Association between serum ferritin levels and mild cognitive impairment risk in middle-aged and older adults: evidence from the Health and Retirement Study (HRS)

Background: Ferritin serves as the main iron‑storage form in the human body. Iron ions are critical for numerous brain‑related physiological processes. This study aimed to explore the association between serum ferritin levels and the risk of mild cognitive impairment (MCI) in middle-aged and older adults. Methods: Participants aged 50 years and above with available cognitive function assessments were selected from the Health and Retirement Study (HRS) database. Baseline data for this retrospective cohort study were collected in 2016, and MCI occurrence was recorded through 2022. Cognitive function was assessed using tests of episodic memory and executive function. The primary MCI outcome was based on an operational cognitive-score definition rather than a clinical MCI diagnosis: the cognitive function score was at least one standard deviation (SD) below the age-specific normative value. Cox regression models were employed to explore the association between serum ferritin [tertiles: <76μg/L, 76-151μg/L (reference group), ≥151μg/L] and MCI risk, as well as impairments in episodic memory and executive function. Results: A total of 6,572 participants were enrolled in the analytical cohort. Of these, 1,435 (21.84%) participants developed MCI, while 5,137 (78.16%) were free of MCI events. Individuals with serum ferritin ≥151 μg/L were related to a higher risk of MCI [HR=1.15 (95%CI: 1.01-1.31)] compared to those with serum ferritin 76-151μg/L, but no association was found in those with serum ferritin <76 μg/L [HR=1.04 (95%CI: 0.91-1.19)]. Serum ferritin levels showed a significant U-shaped non-linear association with MCI risk (Pnon-linear = 0.03). Moreover, individuals with serum ferritin ≥151 μg/L were associated with a higher risk of episodic memory impairment [HR=1.15 (95%CI: 1.01-1.30)] versus those with serum ferritin 76-151μg/L. No significant associations were found between serum ferritin and executive dysfunction [HR=0.99 (95%CI: 0.90-1.10)]. Conclusion: High serum ferritin levels were associated with an increased risk of MCI among middle-aged and older adults, especially episodic memory impairment.