Contribution of iron and Aβ to age differences in entorhinal and hippocampal subfield volume

To test the hypothesis that the combination of elevated global β-AMYLOID (Aβ) burden and greater striatal iron content would be associated with smaller entorhinal cortex (ERC) volume, but not hippocampal subfield volumes, we measured volume and iron content using high-resolution MRI and Aβ using PET imaging in a cross-sectional sample of 70 cognitively normal older adults.

Participants were scanned with florbetapir ¹⁸F PET to obtain Aβ standardized uptake value ratios. Susceptibility-weighted MRI was collected and processed to yield R2* images, and striatal regions of interest (ROIs) were manually placed to obtain a measure of striatal iron burden. Ultra-high resolution T2/PD-weighted MRIs were segmented to measure medial temporal lobe (MTL) volumes. Analyses were conducted using mixed-effects models with MTL ROI as a within-participant factor; age, iron content, and Aβ as between-participant factors; and MTL volumes (ERC and 3 hippocampal subfield regions) as the dependent variable.

The model indicated a significant 4-way interaction among age, iron, Aβ, and MTL region. Post hoc analyses indicated that the 3-way interaction among age, Aβ, and iron content was selective to the ERC (β = -3.34, standard error = 1.33, 95% confidence interval -5.95 to -0.72), whereas a significant negative association between age and ERC volume was present only in individuals with both elevated iron content and Aβ.

These findings highlight the importance of studying Aβ in the context of other, potentially synergistic age-related brain factors such as iron accumulation and the potential role for iron as an important contributor to the earliest, preclinical stages of pathologic aging.