Predictive value of QSM for hippocampal atrophy in pre-clinical Alzheimer’s disease

One-third of cognitively normal people over the age of 65 exhibit β-amyloid plaques, a defining pathology of Alzheimer’s disease. The hippocampus also undergoes early and pronounced neurodegeneration in Alzheimer’s disease, which underlies the memory impairment. Cognitively normal people with high β-amyloid pathology are at risk of hippocampal neurodegeneration, but the rate of decline is variable between subjects. Here, we investigate whether the iron load of the hippocampus can be used to stratify risk for future hippocampal atrophy in cognitively normal people with and without β-amyloid. We applied Quantitative Susceptibility Mapping (QSM), a relatively new MRI modality that is sensitive to tissue iron levels, to 70 cognitively normal people who also had a PET scan for β-amyloid, and were monitored for brain volume changes in MRI scans performed every 1.5 years for up to 7.5 years. We found that QSM of the hippocampus was strongly predictive of future atrophy of this region in cognitively normal subjects who had high β-amyloid pathology (P=2.3x10-6), but not in cognitively normal subjects with low pathology. These data support a role for iron in contributing to neurodegeneration in Alzheimer’s disease, and QSM in combination of β-amyloid PET scans could be used to stratify patients at risk for cognitive decline in the pre-symptomatic phase.