National Alzheimers Disease Institute


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Alzheimer’s Disease is Helped by Natural and Synthetic Chelators

P. Anthony Chapdelaine, Jr., MD, MSPH, Exec. Dir./Sec.*


The good news is that a successful intervention in slowing the progression of patients with Alzheimer’s Disease was demonstrated over twenty-five years ago. Unfortunately, researchers have not done similar human studies since then.

In 1991 and 1993 McLachlan et al published evidence of a relationship between the use of a metal chelator and the subsequent decrease in the progression of Alzheimer’s Disease.1,2 They randomized 48 patients identified as likely demented from AD to taking a placebo capsule (lecithin), to taking nothing, or to getting a muscular injection of an iron chelator (known as: desferrioxamine, deferoxamine, Desferal, or DFO) that could bind and remove, or neutralize, the amount of iron in the brain. For this intervention group, the researchers injected desferrioxamine into the patient’s muscle twice a day, five days a week, for two years. This single-blinded study showed, through recorded video of patients over the two years, that the study group declined at half the rate of the patients receiving nothing or placebo. The desferrioxamine was thought to work by decreasing aluminum in the brain (although this chelator mainly binds to iron).

While the McLachlan et al studies were cited at the time, Savory and other researchers felt the severity of the intervention itself was too complicated and impractical.3 “There has been one promising clinical trial [McLachlan] of the treatment of Alzheimer’s disease patients with the Al chelator desferrioxamine (DFO). Further studies are needed, and if confirmation is forthcoming then such data could also support an Al-Alzheimer’s disease link as well as suggesting that DFO offers potential as a therapeutic agent. The possibility that iron might be the offending agent needs to be considered since DFO is a very strong iron chelator.”3 Savory’s team raised a number of critical questions it believed needed further research to answer the question of whether aluminum could be considered one of the causes of AD.3

Savory and his team did a follow up study in 1998 in which they injected aluminum into rabbits.4 Some rabbits served as controls and therefore did not receive a chelator injection. For the remaining intervention rabbits, the researchers injected these in the muscle with a desferrioxamine chelator at either four, six, or eight days after the aluminum injection. These desferrioxamine-injected rabbits were killed two days after each chelator injection.

All the rabbits showed brain degeneration similar to AD. However, those rabbits that received the chelator showed less brain destruction than the rabbits which did not get the chelator. The researchers concluded, “The effectiveness of only two days of DFO treatment in reversing Al-induced neurofibrillary degeneration suggests that further clinical trials of DFO for treatment of Alzheimer’s disease should be attempted using much less frequent administration of DFO than in the initial study [by McLachlan].”4

In 2014 Walton performed a causality analysis to determine whether chronic Aluminum intake contributed to Alzheimer’s Disease by using Sir Bradford Hill’s widely-accepted epidemiological and experimental criteria.5 He concluded that chronic Aluminum intake and metabolism is a strong causative factor in AD.

Over the last few decades, researchers have studied the role of environmental metals and metal chelators in AD.  Recently, the first comprehensive review of studies on the effects of environmental sources (soil, water, air, occupation) of metals on dementia (not just AD) showed that these studies varied widely in their results.6

One cross-sectional (a single point in time) study led early researchers to conclude that the brains of AD patients had a membrane abnormality that allowed the entry and persistence of certain metals and other elements.7

More recent work, using animals with chemically or genetically induced AD, has further refined our understanding of potential metals or elements that may be involved in Alzheimer’s Disease initiation and progression, shifting the focus from aluminum to iron overload.8-10 Nonetheless, prospective (long-term) studies of environmental exposures has consistently indicated the involvement of aluminum (and perhaps iron) absorption in AD (although this does not in itself prove causality).6

Experimental work with animals, which soon followed McLachlan’s team’s successful intervention with human patients exhibiting AD in which they used DFO chelator in the late 1980’s and early 1990’s, strongly supports aluminum and perhaps iron as promoters of AD.1,4,11

These, and other experimental studies, suggest that the gradual accumulation of aluminum in the brain and other body tissues over time creates the potential for neurodegenerative disorders; and although aluminum chelators can reduce some of the toxicity from high levels of brain-stored aluminum, the redistribution within the brain of aluminum-chelator complexes formed during chelation can potentially contribute to neurological damage.11 Yokel pointed out that due to the potential toxicity of injected DFO researchers have sought for decades for a suitable oral iron or aluminum chelator.11 He cited a finding that the combination of ascorbate (vitamin C) plus Feralex-G (a natural complex) was effective, and that “Five consecutive daily i.p. injections of N-(2- hydroxyethyl) ethylenediaminetriacetic acid (HEDTA) to Al [aluminum] loaded rats significantly reduced blood and brain Al nearly to control rat levels.”11

