Mohammadi S, Ghaderi S, Fatehi F. Iron accumulation/overload and Alzheimer's disease risk factors in the precuneus region: A comprehensive narrative review. Aging Med (Milton). 2024 Oct 22;7(5):649-667. doi: 10.1002/agm2.12363. PMID: 39507230; PMCID: PMC11535174.

Key Points:

• Iron overload in the body, which is often associated with conditions such as hereditary hemochromatosis or excessive iron intake, can cause a variety of problems such as oxidative stress, inflammation, and damage to cells and neurons.

• One aspect of Alzheimer’s Disease (AD) that has received increasing attention is the role of iron accumulation and dysregulation of iron homeostasis in the brain.

• Quantitative susceptibility mapping (QSM) is an MRI method that enables the measurement of materials that cause changes in susceptibility.

• Metal dyshomeostasis, intracellular iron deposition, and ferroptosis are key causes of neuronal loss in patients with AD.

• In the early stages of AD, amyloids tend to accumulate mainly in the temporal, basal frontal, and occipital lobes. As the disease advances, amyloid deposition spreads to other areas of the brain.

• Iron is found at high levels in plaques and can cause Aβ to aggregate, which is cytotoxic in vitro.

• Iron overload can also lead to autophagic cell death and ferroptosis as well as contribute to the phosphorylation of tau protein, leading to the formation of neurofibrillary tangles (NFTs), all of which increase the risk of NDD.

• Excessive iron accumulation in the brain can initiate a chemical reaction called the Fenton reaction, leading to increased oxidative stress, which is a hallmark of AD.

• Authors Conclude: Together, these findings suggest that iron accumulation, measurable through QSM, may accelerate pathogenesis in a sensitive hub region, contributing to downstream atrophy and cognitive deficits. As an early non‐invasive neuroimaging biomarker of iron burden and oxidative stress, QSM holds promise for improving early diagnosis, tracking disease stages, and monitoring therapeutic responses in AD and related dementias

Iron Out Comment

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Let’s look a this review first.

It was published in 2017 in The American Journal of Clinical Nutrition by C. Zhang at The National Institute of Child Health and Development and entitled “Dietary Iron Intake, Iron Status and Gestational Diabetes”.

Interesting Points

First, they review how iron overload can damage the cells in the pancreas that produce insulin by creating oxidative stress:

Free iron, with its strong pro-oxidant properties and consequent ability to generate reactive oxygen species, can contribute to increased oxidative stress and cellular damage and, hence, may be potentially hazardous in excess (1).

The pancreatic β cells are vulnerable to oxidative stress because their antioxidative defense mechanisms are particularly weak (2).

Although adequate iron is critical to normal β cell function and glucose homeostasis, studies based on mouse models of hereditary or dietary iron overload show that excess iron may disrupt glucose homeostasis by several potential mechanisms involving multiple tissues and organs.

For example, oxidative stress from excess iron accumulation can lead to β cell damage and apoptosis and, consequently, contribute to decreased insulin secretion (3).

Next they review how high levels of iron affect the liver, and insulin resistance.

High iron stores in the liver may induce insulin resistance by impairing insulin signaling and by attenuating the liver’s ability to extract insulin (4, 5).

In adipocytes, excess iron can diminish insulin-induced glucose transport, whereas in the muscles it may lead to a switch from glucose to fatty acid oxidation (6, 7).

This is important, because high iron levels in the liver are not necessarily reflected in a blood test, unless ferritin levels (iron storage protein) are measured.

The most reliable blood test that indicates if BODY iron stores are high is serum ferritin, the iron storage protein that can be measured in blood.

The authors note the following regarding serum ferritin levels and gestational diabetes:

Serum Ferritin (SF) concentration, an indicator of iron stores, has been most often examined in relation to the risk of gestational diabetes mellitus (GDM). A significant and positive association between SF concentration and GDM has been observed

SF concentrations in both the first and second trimesters were significantly and positively associated with a subsequent risk of GDM, even after accounting for inflammation measured via CRP levels.

One of the meta-analyses (37) that included 4 prospective studies (42, 43, 46, 57), women with the highest SF concentrations had a >3-fold greater risk of GDM compared with those with the lowest concentrations (pooled RR: 3.22; 95% CI: 1.73, 6.00).

Comment- Two Accelerating Factors to Consider

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Ferroptosis, the cellular process underlying the damage that iron overload causes in the body, was first described by Scott Dixon in 2012 in this Cell paper:

Ferroptotic death is morphologically, biochemically, and genetically distinct from apoptosis, various forms of necrosis, and autophagy. This process is characterized by the overwhelming, iron-dependent accumulation of lethal lipid ROS (Reactive Oxygen Species).

A 2023 review on the role of ferroptosis in obesity outlines key points on ferroptosis uncovered since Dixon’s discovery in 2012:

• Ferroptosis is an iron-dependent regulated cell death (RCD) caused by iron overload and reactive oxygen species (ROS)-dependent excessive accumulation of lipid peroxidation.

• Ferroptosis is characterized by changes in mitochondrial morphology, including mitochondrial shrinkage, reduced or absent mitochondrial cristae, and increased mitochondrial membrane density.

• It’s bioenergetic features are iron accumulation and lipid peroxidation.

• It has been established that ferroptosis is involved in the initiation and progression of many diseases.

This figure from that paper outlines diseases linked to ferroptosis:

Mechanistic studies on ferroptosis show that iron induced cell death can be inhibited by iron chelators, which soak up excess iron. This implies that the solution might be very simple.

Comment and further reading

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A few years ago when I was referred to the book, Iron: The Most Toxic Metal, I was skeptical about the veracity of the title.

I had been studying the toxic effects of heavy metals in our bodies for years. Surely aluminum and mercury which accumulate in our brains from various environmental sources and medical products are more toxic. Lead, arsenic and o…

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