β2-microglobulin and cognitive decline: Unravelling the mediating role of the Dunedin Pace of Aging methylation

Yujun Ke ¹ Ping Chen ¹ Chunlan Wu ² Qinqin Wang ³ Kai Zeng ^1* Min Liang ^1*

• ¹ Department of Anesthesiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
• ² Department of Oncology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
• ³ Department of Rheumatology, Affiliated Nanping First Hospital of Fujian Medical University, Nanping, China

Background: Progressive cognitive decline is inevitable with aging. Growing evidence links β2-microglobulin (B2M) to aging and cognitive decline. However, the current evidence is inadequate to establish a definitive association. This study aims to investigate the relationship between B2M levels and cognitive performance, together with the mediating effect of the pace of biological aging.Methods: Utilizing the 1999-2002 National Health and Nutrition Examination Survey (NHANES) database, cognitive performance was measured via the Digit Symbol Substitution Test (DSST), while the pace of biological aging was quantified using a new generation DNA methylation algorithm, Dunedin Pace of Aging methylation (DunedinPoAm). Weighted multivariable linear regression was used to explore the relationship between B2M levels and cognitive performance. Furthermore, subgroup analysis and interaction tests were performed to assess the relationship's stability. Mediation analysis was conducted to investigate the mediating effect of DunedinPoAm on the association between B2M levels and cognitive performance.The study included 1,267 participants aged 60 and over. After correcting for all confounders, for each one-unit increment in log-transformed B2M levels, the DSST score fell by 5.13 points (95%CI -9.03 to -1.24), while the level of DunedinPoAm increased by 0.04 (95%CI 0.01 to 0.07). The analysis of the trend test yielded identical results (P for trend < 0.05). Additionally, across every subgroup analyzed, the correlation between B2M levels and cognitive performance was stable (P for interaction > 0.05). Further mediation analysis showed that DunedinPoAm mediated 9.0% (95%CI 0.1% to 43.2%) of the association between B2M and cognitive performance.Conclusions: These findings suggested a substantial link between elevated B2M levels and cognitive decline among U.S. older adults, partly mediated through the faster pace of aging. This correlation highlights the potential of B2M as a biomarker for early detection and therapeutic intervention of aging-related cognitive decline.