Iron is critical for numerous neurophysiological functions, while its dysregulation is potentially hazardous for neurodegeneration through oxidative stress and ferroptosis. For decades, elevated brain iron levels observed in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis was presumed to drive disease progression; a hypothesis that propelled clinical trials of strong iron chelators like deferiprone. Results from these trials, however, have challenged this paradigm, with deferiprone markedly worsening outcomes in Alzheimer’s and, in certain contexts, Parkinson’s patients. These findings underscore the vital role of iron for brain health and suggest functional compensatory mechanisms that could become deleterious at the extremes of iron distribution (both low and high levels). Here, we outline an evolving understanding of iron’s role in neurodegeneration, and we explore pathways for therapeutic development strategies that mitigate potential iron-mediated damage, while preserving its essential functions in the brain.
One of my friend’s sons was mostly bedridden from the age of seventeen to his mid-twenties with hereditary hemochromatosis, and it made me look at iron very differently. Since I have a good deal of iron in my diet, I mostly avoid adding more with supplements.
Fair point. But I think it’s also worth pointing out that a HUGE percentage of the general population is functionally iron deficient. Around 3% of the general male population, and 8% of the general male population. Worse yet, in the 19-50 year old women demographic, that rises to a staggering 32%. So for a sizeable chunk of people, getting more iron is probably the best thing they can do for their quality of life and their health.
True. I think all of this just points to the complexity of some nutrients that really must be kept in balance, since the body doesn’t necessarily handle overloading well—and yet levels must be maintained.
I’ve had low red blood cell counts for years. Back in 2019 the level was around 4.6 million RBCs per microliter; then last year it was about the same; and just recently, I was around 4.1 million. One of the markers for anemia in males is RBC counts that low. (Yet, I can do heavy weightlifting and not get too tired. I must have learned to adapt to it.)
It’s possible that this is due to low iron intake. I have for a long time worried about my diet, which likely tends not to include a lot of it. I do eat a decent amount of vegetables (including spinach, which only has 0.8 mg of iron per cup), but it’s not enough. Tofu does have a lot, but I don’t eat it often. I don’t eat beef or red meat; I eat mostly chicken, which has half the iron on a weight basis as beef. A lot of my protein comes from sources like a whey protein shake, which has very little (if any) iron. If I add everything up, I probably just barely clear the recommended daily amount of iron. But then I also drink a lot of tea and coffee, which make it harder to absorb – in fact, with breakfast I take in about 2 cups of coffee; with lunch I take in about 3 cups of iced tea or green tea, usually. And with snacks (like oatmeal in the afternoon) I often drink more coffee.
So, I’ve lately been taking an over-the-counter iron pill.
I’ve read that men can retain their iron for years, even after being pushed into a low-iron-intake phase; the body is efficient at recycling it. However, do that long enough, and the system can’t keep up. I’ve probably been living on reduced iron now for 5 years or more, without even fully realizing it.
Addendum: I think I’m going to stop taking iron pills soon. I’ve read that the body doesn’t easily excrete it, and that it builds up and up and up in organs, at least in men. Iron pills are designed with women in mind, and they need a lot more of it than men. Still, they (pills) don’t have much more than is present in 2 or 3 cups of tofu.
Here, we review the literature on iron dysregulation in the brain, blood, and gut in PD and propose that iron dysregulation outside the brain is an important catalyst that may represent a prodromal mechanistic link in gut-first PD.
Existing iron chelator studies have focused on a brain-first approach; however, we propose that for improved efficacy, these therapeutics should be targeted to iron mishandling in the periphery, prior to the unrecoverable loss of DA neurons in the brain.
We propose that ferritin, the primary iron storage protein, may be an early molecular indicator of inflammation and associated mitochondrial stress in the gut that in the future could possibly be used as one of likely many biomarkers to diagnose early stages of PD. However, the role gut-specific iron regulation plays in peripheral immune cell dysfunction and how that may be a risk factor for PD etiopathogenesis is still understudied. Of importance is the understanding that most gut dysbiosis is modifiable and often induced by environmental factors. Understanding how to therapeutically target gut dysbiosis to prevent pathogenic and systemic inflammatory communication through the gut-blood-brain axis represents a promising and tractable goal that could be critically effective to reduce, delay, or arrest development of PD worldwide.
Interestingly, 50–70 % of individuals with inflammatory bowel disease (IBD), a GI condition that has been epidemiologically linked to PD, display chronic illness-induced anemia — which drives toxic accumulation of iron in the gut.
In pro-inflammatory environments, iron accumulates in immune cells, suggesting a possible connection and/or synergy between iron dysregulation and immune cell dysfunction.
A mechanism linking chronic gut inflammation to iron dysregulation and mitochondrial function within peripheral immune cells has yet to be identified in conferring risk for PD.
Interestingly, these same infiltrating immune cells have been reported to have excess ferritin (the primary measure of iron storage) (Kelly et al., 2023; Ward et al., 2011; Rathnasamy et al., 2013), indicating a synergy between toxic iron accumulation and inappropriate immune cell activation.
An excess of the iron storage protein ferritin and dysregulation of the iron importer and exporters FPTN-1 and DMT1 respectively, have been directly linked to mitochondria dysfunction.
We observed that, during basal respiration (baseline consumption of oxygen for mitochondria), both PD and IBD PBMCs that consume more oxygen at baseline also have a higher ferritin content.
