AUTHOR=Tian Cheng , Ye Zhenyao , McCoy Rozalina G. , Pan Yezhi , Bi Chuan , Gao Si , Ma Yizhou , Chen Mo , Yu Jiaao , Lu Tong , Hong L. Elliot , Kochunov Peter , Ma Tianzhou , Chen Shuo , Liu Song 

TITLE=The causal effect of HbA1c on white matter brain aging by two-sample Mendelian randomization analysis

JOURNAL=Frontiers in Neuroscience

VOLUME=17

YEAR=2024

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1335500

DOI=10.3389/fnins.2023.1335500

ISSN=1662-453X

ABSTRACT=<sec id="sec1"><title>Background</title><p>Poor glycemic control with elevated levels of hemoglobin A1c (HbA1c) is associated with increased risk of cognitive impairment, with potentially varying effects between sexes. However, the causal impact of poor glycemic control on white matter brain aging in men and women is uncertain.</p></sec><sec id="sec2"><title>Methods</title><p>We used two nonoverlapping data sets from UK Biobank cohort: gene-outcome group (with neuroimaging data, (<italic>N</italic> = 15,193; males/females: 7,101/8,092)) and gene-exposure group (without neuroimaging data, (<italic>N</italic> = 279,011; males/females: 122,638/156,373)). HbA1c was considered the exposure and adjusted “brain age gap” (BAG) was calculated on fractional anisotropy (FA) obtained from brain imaging as the outcome, thereby representing the difference between predicted and chronological age. The causal effects of HbA1c on adjusted BAG were studied using the generalized inverse variance weighted (gen-IVW) and other sensitivity analysis methods, including Mendelian randomization (MR)-weighted median, MR-pleiotropy residual sum and outlier, MR-using mixture models, and leave-one-out analysis.</p></sec><sec id="sec3"><title>Results</title><p>We found that for every 6.75 mmol/mol increase in HbA1c, there was an increase of 0.49 (95% CI = 0.24, 0.74; <italic>p</italic>-value = 1.30 × 10<sup>−4</sup>) years in adjusted BAG. Subgroup analyses by sex and age revealed significant causal effects of HbA1c on adjusted BAG, specifically among men aged 60–73 (<italic>p</italic>-value = 2.37 × 10<sup>−8</sup>).</p></sec><sec id="sec4"><title>Conclusion</title><p>Poor glycemic control has a significant causal effect on brain aging, and is most pronounced among older men aged 60–73 years, which provides insights between glycemic control and the susceptibility to age-related neurodegenerative diseases.</p></sec>