Elevated HbA1c is associated with advanced brain age in severe obesity

  1. Joshua Juhasz
  2. Brittany DeFeis
  3. Mark K. Britton
  4. Hannah Hoogerwoerd
  5. Kate Worwag
  6. Keyanni J. Johnson
  7. Angel Uribe
  8. John B. Williamson
  9. Eric C. Porges
  10. Ronald A. Cohen
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Abstract

Introduction

Brain-predicted age, estimated from structural MRI data, is a machine learning biomarker of biological brain aging. Greater brain age gap (BAG) indicates advanced brain aging and is associated with cognitive decline and mortality. Cardiometabolic risk factors, including elevated blood glucose, body mass index (BMI), blood pressure, and cholesterol, increase risk of cognitive impairment and dementia in aging. Their relationship with BAG in severe obesity remains poorly characterized despite increased prevalence of cardiometabolic risk factors among this population.

Methods

T1-weighted MRI data from 97 adults (BMI 35-73) were used to calculate BAG using ENIGMA and Pyment brain age models. Associations between BAG and HbA1c, BMI, hypertension, and hyperlipidemia were examined using multiple linear regression and MM-estimation robust regression, adjusting for age, sex, and race. Post hoc analyses stratified models by clinical HbA1c cutoffs (normoglycemic, prediabetic, diabetic).

Results

Higher HbA1c was associated with greater BAG ENIGMA ( B = 1.58, p = .014) and BAG Pyment ( B = 0.93, p = .013) in linear regression models. In robust models, HbA1c remained significantly associated with BAG ENIGMA ( B = 1.70, p = .002) but not BAG Pyment ( B = 0.71, p = .13). BMI, hypertension, and hyperlipidemia were not associated with BAG in either linear or robust models. HbA1c was associated with greater BAG ENIGMA ( B = 2.15, p = .01) and BAG Pyment ( B =1.21, p = .04) in those at or above prediabetic levels and with BAG ENIGMA ( B = 2.49, p = .047) in those with diabetes.

Conclusions

Elevated HbA1c is associated with accelerated brain aging in individuals with severe obesity. BAG was not associated with BMI, hypertension, and hyperlipidemia, which may reflect the restricted BMI range inherent to the sample with severe obesity.

HIGHLIGHTS

  • Elevated HbA1c was associated with advanced brain aging in individuals with severe obesity.

  • HbA1c-BAG associations were seen primarily in the context of clinically elevated levels (i.e. prediabetes and diabetes).

  • The study did not provide evidence to support that BMI, hypertension, and hyperlipidemia are associated with BAG in individuals with severe obesity

  • ENIGMA and Pyment models showed limited agreement in BAG estimates in a sample of individuals with severe obesity.

Article activity feed

  1. Version published to 10.64898/2026.06.04.26354935 on medRxiv