Brain Age Gap Links Sickle Cell Anemia and Economic Deprivation to Cognitive Impairment

A recent cross-sectional study examined 230 adults, including 123 with sickle cell anemia (SCA) and 107 healthy controls, to explore whether brain age gap (BAG)—the difference between estimated brain age and chronological age—relates to cognitive outcomes and mediates associations of SCA and socioeconomic status with cognition. Participants underwent brain MRI and cognitive assessments using the NIH Toolbox and Wechsler Scales, with BAG derived using DeepBrainNet, a deep-learning model.

The study revealed that BAG was significantly elevated in individuals with SCA compared with controls (median BAG: 14.2 vs. 7.3 years, P < .001). Both groups exhibited higher BAG relative to a reference population, suggesting premature brain aging. Higher economic deprivation, measured using the Area Deprivation Index (ADI), was associated with increased BAG in the control cohort, while in the SCA cohort, BAG was linked to intracranial vasculopathy and higher hemoglobin S percentages.

Cognitive impairments, particularly in executive function, crystallized intelligence, processing speed, and full-scale IQ, were observed in the SCA group. BAG mediated the relationship between ADI and cognitive performance in controls and between SCA diagnosis and cognition across all domains. Notably, BAG was the strongest predictor of cognitive outcomes in controls, while white matter mean diffusivity—a marker of ischemic injury—better estimated cognitive deficits in the SCA group.

While this study’s cross-sectional design limits causal inferences about the relationship between brain age gap (BAG), SCA, and cognitive outcomes, the researchers plan to obtain 3-year-follow-up brain MRIs for longitudinal analysis. Selection bias may also exist due to matched socioeconomic and racial characteristics in the control group.

“Taken together, these results indicate that individuals with SCA are living into mid-adulthood with signs of premature aging and that beyond the negative impact of chronic disease, economic deprivation is likely playing a critical role in brain development, aging, and, ultimately, cognitive function in reportedly healthy cohorts,” the study authors concluded.

Reference
Ford AL, Fellah S, Wang Y, et al. Brain age modeling and cognitive outcomes in young adults with and without sickle cell anemia. JAMA Netw Open. 2025;8(1):e2453669. Published 2025 Jan 2. doi:10.1001/jamanetworkopen.2024.53669