Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer’s disease

ABSTRACT

Rare variation in the TREM2 gene is associated with a broad spectrum of neurodegenerative disorders including Alzheimer’s disease (AD). TREM2 encodes a receptor expressed in microglia which is thought to influence neurodegeneration by sensing damage signals and regulating neuroinflammation. Many of the variants reported to be associated with AD, including the rare R47H variant, were discovered in populations of European ancestry and have not replicated in diverse populations from other genetic backgrounds. We utilized a cohort of elderly Chinese individuals diagnosed as cognitively normal, or with mild cognitive impairment or AD to identify a rare variant, A192T, present in a single patient diagnosed with AD. We characterized this variant using biochemical cell surface expression assays and found that it significantly altered cell surface expression of the TREM2 protein. Together these data provide evidence that the A192T variant in TREM2 could contribute risk for AD. This study underscores the increasingly recognized role of immune-related processes in AD and highlights the importance of including diverse populations in research to identify genetic variation that contributes risk for AD and other neurodegenerative disorders.

KEYWORDS:

• TREM2
• Alzheimer’s disease
• dementia
• genetics
• case report
• Chinese
• rare variant

Acknowledgments

We would like to thank the participants and their families for  supporting research activities at the UCSF Memory and Aging Center.

Disclosure statement

Takeda Pharmaceutical Company Limited provided funding for genotyping participants, but played no role in the design, execution, or interpretation of this study's results. The authors declare no competing interests.

Additional information

Funding

Primary support for data analyses was provided by the NIA F32 AG050404 (DWS), NIA K01 AG049152 (JSY), Larry L. Hillblom Foundation 2012-A-015-FEL and 2016-A-005-SUP (JSY), and AFTD Susan Marcus Memorial Fund Clinical Research Grant (JSY). Additional support, including for assembly of cohorts, was provided by Hillblom Aging Network (BLM), NIA P50 AG023501 (BLM), NIA P01 AG1972403 (BLM), NIA K24 AG045333 (HJR), the John Douglas French Alzheimer’s Foundation (GC), and Takeda Pharmaceutical Company Limited.