Higher Peripheral TREM2 mRNA Levels Relate to Cognitive Deficits and Hippocampal Atrophy in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment

Article type: Research Article

Authors: Tan, Yi Jayne^{a; b; 1} | Ng, Adeline S.L.^{b; 1} | Vipin, Ashwati^a | Lim, Joseph K.W.^a | Chander, Russell J.^b | Ji, Fang^a | Qiu, Yingwei^a | Ting, Simon K.S.^c | Hameed, Shahul^c | Lee, Tih-Shih^a | Zeng, Li^d | Kandiah, Nagaendran^{b; 2; *} | Zhou, Juan^{a; e; 2; *}

Affiliations: [a] Center for Cognitive Neuroscience, Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School, Singapore | [b] Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore | [c] Department of Neurology, Singapore General Hospital, Singapore | [d] Department of Research, Neural Stem Cell Research Lab, National Neuroscience Institute, Singapore | [e] Clinical Imaging Research Centre, The Agency for Science, Technology and Research and National University of Singapore, Singapore

Correspondence: [*] Correspondence to: Dr. Juan Zhou, Center for Cognitive Neuroscience, Duke-NUS Medical School, 8 college road, #06-15, 169857, Singapore. Tel.: +65 66012392; Fax: +65 62218685; E-mail: [email protected] and Dr. Nagaendran Kandiah, Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng Hospital, 308433, Singapore. Tel.: +65 6357 7171; Fax: +65 6357 7135; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Joint senior authors.

Abstract: Background: Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimer’s disease (AD) risk. Recent studies have reported inconsistent peripheral TREM2 mRNA expression levels and relationship with cognitive scores in AD and mild cognitive impairment (MCI). Additionally, no study has examined the association of peripheral TREM2 levels with neuroimaging measures in AD and MCI. Objective: To determine peripheral TREM2 mRNA levels in AD, amnestic MCI (aMCI) and healthy controls, and the association with cognitive performance and brain structural changes. Methods: We measured peripheral TREM2 mRNA levels in 80 AD, 30 aMCI, and 86 healthy controls using real time polymerase chain reaction. TREM2 levels were correlated with various cognitive performance and brain volumes, correcting for APOE4 status. Results: TREM2 mRNA levels were significantly higher in AD compared to controls and aMCI. Levels did not differ between aMCI and controls. Corrected for APOE4, higher TREM2 levels correlated with lower Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and episodic memory scores, and lower total grey matter and right hippocampal volumes. Whole-brain voxel-based morphometry analysis found negative association between TREM2 mRNA levels and grey matter volumes in temporal, parietal and frontal regions. AD subjects with MoCA scores ≤20 had higher TREM2 levels correlating with smaller total grey matter, left hippocampal and right hippocampal volumes. Conclusion: Peripheral TREM2 mRNA levels are higher in AD and are associated with AD-related cognitive deficits and hippocampal atrophy. Our findings suggest that TREM2 may be a potential non-invasive peripheral biomarker for AD diagnosis.

Keywords: Alzheimer’s disease, atrophy, blood-based biomarkers, hippocampus, mild cognitive impairment, TREM2

DOI: 10.3233/JAD-161277

Journal: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 413-423, 2017