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Accounting for iron-related off-target binding effects of 18F-AV1451 PET in the evaluation of cognition and microstructure in APOE-e4+ MCI

The pathology of Alzheimer's disease (AD) and mild cognitive impairment (MCI) is characterized by the presence of beta-amyloid extracellular plaques and neurofibrillary tangles containing hyper-phosphorylated tau. Individuals carrying the apolipoprotein E-e4 (APOE-e4) allele are at increased risk of cognitive decline and developing AD pathology. The development of positron emission tomography (PET) radioligands sensitive to tau neurofibrillary tangles, such as 18F-AV1451, has allowed for visualization and assessment of AD pathology in vivo. The radioligand used in 18F-AV1451 binds with iron in addition to tau neurofibrillary tangles. We employ multimodal neuroimaging analyses, combining iron-sensitive measures from MRI with 18F-AV1451 PET, to examine off-target binding effects in cohorts of 20 APOE-e4 negative, 20 APOE-e4 positive MCI, and 29 control participants. Increased tau pathology, after controlling for tissue susceptibility, was found in the temporal lobe and hippocampus of APOE-e4+ MCI participants as compared to APOE-e4 negative MCI and control participants. Tau pathology in the hippocampus was significantly related to memory, but only in APOE-e4+ participants. Correlations between hippocampal 18F-AV1451 PET uptake and cognitive correlations did not significantly differ when correcting for the influence of iron on 18F-AV1451 PET signal. However, controlling for susceptibility was found to influence correlations between tau-PET uptake and diffusion metrics and the change in this interaction may be due to the influence of iron on diffusivity. Taken together, these results suggest that iron does not need to be accounted for in group comparisons of tau-PET uptake or correlations between cognitive measures and tau-PET SUVR. However, iron should be taken into account in correlations between diffusion measures and tau-PET uptake.