Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 May;15(5):e70521.
doi: 10.1002/brb3.70521.

Associations Between Cortical Iron Accumulation and Memory in Patients With Amnestic Mild Cognitive Impairment and in Cognitively Normal Individuals

Subin Lee  1 , Suhyeon Lee  2 , Ina Park  2 , Yeonsil Moon  3 , Younghee Yim  4 , Jongho Lee  1 , June Sic Kim  5 , Won-Jin Moon  2   6
Affiliations

Associations Between Cortical Iron Accumulation and Memory in Patients With Amnestic Mild Cognitive Impairment and in Cognitively Normal Individuals

Subin Lee et al. Brain Behav. 2025 May.

Abstract

Background and purpose: Brain iron accumulation is recognized as a cause and therapeutic target in Alzheimer's disease (AD). We investigated the differences in both volume and iron accumulation between cognitively normal (CN) older adults and patients with amnestic mild cognitive impairment (aMCI). Additionally, we assessed which combination of these measures best explains the group differences in visual and verbal memory performance.

Materials and methods: We retrospectively analyzed data from 48 patients with aMCI and 33 age-matched CN individuals. Structural differences were investigated using voxel-based comparisons of T1-weighted magnetic resonance images. Differences in iron accumulation were investigated using voxel-based comparisons of quantitative susceptibility mapping (QSM) images. Subsequently, significant clusters from these voxel-based analyses (amygdala, posterior cingulate cortex, precuneus, lateral occipital cortex, and pericalcarine cortex) were entered into a stepwise regression to predict verbal and visual memory scores, while accounting for age, sex, and education as covariates.

Results: In comparison to CN, patients with aMCI had significantly lower scores in both verbal and visual memory tests (p < 0.001). The T1-weighted voxel-based morphometry (VBM) results showed significant hippocampal atrophy in the aMCI group relative to CN individuals. The QSM-VBM results showed increased iron accumulation in the amygdala, posterior cingulate cortex, precuneus, lateral occipital cortex, and pericalcarine cortex (FWE-corrected p < 0.05). Lower hippocampal volume (B = 2015.91, SE = 469.61, p < 0.001) and higher posterior cingulate cortex susceptibility (B = -189.63 SE = 89.11, p = 0.037) were significant predictors of verbal memory. For visual memory, higher lateral occipital susceptibility (B = -659. 96, SE = 253.03, p = 0.011) was significant imaging predictor.

Conclusions: These results suggest that iron accumulates in regions where atrophy has not yet occurred, suggesting that iron may serve as an earlier imaging marker of neurodegeneration compared to volume atrophy. Further studies are needed to investigate the longitudinal relationship between brain volume and iron accumulation during cognitive decline.

Keywords: iron; memory; mild cognitive impairment; quantitative susceptibility mapping.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest related to the content of this article.

Figures

FIGURE 1
FIGURE 1
Overview of (A) QSM processing and (B) voxel‐based analysis of T1 volume and QSM.
FIGURE 2
FIGURE 2
Patterns of GM atrophy (A) and iron accumulation (B) in patients with aMCI versus NC group. The results are shown on a 3D surface render (top) and overlaid on representative axial, coronal, and sagittal slices (bottom). Statistical significance of p < 0.05, corrected for multiple comparisons using few, are used. (A) T1‐VBM results: significant atrophy in the hippocampus in aMCI compared to NC group. (B) QSM‐VBM results: increased iron accumulation (noted as higher positive QSM values) in the amygdala/hippocampus, precuneus, posterior cingulate cortex, lateral occipital cortex, and pericalcarine cortex. Abbreviations: aMCI, amnestic mild cognitive impairment; CN, cognitively normal; GM, gray matter; QSM‐VBM, quantitative susceptibility mapping‐voxel‐based morphometry.
FIGURE 3
FIGURE 3
Correlation between the specific memory scores and the regional susceptibilities.
See this image and copyright information in PMC

References

    1. Albert, M. S. , DeKosky S. T., Dickson D., et al. 2011. “The Diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease: Recommendations from the National Institute on Aging‐Alzheimer's Association Workgroups on Diagnostic Guidelines for Alzheimer's Disease.” Alzheimer's & Dementia 7, no. 3: 270–279. 10.1016/j.jalz.2011.03.008. - DOI - PMC - PubMed
    1. Ashburner, J. , and Friston K. J.. 2000. “Voxel‐Based Morphometry—The Methods.” Neuroimage 11, no. 6 Pt 1: 805–821. 10.1006/nimg.2000.0582. - DOI - PubMed
    1. Ayton, S. , Faux N. G., and Bush A. I.. 2015. “Ferritin Levels in the Cerebrospinal Fluid Predict Alzheimer's Disease Outcomes and Are Regulated by APOE.” Nature Communications 6, no. 1: 1–9. - PMC - PubMed
    1. Ayton, S. , Portbury S., Kalinowski P., et al. 2021. “Regional Brain Iron Associated With Deterioration in Alzheimer's Disease: A Large Cohort Study and Theoretical Significance.” Alzheimer's & Dementia 17, no. 7: 1244–1256. 10.1002/alz.12282. - DOI - PMC - PubMed
    1. Bell, R. D. , and Zlokovic B. V.. 2009. “Neurovascular Mechanisms and Blood‐Brain Barrier Disorder in Alzheimer's Disease.” Acta Neuropathologica 118, no. 1: 103–113. 10.1007/s00401-009-0522-3. - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources