Serum Mac‐2 Binding Protein Glycan Isomer and Cerebral White Matter Injury in Older Adults: A Hepatic–Cerebral Link

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic condition with extrahepatic complications; however, its impact on cerebral microvascular pathology remains poorly understood. This study aimed to examine the association between serum Mac-2 binding protein glycan isomer (M2BPGi), a validated biomarker of liver fibrosis, and cerebral small vessel disease (CSVD), as reflected by T1-weighted white matter hypointensity volume (WM hypointensity). METHODS: We conducted a cross-sectional analysis of 1577 community-dwelling older adults enrolled in the Arao cohort, of whom 602 participants met the inclusion criteria and were included in the final analysis. MASLD was defined using the fatty liver index (FLI) ≥ 30 in combination with metabolic criteria. WM hypointensity volume was quantified using MRI and analyzed with FreeSurfer software. Multivariable linear regression analyses were performed to identify factors associated with WM hypointensity, adjusting for age, sex, and established vascular risk factors. RESULTS: Higher serum M2BPGi levels were independently associated with increased WM hypointensity (β = 1190.39, 95% CI 149.15-2231.63; p = 0.025) after adjustment for age, sex, hypertension, diabetes mellitus, hyperlipidemia, and high-sensitivity C-reactive protein. The association between M2BPGi and WM hypointensity was consistent regardless of MASLD status. CONCLUSIONS: Serum M2BPGi levels are independently associated with greater WM hypointensity burden in older adults, irrespective of MASLD status or systemic inflammation. These findings support the presence of a hepatic-cerebral axis and suggest that liver fibrosis biomarkers may help identify individuals at increased risk of cerebral microvascular injury.