Alzheimer’s disease is the leading cause of dementia in older adults, driven by a mix of genetic and environmental factors. Many genetic locations have been identified as influencing risk, yet one major part of the genome has been largely left out of studies: the X-chromosome. This chromosome, which determines biological sex along with the Y-chromosome, differs between men and women, as males have one X-chromosome and females have two, with one typically inactivated. This distinction affects how genes are expressed and contributes to differences in disease manifestation. By delving into this understudied area, scientists aim to complete the genetic picture of Alzheimer’s and uncover new pathways for understanding, diagnosing, and treating the disease.
Researchers led by Dr. Céline Bellenguez from Institut Pasteur de Lille and colleagues from various European institutions has conducted one of the most detailed investigations into this area. Published in Molecular Psychiatry, the study highlights how certain regions on the X-chromosome may influence the risk of developing Alzheimer’s disease, offering fresh insights into this complex condition.
The study involved an exceptionally large group of participants, which allowed for a thorough examination. According to Dr. Bellenguez, “The X-chromosome accounts for about five percent of the human genome, yet its role in Alzheimer’s disease has been largely ignored.” The researchers used advanced statistical techniques, which are mathematical tools to identify patterns in complex data, to explore the unique characteristics of the X-chromosome, such as the way it is differently expressed in males and females. Despite the difficulties, they identified several areas of interest that may be linked to Alzheimer’s disease risk.
Their findings revealed key regions on the X-chromosome that could be connected to the likelihood of developing Alzheimer’s disease. Although they did not find conclusive genetic risk factors, the study pinpointed significant regions, including variants, or slight changes in DNA, in genes like FRMPD4 and DMD. These genes are known to play roles in brain function and cognitive processes, which involve thinking, memory, and decision-making—essential to understanding how neurodegenerative conditions develop. Rare changes in genes such as WNK3 and DACH2 were also noted, underlining the need for additional research into these areas.
The research team highlighted the study’s significance for its careful methods. Unlike earlier genetic studies, which often excluded the X-chromosome due to its complex nature, this work included it and used specialized methods, meaning approaches designed specifically for the unique biology of the X-chromosome, to address its unique features. This represents a step forward in understanding the full genetic landscape of Alzheimer’s disease.
Dr. Bellenguez’s team believe these findings could lead to better ways of diagnosing and treating Alzheimer’s disease. They emphasized the importance of larger, more detailed studies to further investigate the genetic structure of the X-chromosome. As Dr. Bellenguez explained, “This research marks the beginning of new investigations into how the X-chromosome affects the development of Alzheimer’s disease and the differences seen between men and women.” The distinct ways Alzheimer’s manifests in men and women, explored through this study, could ignite broader discussions about the importance of personalized medicine and treatment approaches tailored to individual genetic and biological differences.
This work also shines a light on why women are disproportionately affected by Alzheimer’s disease, a disparity that has puzzled researchers for decades. By examining the genetic contributions linked to the X-chromosome, the study not only uncovers new areas for investigation but also offers hope for developing more effective diagnostic tools and therapeutic strategies that address this imbalance.
These discoveries encourage scientists to rethink long-held beliefs about Alzheimer’s disease and its causes. By including the X-chromosome in genetic research, this study broadens our understanding of the disease and highlights the need to consider gender-specific factors, which are differences based on biological sex, when studying and treating Alzheimer’s disease. The revelation of the X-chromosome’s potential role provides a sense of discovery and innovation, emphasizing the importance of integrating previously overlooked aspects into Alzheimer’s research.
Journal Reference
Le Borgne J., Gomez L., Heikkinen S., Amin N., Ahmad S., Choi S.H., et al. “X‐chromosome-wide association study for Alzheimer’s disease.” Molecular Psychiatry, 2024. DOI: https://doi.org/10.1038/s41380-024-02838-5
About the Author
Dr. Céline Bellenguez is a renowned researcher in the field of neurogenetics, with a primary focus on unraveling the genetic mechanisms underlying Alzheimer’s disease and related neurodegenerative disorders. Based in Europe, she has dedicated her career to exploring how genetic variations contribute to disease susceptibility, aiming to bridge the gap between fundamental genetics and clinical applications.
Dr. Bellenguez’s research is characterized by its innovative use of large-scale genetic studies, including genome-wide association studies, to identify key genetic loci involved in disease processes. Her work often emphasizes the importance of including overlooked genomic regions, such as the X-chromosome, to gain a more comprehensive understanding of complex diseases.
A highly respected figure in her field, Dr. Bellenguez collaborates with international research teams to push the boundaries of Alzheimer’s research. Her contributions have paved the way for potential advances in diagnostic tools and personalized treatment strategies, offering hope to millions affected by neurodegenerative diseases.
