Association between Plasma LRG1 and Lower Cognitive Function in Asians with Type 2 Diabetes Mellitus

Serena Low; Angela Moh; Bhuvaneswari Pandian; Xin Li Tan; Sharon Pek; Huili Zheng; Keven Ang; Wern Ee Tang; Ziliang Lim; Tavintharan Subramaniam; Chee Fang Sum; Su Chi Lim

doi:10.1210/clinem/dgad768

Association between Plasma LRG1 and Lower Cognitive Function in Asians with Type 2 Diabetes Mellitus

J Clin Endocrinol Metab. 2024 Jan 3:dgad768. doi: 10.1210/clinem/dgad768. Online ahead of print.

Authors

Serena Low^{1

2

3}, Angela Moh¹, Bhuvaneswari Pandian¹, Xin Li Tan¹, Sharon Pek¹, Huili Zheng¹, Keven Ang¹, Wern Ee Tang⁴, Ziliang Lim⁴, Tavintharan Subramaniam², Chee Fang Sum², Su Chi Lim^{1

2

3

5}

Affiliations

¹ Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, 90 Yishun Central, Singapore 768828.
² Diabetes Centre, Admiralty Medical Centre, Singapore, Block 676, Level 4, Kampung Admiralty, Woodlands Drive 71, Singapore 730676.
³ Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232.
⁴ National Healthcare Group Polyclinics, Singapore, 3 Fusionopolis Link, Nexus@one-north, South Tower, Singapore 138543.
⁵ Saw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, #10-01, Singapore 117549.

PMID: 38170213
DOI: 10.1210/clinem/dgad768

Abstract

Context: Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear.

Objective: Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian Randomization (MR), and the role of arterial stiffness as a potential mediator.

Methods: T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism (SNP). Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function.

Results: Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients -1.38 (95%CI -2.55 to -0.21; p = 0.021) and -1.38 (95%CI -2.70 to -0.07; p = 0.039), respectively. Genetically-predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient -7.44 (95%CI -14.14 to -0.74; p = 0.030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score.

Conclusions: Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up.

Keywords: Arterial stiffness; Cognitive decline; Leucine-rich α-2-glycoprotein; Type 2 diabetes.