Gene variant in Chinese linked to higher Alzheimer’s risk and more severe pathology

The TREM2 H157Y variant gene significantly increases the risk of Alzheimer’s disease (AD) in ethnic Chinese and is associated with more rapid clinical progression and more severe neurodegeneration, researchers from the Hong Kong University of Science and Technology (HKUST) have found.

The landmark research involved in-depth study of clinical cases from a genetic variant (GV) cohort, which consisted of 22 Chinese individuals from six unrelated families, including 15 TREM2 H157Y variant carriers and seven non-carriers. Other Chinese study subjects included cognitively normal individuals and patients with mild cognitive impairment (MCI) or AD (determined by clinical assessment) recruited from the Prince of Wales Hospital, Queen Mary Hospital, and the United Christian Hospital. [Alzheimers Dement 2025;21:e70586]

In an earlier study, the team found several TREM2 H157Y variant carriers in their in-house Hong Kong Chinese cohort, and that the variant might influence the amyloid ß 42/40 ratio and levels of immune-associated blood proteins in plasma among patients with AD. [Alzheimers Dement 2020;12:e12074]

“We found that the TREM2 H157Y variant is associated with a significantly higher risk of AD in the Hong Kong Chinese population [odds ratio (OR), 9.13; 95 percent confidence interval (CI), 1.06–78.4; p=0.044],” reported the team led by Professor Nancy Ip, President and Morningside Professor of Life Science at HKUST, as well as Director of the InnoHK Hong Kong Center for Neurodegenerative Diseases.

The allele frequencies of the TREM2 H157Y variant were 0.220 percent in the overall Hong Kong Chinese population and 0.455 percent in those with AD (vs 0.041–0.064 and 0.073–0.178, respectively, in Europeans).

“These findings are consistent with a previous study that reported a similar association between the H157Y variant and increased AD risk in the Chinese population,” the researchers added. [Neurobiol Aging 2016;42:217.e1-3]

“Notably, the risk of AD associated with carrying a single copy of the H157Y variant is comparable to that of carrying a single copy of APOE-ε4. Patients carrying a single copy of both the H157Y variant and APOE-ε4 exhibited quicker progression from MCI to moderate AD,” they noted.

Cognitively normal TREM2 H157Y carriers were found to have altered disease-associated blood proteins related to peripheral immune response. Irrespective of disease state, TREM2 H157Y was also found to be associated with neurodegeneration, as well as altered immune and vascular processes.

Dementia affects 9.7 percent of older adults aged ≥60 years in Hong Kong in 2019–2023. [https://www.chp.gov.hk/files/pdf/ncd_watch_aug_2025_en.pdf] AD contributes to 60–70 percent of dementia cases globally. [https://www.who.int/news-room/fact-sheets/detail/dementia] The most studied TREM2 variant, R47H, is reported to increase AD risk in populations of European descent but is rarely found in the Chinese population. Despite evidence of the association of TREM 2 H157Y with late-onset AD, and its possible pathogenic contribution to AD in Chinese patients, few studies have focused on it, underscoring the need for research on its impact in this population. [Neurobiol Aging 2015;36:546.e9-546.e13; Neurobiol Aging 2014;35:937.e1-937.e3; Psychiatr Genet 2018;28:16-18; Int J Mol Sci 2020;21:2381]

“This study is the first to demonstrate that the TREM2 H157Y genetic variant is associated with more severe AD pathology and neurodegeneration. It also highlights the critical clinical implications of the genetic variant for timely intervention and personalized disease management,” noted Ip.