In support of our hypothesis, we observed that the increased frequency in iron-transcript dysregulation in IBD and PD PBMCs but not in NHC PBMCs directly correlates with a change in mitochondrial function. Excess ferric iron is housed in ferritin, which is the dominant ferric iron storage protein in the central nervous system and a surrogate for total‑iron content (Capelle et al., 2023). In individuals with PD, there is an increase in ferritin load in the cerebrospinal fluid (CSF) as compared to age-matched controls (Capelle et al., 2023). A separate study also reported that ferritin concentrations increased in PD CSF with progression of motor symptom severity (Kuiper et al., 1994). Increases in iron deposition have been reported in mitochondrial dysfunction and can catalyze an inflammatory phenotype in immune cells (Kelly et al., 2023)– which our findings suggest may be abolished with chronic use of NSAIDs.
However, we identified a unique significant relationship whereby PBMCs from individuals with PD or IBD that displayed enriched ferritin also showed an increase in basal mitochondrial respiration not observed in NHCs. Also, via SIMCA analysis, we identified that ferritin transcript is highly expressed in PBMCs and was one of the most reliably detected transcripts within these data—indicating that ferritin transcripts in PBMCs may be an accessible potential biomarker of immune dysfunction and risk for PD (Supp. Fig. 3).
Practical interpretation for “best energy” and general health
Ferritin ‹ 30 ng/mL: likely to impair energy; treatment typically beneficial.
Ferritin 30-50 ng/mL: optimal zone for most individuals; symptom improvement plateaus beyond this.
Ferritin ›50-100 ng/mL: adequate stores; raising further does not improve energy.
Avoid targeting ›100 ng/mL unless a disease-specific indication exists.
Bottom line: Most adults experience the best energy, exercise tolerance, and overall physiologic function when ferritin is maintained around 30-50 ng/mL. Beyond this range, raising ferritin does not improve health or vitality and may introduce unnecessary risk.
There’s a good question as to whether the same is the case for ALS/MND.
Although high neuronal iron is likely to cause problems with mitophagy it could be that a change in splicing for SLC40A1 which is ferroportin results in a growth in iron levels.
Ferroportin (FPN) is a transmembrane protein and is the only known iron exporter that helps in maintaining iron homeostasis in vertebrates. To maintain stable iron equilibrium in the body, ferroportin works in conjunction with a peptide called hepcidin. In this study, we have identified an alternatively spliced novel isoform of the human SLC40A1 gene, which encodes for the FPN protein and is found to be expressed in different tissues. The novel transcript has an alternate last exon and encodes 31-amino acid long peptide sequence that replaces 104 amino acids at C-terminal in the novel transcript. Molecular modelling and molecular dynamics (MD) simulation studies revealed key structural features of the novel isoform (FPN-N). FPN-N was predicted to have 12 transmembrane domains similar to the reported isoform (FPN), despite being much smaller in size. FPN-N was found to interact with hepcidin, a key regulator of ferroportin activity. Also, the iron-binding sites were retained in the novel isoform as revealed by the MD simulation of FPN-N in bilipid membrane. The novel isoform identified in this study may play important role in iron homeostasis. However, further studies are required to characterize the FPN-N isoform and decipher its role inside the cell.
By removing labile iron from the extracellular space, amyloid β keeps iron away from invading microorganisms thereby preventing or limiting an infection. Furthermore, the clearance of iron bound amyloid β would deliver the iron to other cells for reuse or storage. […] Therefore, amyloid β is essentially acting as a mammalian siderophore. In addition, amyloid β is preventing redox chemical reactions from causing tissue damage by removing loosely bound iron in the interstitial fluid.
During aging, the clearance of amyloid β from the extracellular fluid can decrease, e.g., due to lower expression of LRP-1 receptor (Silverberg et al., 2010; Osgood et al., 2017). Less clearance allows greater opportunity for amyloid β to form fibrils and aggregate, and iron may facilitate this process. The iron bound to amyloid β in plaques and vessels would be less available to microbes than labile iron, but since some bacteria and their products have been found to be present in plaques (Miklossy et al., 2004; Allen, 2016; Miklossy, 2016; Zhan et al., 2016; Senejani et al., 2022), it is possible that the iron can leach out over time and support microbial growth. Similarly, iron bound to plaques and vessels likely causes less tissue damage than labile iron, but whether this iron is redox active is uncertain (Cheignon et al., 2018), and it is possible that iron deposited with amyloid β at vessels promotes additional pathology, e.g., hemorrhagic lesions, and impairs vessel function.
The clearance of iron and other redox active metals by amyloid β may be a critical function to help preserve brain health by protecting it from redox-mediated tissue damage and the development and spread of infections. Given that oral bacteria and other infections that enter the blood stream have the potential to access the brain (Parra-Torres et al., 2023; Anand and Lahariya, 2025), the clearance of labile iron by amyloid β would have been particularly valuable to our ancestors when oral hygiene was comparatively poor and antibiotics were not available. The importance of the clearance of iron by amyloid β within the brain may have been evolutionarily selected for even at the expense of managing a peptide with the potential to mediate pathology.
The protein lactoferrin, both sequesters iron and generates proteolytic fragments with antimicrobial properties, and amyloid β may have similar traits.
Some proteins, such as lactoferrin, can have dual antimicrobial functions by scavenging iron, thereby limiting its availability for microbes, as well as being cleaved into peptides with antimicrobial activity (Yen et al., 2018; Kim et al., 2025b). APP and amyloid β may share some properties with lactoferrin given the regulatory role on iron homeostasis by APP and the antimicrobial activity by amyloid β (Vijaya Kumar et al., 2025).
So if the preprint’s framework is correct, then lactoferrin could be beneficial as an iron-sequestering, antimicrobial, redox-buffering protein. But oral lactoferrin mostly acts in the gut/periphery and there’s no evidence that oral supplementation can increase brain levels (very short serum half-life).
