On Feb. 4, 2025, an international research teams led by Hong Kong University of Science and Technology (HKUST) announced they have identified key genetic factors that confer protective effects against Alzheimer’s disease (AD) through a comprehensive genetic analysis of East Asian populations, including Chinese and Japanese, as well as European populations. This groundbreaking discovery sheds light on how these genetic factors can exert protective effects, unveiling the biological mechanisms underlying AD pathogenesis.

Affecting over 50 million people worldwide, AD is a devastating neurodegenerative disorder that imposes a substantial socioeconomic burden. However, effective treatments remain limited due to the complex mechanisms of the disease and the few effective targets for drug development.

In the past decade, research into the SORL1 gene (Sortilin-Related Receptor 1) has gained attention in the field of AD, as the protein it encodes, SORL1, plays a crucial role in regulating the production and clearance of amyloid-beta, a toxic protein that contributes to the pathology of AD. Studies conducted in individuals of European descent have suggested that certain SORL1 genetic variants exert protective effects against AD, making it a potential target for disease intervention. However, most genetic studies have mainly focused on the European population, leaving gaps in understanding how SORL1 variants affect other ethnic groups.

Therefore, investigating SORL1 genetic variants in the East Asian population will provide new insights into how these variants may exert protection against AD. This highlights the importance of comprehensive research that includes diverse ethnic groups to enhance our understanding of how ancestral backgrounds influence the genetic mechanisms underlying the disease.

To investigate how SORL1 genetic variants protect against AD in diverse populations, a multidisciplinary team performed a comprehensive genetic association analysis across East Asian populations, including individuals from mainland China, Hong Kong, and Japan, as well as European populations.

The team identified key SORL1 genetic variants in both East Asian and European populations. In particular, the Hap_A variant showed a strong protective effect against AD in the East Asian population, while it is relatively rare in the European population. The prevalence of Hap_A in East Asians is 168 times that of Europeans. Their analysis revealed that individuals carrying the Hap_A variant had better cognitive function, decreased neurodegeneration, and less severe AD pathology when compared with those not carrying the variant. Their findings demonstrated that different ethnic groups exhibit distinct sets of variants that exert AD-protective roles.