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

See also the article by Chen et al in this issue.

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Alzheimer 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 β-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 β-amyloid deposition, pathologic τ, and neurodegeneration (1). However, 10%–40% of cognitively normal older individuals have evidence of cerebral β-amyloid deposition but no symptoms (2), which suggests that β-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 β-amyloid plaques and neurofibrillary tangles. These β-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 β-amyloid plaques can abolish these interactions, reducing downstream oxidative stress and neurofibrillary tangle formation (4–6). Therefore, iron may have a synergistic role with β-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 β-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 β-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, β-amyloid, 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, β-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 β-amyloid (n = 97), (c) the subgroup that had negative amyloid PET scans (n = 75), and (d) the subgroup that was cognitively normal with no symptoms (n = 121). These sensitivity analyses allow the reader to conjecture how the relationship between iron and β-amyloid may change in these different scenarios.

The first major finding of the study was the strong negative association between hippocampal iron levels and episodic memory, which held true in all subgroup sensitivity analyses. Because the hippocampus is considered an early site for the development of AD pathology and has a key role in memory, it is not surprising that higher levels of iron in this region would be associated with lower memory scores. This also corroborates findings from a previous study (8) that found hippocampal iron levels to be predictive of longitudinal decline in episodic memory among individuals positive for β-amyloid. However, in the study by Chen et al (9), the association between hippocampal iron and memory remained significant, even after adjustment for the presence of cerebral β-amyloid, which suggests that iron may impact memory through processes that are independent of β-amyloid. Iron-mediated oxidative stress and ferroptosis, a type of iron-dependent programmed cell death, could be possibilities.

Second, hippocampal iron levels were associated with global cognitive and executive function scores, but the associations were largely driven by the β-amyloid negative group. It is possible that, once significant cerebral β-amyloid has accumulated, the patient is already further along in AD pathogenesis and other disease processes may influence cognition more than hippocampal iron, such as τ or metabolic deficits.

Beyond the hippocampus, iron appeared most closely associated with cognitive function in the β-amyloid negative group, with frontal, parietal, temporal, mesial temporal, and basal ganglia iron levels all showing significant associations with cognition. Altered iron homeostasis may thus be most meaningful to study in the earliest stage of disease, before there is significant cerebral β-amyloid deposition. One could even speculate as to whether iron plays a role in β-amyloid plaque formation. Therapeutic trials targeted to iron in this stage could ascertain whether β-amyloid deposition can be delayed or even prevented.

The voxel-based analyses of iron, β-amyloid, and cognition raise other important questions. Specifically, there were nine clusters in which iron levels were negatively correlated with β-amyloid, two of which were associated with global cognition, and only three clusters in which they were positively correlated. Preclinical and postmortem studies suggest that iron and β-amyloid colocalize and act synergistically to effect downstream AD pathogenesis (4,5). However, these analyses suggest that iron and β-amyloid may arise independently and in spatially distinct areas. Whether iron accumulates in a stereotypical fashion, like β-amyloid and τ, warrants further research. Importantly, cerebral β-amyloid levels at PET and regional brain volumes derived from MRI, our standard methods of assessing AD pathology, were not associated with cognition.

A few limitations of this study warrant discussion. First, this was a cross-sectional study that used the presence or absence of cerebral β-amyloid and cognitive symptoms to assess the relationship between iron and cognition in nondemented individuals. Because iron was most closely linked to cognition in the β-amyloid– negative group, it would be important to follow these participants longitudinally to see if they subsequently develop β-amyloid plaques, or whether the iron predicts non-AD forms of cognitive decline. Could these participants have higher iron levels and subtle cognitive deficits from subclinical ischemic or traumatic events, rather than AD?

Another limitation is the lack of a τ biomarker in these analyses. Iron has been reported to interact with neurofibrillary tangles in preclinical studies (5). Could the relationship between hippocampal iron levels and episodic memory be mediated by the presence of neurofibrillary tangles, which are known to accumulate early in the hippocampus on the basis of Braak staging?

Finally, should iron be included in the proposed ATN classification system, particularly early in the disease course, perhaps even earlier than the presence of β-amyloid? Interestingly, iron chelation in patients with AD was attempted previously. A study from 1991 reported that intramuscular administration of deferoxamine slowed the rate of decline in daily living skills in patients with AD during a period of 24 months (10). With current imaging techniques allowing for in vivo quantification of brain iron, β-amyloid, τ, and neurodegeneration, the effects of such iron chelation therapy on AD pathology could be more specifically monitored.

Because there is a potential antiamyloid therapy on the horizon, the amyloid hypothesis of AD appears to be validated. However, numerous concomitant disease processes may contribute to AD pathogenesis, including iron accumulation, and these deserve further investigation. It is possible that the most effective treatment of AD will depend on a combination of therapies, particularly if they target processes that precede the appearance of β-amyloid plaques.