Focusing on iron, Singh et al published a review in 2014 describing the role of iron in brain neurotoxicity and degenerative diseases such as Alzheimer’s Disease.8 They suggested the use of certain clinical interventions with AD patients, although they recognized that gaps remain in our understanding of iron homeostasis in the brain. Their review summarized multiple models for the causes of AD that developed in the last two decades, admitting that “the causes of AD are still rather poorly known, with different etiologies (e.g., [amyloid-beta] Aβ overproduction, genetics, Aβ impaired clearance, and NFT formation) leading to senile plaques, neurofibrillary tangle (NFT) formation, and extensive neuronal death,” but then concluding that Amyloid-beta protein is “currently favored as primary in the pathogenesis and development of Alzheimer’s Disease.”8

However, the role of Amyloid-beta protein is complicated, and its effect on the brain depends on the age of the brain.9 Amyloid-beta protein helps the younger, developing brain, but harms the older brain. Ongoing research indicates that Amyloid-beta proteins within the developing brain, in certain forms and in physiological doses, offer neuroprotective antioxidant, trophic, and synaptic plasticity protections, (thus improving the growth and function of the developing brain cells).9 “In summary, blockade, inhibition, or modulation of those sites, effects, and negative processes in which Aβ is involved, but simultaneously respecting those sites and physiologic processes in which Aβ is also taking part, remain a major challenge for therapeutic research in the future.”9 Singh et al reviewed herbal and synthetic interventions that target Amyloid-beta protein.9 According to their review, copper, zinc, and iron were considered prime candidates for AD (by binding to Amyloid-beta protein and thus creating hydrogen peroxide free radical damage to brain tissue). They concluded that studies involving chelation of copper and zinc using synthetic chemicals (such as clinoquinol), and natural agents (such as flavonoids from vegetables, fruit, and nuts) confirm the close relationship between metal ions from copper, zinc, and iron and the creation, or enhancement, of AD neurodegeneration.9

In an article published in 2015, Peters also argued that the brain’s mishandling of iron metabolism is likely an early cause of neurodegeneration, which ends with AD.10 “The dysregulation of iron metabolism in Alzheimer’s disease is not accounted for in the current framework of the amyloid cascade hypothesis. Accumulating evidence suggests that impaired iron homeostasis is an early event in Alzheimer’s disease progression.”10

Several studies published between 2012 and 2015 by Fine et al, and Guo et al, concluded that using intranasal desferrioxamine [DFO, an iron and aluminum chelator] with mouse-models for AD resulted in a decrease in the progression of the mouse-AD.12-15 “Collectively, the present data suggest that intranasal DFO treatment may be useful in AD, and amelioration of iron homeostasis is a potential strategy for prevention and treatment of this disease.”15

Fine et al further suggested that intranasal desferrioxamine is a potential treatment for AD and other neurodegenerative and psychiatric diseases.12

In 2016 Killin’s literature review on environmental exposures and dementia had pointed out that very few studies have examined long-term consequences of aluminum exposure, and that most studies showed wide variation in size and quality, making their conclusions uncertain and difficult to assess.6 None of the studies they examined measured the actual level of metals or elements in brain tissue. “Nevertheless, this extensive review suggests that future research could focus on a short list of environmental risk factors for dementia. . . There is at least moderate evidence consistently supporting air pollution, aluminum, pesticides, vitamin D, and electromagnetic fields as putative environmental risk factors for dementia.”6

Regarding treatment of AD, the NIH concludes that, “Alzheimer’s disease is complex, and it is unlikely that any one drug or other intervention can successfully treat it. Current approaches focus on helping people maintain mental function, manage behavioral symptoms, and slow or delay the symptoms of disease. Researchers hope to develop therapies targeting specific genetic, molecular, and cellular mechanisms so that the actual underlying cause of the disease can be stopped or prevented. . . . Alzheimer’s disease research has developed to a point where scientists can look beyond treating symptoms to think about addressing underlying disease processes. In ongoing clinical trials, scientists are developing and testing several possible interventions, including immunization therapy, drug therapies, cognitive training, physical activity, and treatments used for cardiovascular and diabetes.”16

It would appear from the initial, and only, study with humans by McLachlan et al to the recent studies with mice and rabbits that using desferrioxamine (or similar chemical or herbal chelators) offers a successful clinical intervention for millions of potential AD patients, offering a treatment much sooner than any of those promised by many of the current NIH-funded studies. Indeed, twenty years ago, Savory et al called for researchers to perform clinical studies on humans using chelators for AD, but no researcher has done this yet.3

The diverse results from environmental and experimental studies involving metals and other elements show our current uncertainty regarding environmental exposures in the causation or progression of AD. The elements most often found to be implicated in the causation and or development of AD include: Aluminum, Iron, Silicon, Selenium, Copper, and Zinc. It is possible that an interaction among some, or all, of these elements creates or takes advantage of increased leakage in the brain’s protective membrane.

