New Gene Variants Identified as Potential Risk Factors for Alzheimer’s

New genetic variants that may affect a person’s risk for developing Alzheimer’s disease have now been identified as part of the national Alzheimer’s Disease Sequencing Project (ADSP).

These findings “will provide insight into disease mechanisms and targets for biological experiments to gain further understanding about the role of these genes in AD [Alzheimer’s disease] pathogenesis,” study author Lindsay A. Farrer, PhD, Chief of Biomedical Genetics and a professor at Boston University Schools of Medicine and Public Health, said in a press release.

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

The ADSP was developed by the National Institute on Aging (NIA) and National Human Genome Research Institute (NHGRI) in response to the National Alzheimer’s Project Act milestones to fight Alzheimer’s. These include identifying potential risk genetic factors, which are still poorly known, that might predispose someone to develop the disease.

ADSP analyzed and compared the genomes of 5,740 late-onset Alzheimer’s disease patients and 5,096 cognitively healthy older adults — the largest genome-wide study ever performed in Alzheimer’s disease.

Researchers focused on the so-called exome part of the genome, the one that contains the information for protein production.

The analysis identified 16 single variants — changes in a single nucleotide (the genome building blocks) — and 19 genes that met researchers’ criteria as probable factors influencing Alzheimer’s disease risk.

Researchers tested these genes further, using genome data from four independent datasets, including ADSP’s whole-genome family-based data — 197 members of 42 families of European ancestry and 501 members of 157 Caribbean Hispanic families.

The analysis identified novel variants, not previously implicated in Alzheimer’s disease, in three genes — the IGHG3, AC099552.4 and ZNF655 genes.

The IGHG3 gene codes for antibodies that react with beta-amyloid plaques in the brain — a hallmark event in Alzheimer’s disease. These plaques, or toxic forms of the amyloid protein, are called beta amyloid oligomers.

The AC099552.4 gene codes for a long non-coding RNA — a molecule that regulates gene expression — and may affect nerve cell development, plasticity and cognition. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

The ZNF655 gene is expressed in the brain and codes for Krüppel-like factors (KLFs), a special class of proteins that regulate a set of varied biological processes, such as growth and cell survival, as well as responses to stressful environmental cues. Several of these KLFs have been linked to nerve cell regeneration in the central nervous system.

Moreover, the genome-wide analysis confirmed associations with common and rare variants in several previously established Alzheimer’s disease risk genes, including ABCA7, APOE, HLA-DPA1, MS4A6A, PILRA, SORL1 and TREM2 genes.

“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,” said Eliezer Masliah, MD, director of the Division of Neuroscience at the NIA, a part of the National Institutes of Health (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,” Masliah said.

The genome-wide study will continue to identify other genes linked to Alzheimer’s disease.