An international research collaboration has discovered significant genetic factors that help protect against Alzheimer’s disease (AD) by conducting an extensive genetic analysis involving East Asian populations, such as Chinese and Japanese, along with European groups. This groundbreaking finding provides insights into how these genetic factors function protectively and clarifies the biological mechanisms involved in the development of AD.
A global research team headed by the Hong Kong University of Science and Technology (HKUST) has unveiled crucial genetic elements that offer protective effects against Alzheimer’s disease (AD) through an extensive genetic study of East Asian cohorts, notably including Chinese and Japanese populations, as well as those from Europe. This milestone achievement elucidates the protective capabilities of these genetic factors, revealing the biological processes that contribute to AD’s progression.
Key Highlights:
- Discovery: A genetic variant named Hap_A of SORL1, associated with AD protection, was identified. This variant is found in East Asians—Chinese and Japanese—at a rate 168 times higher than in Europeans.
- Evidence: Hap_A demonstrates a correlation with improved cognitive performance and is associated with heightened expression of the SORL1 protein, which is crucial in the context of AD.
- Significance: This study illustrated how genetic research across various populations can unravel the influence of genetic factors on AD. A particular coding variant of a new SORL1 protein isoform was detected, offering a potential target for more detailed studies regarding the disease’s mechanisms.
Alzheimer’s disease affects over 50 million individuals globally and represents a severe neurodegenerative challenge with substantial socio-economic impacts. Unfortunately, viable treatment options remain scarce due to the intricate nature of the disease and limited drug development targets.
In the last ten years, the SORL1 gene (Sortilin-Related Receptor 1) has drawn significant attention in Alzheimer’s studies, as the protein it encodes, SORL1, is pivotal in managing the production and removal of amyloid-beta, a harmful protein linked to AD pathology. Prior research conducted mainly among individuals of European descent indicated that certain genetic variants of SORL1 may provide protective benefits against the disease, suggesting it as a potential intervention target. However, much of the genetic research has predominantly focused on European-derived populations, creating a gap in understanding how SORL1 variants influence other ethnicities. Thus, assessing SORL1 variants in East Asian populations could yield fresh perspectives on their role in AD protection, highlighting the need for extensive studies that include varied ethnic backgrounds to deepen our understanding of genetic pathways in the disease’s development.
To explore the protective function of SORL1 variants against AD among different populations, a multidisciplinary team led by Prof. Nancy IP, the President and Morningside Professor of Life Science at HKUST and Director of the Hong Kong Center for Neurodegenerative Diseases (HKCeND), conducted a thorough genetic association study involving East Asian groups from mainland China, Hong Kong, and Japan, alongside European cohorts. They collaborated with experts including Prof. John Hardy from University College London, Prof. Akinori Miyashita from Niigata University, and Prof. Yu Chen from the Shenzhen Institutes of Advanced Technology at the Chinese Academy of Sciences, and also utilized data from international databases, such as the Alzheimer’s Disease Neuroimaging Initiative.
The research team pinpointed critical SORL1 genetic variants in both East Asian and European populations, specifically highlighting the Hap_A variant, which displayed a significant protective effect against AD in East Asians but is relatively unknown in European populations. The incidence of Hap_A in East Asians is 168 times higher compared to Europeans. Their assessments indicated that individuals possessing the Hap_A variant exhibited better cognitive function, less neurodegeneration, and milder AD pathology than those without it, underscoring the fact that various ethnic groups possess unique sets of variants contributing to AD protection.
To dive deeper into the biological functions of these AD-protective SORL1 genetic variants, the team conducted an extensive analysis of their functional roles. Findings revealed that these protective variants correlate with heightened SORL1 protein levels and may influence biological pathways integral to both immune responses and neural activities. Importantly, they identified a specific coding variant that governs the expression and activity of a newly recognized SORL1 protein isoform, which had not been extensively characterized before. This discovery sheds light on the molecular mechanisms that could clarify how SORL1 impacts AD risk.
“This study broadens our understanding of SORL1’s involvement in AD and unveils its potential for therapeutic innovations,” stated Prof. Ip. “Our project, supported by international collaboration, contributes to one of the most comprehensive databases focused on East Asians concerning AD, serving as a vital asset for researching AD genetic factors across diverse ethnicities.”
The research was funded by the National Natural Science Foundation of China (NSFC) and the Research Grants Council (RGC) of Hong Kong Joint Research Scheme, as well as the InnoHK initiative backed by the HKSAR government. The study involved collaborations with researchers from University College London and Niigata University, along with clinical professionals from the Prince of Wales Hospital and Queen Elizabeth Hospital. These findings have recently been published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association and highlighted on Alzforum, a scholarly platform dedicated to AD research.