Killin (2016) et al concluded, “More and better research is needed and we suggest that this shortlist should form the initial focus of attention.”6 Yokel concluded, “A better understanding of the factors that impact on the redistribution of the Al-chelator complex to the brain, and identification of chelators that have less or no risk to do this would be valuable. It would be highly desirable to resolve the contentious controversy of the role of, or lack of, Al as a contributing factor in AD.”11

The National Alzheimer’s Disease Institute agrees. We advocate funding be provided for studying humans with AD, using oral DFO and already proven natural and synthetic chelators.


* The National Alzheimer’s Disease Institute is a project of The National Fund for Alternative Medicine



  1. McLachlan DR, et al, “Intramuscular Desferrioxamine in Patients with Alzheimer’s Disease,” The Lancet, 1991, 337(8753), Pgs 1304-1308.
  2. McLachlan DR, et al, “Desferrioxamine and Alzheimer’s Disease: Video Home Behavior Assessment of Clinical Course and Measures of Brain Aluminum,” Ther Drug Monit, 1993, 15(6), Pgs 602-607.
  3. Savory J, et al, “Can the Controversy of the Role of Aluminumin Alzheimer’s Disease Be Resolved? What Are the Suggested Approaches to This Controversy and Methodological Issues to be Considered?” J Toxicol Environ Health, 1996, 48(6), Pgs. 615-635.
  4. Savory J, et al, “Reversal by Desferrioxamine of Tau Protein Aggregates Following Two Days of Treatment in Aluminum-induced Neurofibrillary Degeneration in Rabbit: Implications for Clinical Trials in Alzheimer’s Disease,” Neurotoxicology, 1998, 19(2), Pgs 209-214.
  5. Walton JR, et al, “Chronic Aluminum Intake Causes Alzheimer’s Disease: Applying Sir Austin Bradford Hill’s Causality Criteria,” J Alzheimers Dis, 2014, 40(4), Pgs. 765-838, DOI: 10.3233/JAD-132204.
  6. Killin LOJ, et al,, “Environmental Risk Factors for Dementia: A Systematic Review,” published online BMC Geriatr, 2016 Oct 12, 16(1), Pg. 175 et seq, DOI: 10.1186/s12877-016-0342-y.
  7. Thompson CM, et al, “Regional Brain Trace-element Studies in Alzheimer’s Disease,” Neurotoxicology, 1988, 9(1), Pgs. 1-7.
  8. Singh N, et al, “Brain Iron Homeostasis: from Molecular Mechanisms to Clinical Significance and Therapeutic Opportunities,” Antioxid Redox Signal, 2014, 20(8), Pgs 1324-1363.
  9. Singh KS, et al, “Overview of Alzheimer’s Disease and Some Therapeutic Approaches Targeting Aβby Using Several Synthetic and Herbal Compounds,” Oxid Med Cell Longev, 2016, Oxidative Medicine and Cellular Longevity, Volume 2016 (2016), Article ID 7361613, 22 pages,
  10. Peters DG, et al, “The Relationship between Iron Dyshomeostasis and Amyloidogenesis in Alzheimer’s Disease: Two Sides of the Same Coin,” Neurobiol Dis, 2015, 81, Pgs 49-65, doi: 10.1016/j.nbd.2015.08.007.
  11. Yokel, Robert A., “The Pharmacokinetics and Toxicology of Aluminum in the Brain,” Current Inorganic Chemistry, 2012, 2(1), Pgs. 54-63, DOI: 2174/1877944111202010054.
  12. Fine JM, et al, “Intranasal Deferoxamine Improves Performance in Radial Arm Water Maze, Stabilizes HIF-1α, and Phosphorylates GSK3β in P301L Tau Transgenic Mice,” Exp Brain Res, 2012, 219(3), Pgs. 381-390.
  13. Guo C, et al, “Intranasal Deferoxamine Attenuates Synapse Loss via Up-regulating the P38/HIF-1α pathway on the Brain of APP/PS1 Transgenic Mice,” Front Aging Neurosci, 2015, Jun 2, 7,
  14. Guo C, et al, “Deferoxamine Inhibits Iron Induced Hippocampal Tau Phosphorylation in the Alzheimer Transgenic Mouse Brain,” Neurochem Int, 2013, 62(2), Pgs. 165-172.
  15. Guo C, et al, “Intranasal Deferoxamine Reverses Iron-induced Memory Deficits and Inhibits Amyloidogenic APP Processing in a Transgenic Mouse Model of Alzheimer’s Disease,” Neurobiol Aging, 2013, 34(2), Pgs. 562-575.