to help evaluate which patients with cognitive impairment will go on to develop AD within three years of its clinical manifestation.
The genetic risk score is usable only at the population level and not for individual assessments in the clinic, Lambert stresses. It’s a statistical tool to help differentiate people at low and high risk of disease and, for drug development purposes, potentially to define subpopulations with the specific biological characteristics for which a therapy has been developed.
Researchers increased the sample size of GWAS by combining clinically diagnosed AD cases and controls from 15 European countries with “proxy-AD” GWAS of the UK Biobank based on questionnaire data indicating if one’s parents had dementia. This created the largest-ever group of AD patients (111,326, plus 677,663 controls) for a study of this type for the common but complex disease, says Lambert.
The intent of the analyses was to characterize the pathogenic code of AD pathways, and validation of the involvement of amyloid and tau is “good news” because currently available treatments largely target these pathways, Lambert says. But less than a decade ago most scientists in the field were still paying no mind to the trash collector role being played by microglia cells in the human immune system.
It is today unquestioned that microglial cells are critical to the development of AD, he adds, as has been established in multiple genetic studies. Commercial interest in microglia-targeting therapeutics for Alzheimer’s as well as other neurodegenerative diseases is at an all-time high.
Beyond influences by LUBAC, the TNF-alpha pathway was also flagged by other genetic findings in the new study, says Lambert. The additional risk factors included activation of the pathway by the does-it-all ADAM-17 enzyme and inhibition of it by the gene product of the previously known genetic risk factor TNIP1.
It was also previously shown that anti-TNF-alpha compounds can forestall the development of AD by reducing levels of amyloid plaques and tau phosphorylation and increasing the marker for immune-response-boosting dendritic cells in transgenic mice. Given the abundance of evidence, he says, drug makers are likely to continue investing in compounds targeting the TNF-alpha signaling pathway.
Adoption of the new genetic risk score will come later with the development of personalized medicine, Lambert says. Once treatments are conceived that take the identified disease pathways into account, they can be directed to genetically suited patient groups. “We are really at the beginning of the story.”
Populations involved with the GWAS meta-analysis were mainly of European ancestry, and the lack of genetic diversity means the produced genetic risk score will likely be less effective for people of other backgrounds, says Lambert. The long-term plan is to design population-specific risk scores, since AD may have different genetic drivers and functional variants across statistically homogeneous populations around the world.
To that end, Inserm is collaborating with colleagues in the United States and a dozen or so organizations in South America, Central America, and Asia. “Unfortunately, Africa is again out of the map… specific efforts are required to develop collaborations with countries in this continent,” he says.
Meanwhile, Lambert and his team are developing various cellular and molecular biology approaches to determine the role of genetic risk factors in the development of AD. They are currently exploring genetic risk factors driving synaptic loss, for example, which is a “very early disease marker."