Genetic predisposition remains to be one of strongest risk factors for developing Alzheimer's disease (AD), and genome-wide association studies (GWAS) have identified many genetic variants associated with AD. However, over 90% of association studies were carried out in individuals of European descent, with a large imbalance between ethnic groups. To understand the effects of genetic variants in AD among Han Chinese population, our group studied the known AD-associated variants in a Hong Kong Chinese cohort. We established a polygenic risk score (PRS) model for AD risk prediction locally and identified individuals carrying the rare AD-risk associated mutation, the H157Y variant (rs2234255), located in the triggering receptor expressed on myeloid cells 2 (TREM2) gene loci. We found that the frequency of the TREM2 H157Y A allele is up to 0.46% in this local AD population with an odds ratio of 9.13 for AD. The TREM2 H157Y A allele carriers with AD exhibited more severe AD pathology and neurodegeneration based on blood biomarkers (p- tau217, NfL) and brain MRI. The TREM2 H157Y A allele carriers exhibited a quicker decline from MCI to moderate AD in the presence of the APOE-ɛ4 allele based on clinical observations. Through the study of the TREM2 H157Y variant, we aim to raise the awareness of physicians and the general public about the importance of the genetic predisposition of AD and the early identification of individuals at risk of AD. Integration of both genomics, blood and imaging biomarkers into clinical practice align AD biology with patient care and allow accurate patient stratification for prescribing disease modifying drugs. Early interventions including controlling the risk factors, adopting healthy lifestyles and prescribing medication in a timely manner will reduce long-term care costs and the burden on caregivers, healthcare system and society.
