Researchers Find 17 Novel Genetic Variants Associated with Alzheimer

In an effort to inform the creation of future therapy and prevention strategies, a recent study used whole genome sequencing to precisely identify specific genes and genetic changes inside regions previously related to Alzheimer’s disease.

Finding genetic variations that increase the risk of Alzheimer’s disease is essential to improving our knowledge of how to treat this neurological disease, which is incurable. Many genetic variations that may impact the risk of Alzheimer’s disease have been identified by a collaborative study between Boston University School of Public Health (BUSPH) and UTHealth Houston School of Public Health. This finding brings scientists one step closer to figuring out the biological mechanisms that may be targeted in the creation of treatments and preventative measures.

The study, which used whole genome sequencing and was published in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, found 17 significant variations in five genomic areas that were linked to Alzheimer’s disease. By using this data, researchers can identify rare and significant genes and variations, expanding on the findings of genome-wide association studies, which are limited to common variants and regions.

The results highlight the importance of whole genome sequencing data in providing long-needed light on the underlying causes and risk factors of Alzheimer’s disease, the nation’s fifth-leading cause of mortality for those over 65. Alzheimer’s disease, the most prevalent type of dementia, presently affects over 6 million Americans, and by 2050, that figure is predicted to soar to around 13 million.

According to Dr. Anita DeStefano, a professor of biostatistics at BUSPH and co-senior author of the study,“Prior genome-wide association studies using common variants have identified regions of the genome, and sometimes genes, that are associated with Alzheimer’s disease,” “Whole genome sequence data interrogates every base pair in the human genome and can provide more information about which specific genetic change in a region may be contributing to Alzheimer’s disease risk or protection.”

Diversity Is Important for Genetic Research

The Alzheimer’s Disease Sequencing Project (ADSP) is a genetics initiative developed in 2012 by the National Institutes of Health with the aim of treating and preventing Alzheimer’s disease. The researchers used whole genome sequencing data from ADSP to conduct rare variant aggregation association tests and single variant association analyses for the study. 4,567 persons with or without the condition had more than 95 million variations in the ADSP data.

Given that it was connected to the condition in both the single and rare variant studies, the KAT8 variant stood out among the 17 significant variants that were connected to Alzheimer’s disease. A number of uncommon TREM2 mutations were also linked, the researchers discovered.

Dr. Chloé Sarnowski, an assistant professor in the Department of Epidemiology at the UTHealth Houston School of Public Health and co-lead of the study, says, “By using whole genome sequencing in a diverse sample, we were able to not only identify novel genetic variants associated with Alzheimer’s disease risk in known genetic regions, but also characterize whether the known and novel associations are shared across populations.”

Participants in the ADSP come from a variety of ethnic backgrounds. The population-specific assessments included a multi-population meta-analysis and three subgroups: White/European ancestry, Black/African American, and Hispanic/Latino. Even though Black and Latino communities have a higher prevalence of Alzheimer’s disease than other ethnic groups, they have historically been underrepresented in genetic research of the disease.

Dr. DeStefano states that “but we replicated known population differences for the APOE gene, which is one of the best-known and strongest risk genes for Alzheimer’s disease.” “Including participants that represent diverse genetic ancestry and diverse environments in terms of social determinants of health is important to understanding the full spectrum of Alzheimer’s disease risk, as both the prevalence of the disease and the frequencies of genetic variants can differ among populations,”

Future Prospects for Genetic Research on Alzheimer’s Disease

The researchers intend to investigate the effects of the population-specific variations they found on biological functioning in bigger sample sizes in further study.

Co-senior author Dr. Gina Peloso, an associate professor of biostatistics at BUSPH, says, “We are currently working on expanding this research to be able to use whole genome sequencing with larger sample sizes in the ADSP to be able to look at the full array of genetic variants, not only within known Alzheimer’s disease genetic regions, but across the whole genome.”