Recent research has uncovered genetic variants associated with Alzheimers disease risk, using whole genome sequencing to provide new insights into potential treatment pathways. This study highlights the importance of diversity in genetic research and aims to further explore these variants in future studies.

A recent study utilized whole genome sequencing to accurately identify particular genes and genetic alterations within regions previously linked to Alzheimers disease, aiming to guide the development of upcoming treatment and prevention approaches.

Uncovering genetic variants that contribute to the likelihood of developing Alzheimers disease is key to advancing our understanding of how to manage this incurable neurodegenerative disorder. A collaborative study between Boston University School of Public Health (BUSPH) and UTHealth Houston School of Public Health has pinpointed multiple genetic variants that could affect the risk of Alzheimers, moving scientists a step nearer to identifying biological mechanisms that could be targeted in the development of treatments and preventative strategies.

Published in the journal Alzheimers & Dementia: The Journal of the Alzheimers Association, the study utilized whole genome sequencing and identified 17 significant variants associated with Alzheimers disease in five genomic regions. This data enables researchers to pinpoint rare and important genes and variants, building upon genome-wide association studies, which focus only on common variants and regions.

The findings underscore the value of whole genome sequencing data in gaining long-sought insight into the ultimate causes and risk factors for Alzheimers disease, which is the fifth leading cause of death among people 65 and older in the United States. As the most common form of dementia, Alzheimers disease currently affects more than 6 million Americans and that number is expected to skyrocket to nearly 13 million by 2050.

Prior genome-wide association studies using common variants have identified regions of the genome, and sometimes genes, that are associated with Alzheimers disease, says study co-senior author Dr. Anita DeStefano, professor of biostatistics at BUSPH. 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 Alzheimers disease risk or protection.

For the study, the researchers conducted single variant association analyses and rare variant aggregation association tests using whole genome sequencing data from the Alzheimers Disease Sequencing Project (ADSP), a genetics initiative that the National Institutes of Health developed in 2012 as part of the National Alzheimers Project Acts goal to treat and prevent the disease. The ADSP data include more than 95 million variants among 4,567 participants with or without the disease.

Among the 17 significant variants that were linked to Alzheimers disease, the KAT8 variant was one of the most notable, as it was associated with the disease in both the single and rare variant analyses. The researchers also found associations with several rare TREM2 variants.

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

The ADSP includes ethnically diverse participants, and the population-specific assessments focused on White/European-ancestry, Black/African-American, and Hispanic/Latino subgroups, as well as a multi-population meta-analysis. Historically, Black and Latino populations have been underrepresented in genetic studies of Alzheimers disease despite having a higher prevalence of the disease than other ethnic groups.

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 Alzheimers disease risk, as both the prevalence of the disease and the frequencies of genetic variants can differ among populations, says Dr. DeStefano. The sample sizes in the population-specific analyses were small, so the team had limited ability to detect associations, she says, but we replicated known population differences for the APOE gene, which is one of the best-known and strongest risk genes for Alzheimers disease.

In future studies, the researchers hope to examine the population-specific variants they identified in much larger sample sizes, as well as explore how these variants affect biological functioning.

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 Alzheimers disease genetic regions, but across the whole genome, says co-senior author Dr. Gina Peloso, associate professor of biostatistics at BUSPH.

Reference: Key variants via the Alzheimers Disease Sequencing Project whole genome sequence data by Yanbing Wang, Chlo Sarnowski, Honghuang Lin, Achilleas N. Pitsillides, Nancy L. Heard-Costa, Seung Hoan Choi, Dongyu Wang, Joshua C. Bis, Elizabeth E. Blue, , Eric Boerwinkle, Philip L. De Jager, Myriam Fornage, Ellen M. Wijsman, Sudha Seshadri, Jose Dupuis, Gina M. Peloso, Anita L. DeStefano and , 21 March 2024, Alzheimers & Dementia. DOI: 10.1002/alz.13705

The study was also co-led by Yanbing Wang while she was a PhD student in biostatistics at BUSPH. It was funded by the National Institute on Aging under Award Numbers U01 AG058589 and U01 AG068221.

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Scientists Discover 17 New Genetic Variants Linked to Alzheimer's Disease - SciTechDaily