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

Objective To test the hypothesis that the combination of elevated global beta-AMYLOID (A beta) 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 A beta using PET imaging in a cross-sectional sample of 70 cognitively normal older adults. Methods Participants were scanned with florbetapir F-18 PET to obtain A beta 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 A beta as between-participant factors; and MTL volumes (ERC and 3 hippocampal subfield regions) as the dependent variable. Results The model indicated a significant 4-way interaction among age, iron, A beta, and MTL region. Post hoc analyses indicated that the 3-way interaction among age, A beta, and iron content was selective to the ERC (beta = -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 A beta. Conclusions These findings highlight the importance of studying A beta 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.