Iron is an essential nutrient, but like any good thing, too much of it may do harm. According to an autopsy study published February 18 in Molecular Psychiatry, people who had had dementia and moderate to high burdens of plaques and tangles had more iron in their temporal cortices than those with less pathology. Does this iron do anything? It correlated with cognitive decline in the years prior to death, but whether it accelerated that decline is unclear. The researchers, led by Ashley Bush of the University of Melbourne and Martha Morris of Rush University Medical Center in Chicago, suggest that brain iron kills neurons via ferroptosis, a cell-death pathway driven by reactive forms of the element.
- Only people with clinical and pathological hallmarks of Alzheimer’s disease had more cortical iron.
- Among people with AD pathology, cortical iron correlated with cognitive decline.
- This means iron rises late in AD pathogenesis.
Bush and colleagues had previously cast brain iron, in the form of ferritin, as a predictor of Alzheimer’s disease progression, and proposed that the element facilitates the genetic risk imposed by ApoE4 (Ayton et al., 2015). However, the current study found normal brain levels of iron in people who had high plaque and tangle burden but no dementia, suggesting the element ticks up late in the disease process. Because iron levels were only measured at autopsy, the study leaves unclear when in the course of disease iron levels started to rise.
The role of iron in AD has long been debated but never drawn much consensus in the field. Recent work has tried to link markers of brain iron and cognitive decline, and neuropathological studies have detected more iron in the brains of people with AD than controls, but the studies were too small to tease out the relationship between cortical iron, AD neuropathology, and clinical symptoms (Tao et al., 2014).
First author Scott Ayton and colleagues used data from the Religious Orders Study and Memory and Aging Project cohorts (ROSMAP), in which participants were tracked for biomarker and cognitive changes during life, and their brains autopsied. The researchers quantified iron levels in gray matter from the inferior temporal cortices and cerebella of 209 people in the cohort. They found more iron in the cortex, but not cerebellum, in people who had a moderate to high burden of plaques and tangles, but only if they had been living with dementia. People who had been cognitively normal had normal iron levels, even if they had substantial AD pathology. Iron levels were also normal among 14 people who had been given a clinical dementia diagnosis but had little to no AD pathology. Ayton et al. also found that in people with high burdens of plaques and tangles, as assessed by National Institute on Aging/Reagan scale, cortical iron levels correlated with the rate of cognitive decline in their last 10 to 12 years of life. However, AD pathological burden itself was by far the greatest predictor of antemortem cognitive decline.
“While excess iron has been implicated in AD either as a cause or result for several decades, this study is one of the first reporting that the amount of increased iron correlates to the rate of cognitive decline,” commented Jeff Bulte of Johns Hopkins School of Medicine in Baltimore.
What it means is unclear. Iron might be an independent marker of synaptic loss or neuronal death, or it might somehow contribute to either or both, the authors suggest. Among people with substantial AD pathology, iron did not correlate with plaque burden, but did correlate with tangle burden, as judged by silver staining of sections from multiple cortical regions. However, a statistical mediation analysis indicated iron correlated with cognitive decline largely independently of tau.
In a joint comment to Alzforum, Neil Telling of Keele University and Joanna Collingwood of Warwick University, both in the U.K., wrote that the lack of a strong correlation between brain iron and neuropathological burden was expected. They believe the chemical form of iron, as opposed to its total amount, is important for toxicity. For example, they cited work from their group indicating that Aβ peptides interact with iron and trigger its reduction into a ferrous form, which can react with peptides to produce hydroxyl radicals (Collingwood et al., 2008; Everett et al., 2018). “It is likely to be the amount of reactive iron that is available to drive overproduction of radical species that is the crucial factor, rather than the total amount of iron at that site,” they wrote.
Bush noted that the iron associated with Aβ plaques represents but a small fraction of the total iron in the brain, most of which is inside cells. He believes this intracellular iron harms neurons, and accumulates because trafficking of amyloid precursor protein (APP), a purported iron transporter, falters in AD (Feb 2012 news; Lumsden et al., 2018). Iron is the key component of the ferroptosis cell-death pathway, in which the metal drives accumulation of harmful lipid hydroperoxides, which Bush said are abundant in the AD brain (Stockwell et al., 2017).
Bush is involved in a multicenter, Phase 2 clinical trial testing the iron chelator drug deferiprone in people with mild AD (see clinicaltrials.gov). This follows trials of clioquinol, which were canceled due to a toxic contaminant (Jan 2004 news; Apr 2005 news). The second-generation compound PTB2 failed to slow cognitive decline in people with AD (Apr 2014 news).—Jessica Shugart
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