Researchers identify 17 novel genetic variants associated with risk of alzheimer’s disease

Alzheimer’s disease, a progressive brain disorder causing memory loss and cognitive decline, affects millions of people worldwide. Scientists have long sought to uncover the genetic factors contributing to this condition to develop better treatments and prevention strategies. Recently, researchers made significant strides by identifying 17 novel genetic variants linked to Alzheimer’s disease, bringing us closer to understanding and potentially combating this devastating illness.

Uncovering genetic clues

Alzheimer’s disease is the most common form of dementia, characterised by the gradual deterioration of memory, thinking, and language skills. As the disease progresses, individuals may lose the ability to carry on conversations and respond to their environment, leading to severe impairment and ultimately death. Despite its prevalence, the precise genetic mechanisms behind Alzheimer’s have remained elusive.

In a collaborative effort, scientists from Boston University School of Public Health (BUSPH) and UTHealth Houston School of Public Health conducted a comprehensive study using whole genome sequencing. This advanced technique allows researchers to examine every base pair in the human genome, offering a more detailed view of genetic variations that might contribute to Alzheimer’s disease. Their findings, published in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, revealed 17 significant genetic variants associated with Alzheimer’s, spread across five genomic regions.

The value of whole genome sequencing

Traditional genome-wide association studies (GWAS) have been instrumental in identifying regions of the genome linked to Alzheimer’s disease. However, these studies primarily focus on common genetic variants, leaving rare but potentially important variations unexplored. Whole genome sequencing, on the other hand, provides a comprehensive analysis of the entire genome, including both common and rare variants.

Dr Anita DeStefano, professor of biostatistics at BUSPH and co-senior author of the study, emphasised the significance of this approach. “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,” she explained.

The research team utilised data from the Alzheimer’s Disease Sequencing Project (ADSP), an initiative developed by the National Institutes of Health in 2012. This project aims to uncover genetic factors contributing to Alzheimer’s by analyzing the genomes of a diverse group of individuals, including those with and without the disease. The ADSP data comprises over 95 million genetic variants from 4,567 participants, providing a rich resource for identifying novel genetic associations.

Key findings and implications

Among the 17 newly identified variants, the KAT8 variant stood out as particularly noteworthy. This variant was associated with Alzheimer’s disease in both single and rare variant analyses, suggesting its significant role in the disease’s development. Additionally, several rare variants in the TREM2 gene were linked to Alzheimer’s, highlighting the importance of rare genetic changes in understanding the disease.

Dr Chloé Sarnowski, assistant professor in the Department of Epidemiology at UTHealth Houston School of Public Health and co-lead author of the study, stressed the importance of diversity in genetic research.

“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 characterise whether the known and novel associations are shared across populations,” she noted.

The ADSP includes participants from various ethnic backgrounds, such as White/European-ancestry, Black/African-American, and Hispanic/Latino subgroups. Historically, Black and Latino populations have been underrepresented in genetic studies of Alzheimer’s disease, despite having higher prevalence rates than other ethnic groups. Including these diverse populations is crucial for understanding the full spectrum of genetic risk factors and ensuring that findings are applicable to all groups.

Dr DeStefano highlighted the importance of this inclusive approach. “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,” she said.

Looking ahead

The discovery of these 17 novel genetic variants marks a significant step forward in Alzheimer’s research. However, the journey is far from over. Future studies will need to examine these variants in larger sample sizes to confirm their associations and explore their biological functions. Understanding how these genetic changes influence the development of Alzheimer’s could lead to new targets for treatment and prevention.

Dr Gina Peloso, associate professor of biostatistics at BUSPH and co-senior author of the study, emphasised the ongoing nature of this research.

“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,” she explained.

Genome-wide association studies have identified numerous loci associated with Alzheimer’s, but pinpointing the specific genes or variants responsible has been challenging. Whole genome sequencing offers a more detailed picture, capturing rare variations that GWAS might miss. This comprehensive approach is essential for uncovering the genetic architecture of Alzheimer’s and identifying potential therapeutic targets.

In summary, the identification of 17 new genetic variants linked to Alzheimer’s disease represents a major advancement in our understanding of this complex condition. By leveraging whole genome sequencing and including diverse populations, researchers are uncovering the genetic underpinnings of Alzheimer’s and paving the way for more effective treatments and prevention strategies. As this research continues to evolve, it brings hope for millions of individuals and families affected by Alzheimer’s disease.

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