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Iron Accumulation, Not β-Amyloid or Brain Volumes, Is Linked to Cognition in Older Patients Who Are Nondemented.

A disease (AD) remains the most common cause of dementia and is a devastating diagnosis for individuals and caregivers alike. Researchers and clinical trials have largely focused on b-amyloid plaques, one of the pathologic indicators of AD that is commonly implicated as the inciting factor for neurodegeneration. The 2018 National Institute on Aging–Alzheimer’s Association Research Framework built on this “amyloid hypothesis” by proposing the ATN system for classifying disease stages on the basis of the presence or absence of cerebral b-amyloid deposition, pathologic t, and neurodegeneration (1). However, 10%–40% of cognitively normal older individuals have evidence of cerebral b-amyloid deposition but no symptoms (2), which suggests that b-amyloid alone may not be sufficient for the development of AD. Postmortem studies have shown evidence for iron imbalance and accumulation in AD brain tissue compared with healthy control brain tissue (3), with iron colocalizing with b-amyloid plaques and neurofibrillary tangles. These b-amyloid plaques can bind ferric iron and reduce it to the redox-active form, ferrous iron, which reacts with hydrogen peroxide to generate hydroxyl radicals, leading to oxidative damage (4,5). Studies in animal models of AD have reported that iron chelation of these b-amyloid plaques can abolish these interactions, reducing downstream oxidative stress and neurofibrillary tangle formation (4–6). Therefore, iron may have a synergistic role with b-amyloid in inciting key pathophysiologic processes leading to AD. By using advanced imaging techniques, authors of recent studies have investigated whether altered iron levels can be detected in vivo in patients with AD. Indeed, studies have reported higher levels of brain iron in cortical and subcortical regions in those with AD compared with healthy control patients (7). One study also found that higher baseline hippocampal iron levels predicted accelerated longitudinal decline in episodic memory, executive dysfunction, and attention in individuals with evidence of cerebral b-amyloid deposition (8). These studies further suggest that iron accumulation may have a significant role in AD pathogenesis. In this issue of Radiology, Chen et al (9) investigated the relationship between brain iron levels and cognition in a nondemented cohort. By using the Biomarkers for Older Controls at Risk for Dementia, or BIOCARD, study, they retrospectively analyzed imaging and neuropsychologic data from 150 nondemented older participants (mean age, 69 years), 121 of whom were cognitively normal and 29 of whom had cognitive symptoms but did not meet criteria for mild cognitive impairment. All participants had undergone 3.0-T MRI that included quantitative susceptibility mapping, a contrast-free technique used to quantify tissue iron concentration. The majority (97 of 150; 65%) of participants also underwent PET with the amyloid tracer Pittsburgh compound B to assess for cerebral b-amyloid deposition. Twelve regions of interest were segmented to quantify regional iron levels and volumes: the frontal, parietal, temporal, and occipital cortex; mesial temporal structures, including the entorhinal cortex, hippocampus, and amygdala; the cingulate; and the basal ganglia. Biologic parametric mapping was used to explore voxel-based correlations among iron, bamyloid, and cognitive scores. Twelve neuropsychologic tests were used to assess four cognitive domains—verbal episodic memory, executive function, visuospatial processing, and language—as well as global cognition. Major strengths of this study include the richness of the data set and large sample size, allowing the authors to investigate associations among iron, b-amyloid, and cognitive scores in four ways. Multiple linear regressions were applied to (a) the entire cohort of 150 nondemented participants, (b) the subgroup that had amyloid PET imaging to adjust for the presence of b-amyloid (n = 97), (c) the subgroup that had negative amyloid PET scans (n = 75), and (d) the subgroup that was cognitively normal with no Iron Accumulation, Not b-Amyloid or Brain Volumes, Is Linked to Cognition in Older Patients Who Are Nondemented