Scientists at the Boston University School of Medicine with other researchers on the Alzheimer’s Disease Sequencing Project (ADSP) have discovered new genes that could further current understanding of the genetic risk factors that predispose people to the development of Alzheimer’s disease (AD). The ADSP was developed by the National Institutes of Health (NIH) in response to the National Alzheimer’s Project Act milestones to fight AD.

The team published its study (“Whole-exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation”) in Molecular Psychiatry.

The ADSP undertook whole exome sequencing in 5,740 late-onset AD cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE-based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for an association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls),” write the investigators.

“The top findings in the discovery sample were also followed up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long noncoding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.”

“This large and deep gene sequencing study is an important part of identifying which variations may play a part in risk of getting Alzheimer’s or protection against it,” says Eliezer Masliah, M.D., director of the division of neuroscience at the National Institute on Aging, part of the NIH. “Big data efforts like the ADSP are really helping research move forward. Identifying rare variants could enhance our ability to find novel therapeutic targets and advance precision medicine approaches for Alzheimer’s disease.”

By comparing the exomes of nearly 6,000 individuals with AD and 5,000 cognitively healthy older adults, the researchers were able to find rare variations in genes that they believe may contribute to the development of common AD. These newly discovered genes may suggest an inflammatory response and changes in protein production. These combined changes are thought to contribute to the overall neurodegeneration witnessed in AD. 

The researchers hope their work will help bridge the knowledge gaps of the genetic architecture related to AD, which is a necessary step toward a better understanding of mechanisms leading to AD and eventual therapeutic treatments. 

“Many of our findings will provide insight into disease mechanisms and targets for biological experiments to gain further understanding about the role of these genes in AD pathogenesis,” explains corresponding author Lindsay A. Farrer, Ph.D., chief of biomedical genetics and a professor of medicine, neurology, ophthalmology, epidemiology and biostatistics at Boston University Schools of Medicine and Public Health. 

The research team emphasizes that further research will need to be done to find other genes hidden throughout the genome, as the current paradigm is that many genes contribute to the development of AD.

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