CSF Ferritin predicts cognitive decline in E4s

[Kathleen1]

"The study found that in cognitively normal people who express the APOE ε4 risk allele, high CSF ferritin almost perfectly predicted whether the individual will experience cognitive decline in the subsequent 7 years," said Dr Bush.

The effect of ferritin "was far greater than the most established biomarkers — tau and amyloid β," he said.

Their results also showed that APOE ε4 carriers who have low iron levels were protected from cognitive decline."

this quote came from a Medscape review. I have not read the original report. Study author is Dr Ashley Bush , Florey Inst. of Neuroscience, University of Melbourne,Australia and comment apparently in a letter in JAMA Neurology, January this year.

Will see if I can find the article but if someone else does, feel free to comment. Note this is CSF iron. I do not know how this compares to blood levels.

[MarcR]

TL;DR - to live long and healthfully with greatly reduced risks of cancer, heart disease, diabetes, Alzheimer's, Parkinson's, etc., donate blood at least semiannually.

Five minutes more: Why Iron Is the Most Underrated Factor in Health

I read Mangan's book, Dumping Iron: How to Ditch This Secret Killer and Reclaim Your Health. It was well worth the $7 and and 60 minutes. Mangan makes his points succinctly and doesn't repeat himself to stretch the book. And the 147 scholarly references that occupy the last fifth of the book show that Mangan did his homework.

Mangan suggests that optimal ferritin levels are 20-40 for women and 50-70 for men. That recommendation comes from Dr. William R. Ware in this paper: The Risk of Too Much Iron: Normal Serum Ferritin Levels May Represent Signicant Health Issues. After reviewing the evidence for iron's harm, and in the absence of controlled long-term studies to determine optimal levels, Ware takes an educated guess based on this principle:

Overall, the answer to this question appears to be lower the better, provided anaemia is not the result.

This is logical, and in the absence of solid countervailing evidence, I'm going to target those levels. Of course, if hemoglobin / hematocrit lab tests show anemia, I'll boost iron incrementally until the anemia resolves.

My advice to my sons:

1. Give blood at least twice annually.
2. Know your ferritin levels - if your doctor is ordering blood work, try to get him/her to add a ferritin check.
3. Avoid / minimize consumption of iron-supplemented foods. Because U.S. Federal law requires iron to be added to flour, corn meal, and rice, grains are not your friend. (Note that Denmark and Sweden prohibit iron supplementation and will not allow importation of iron-fortified breakfast cereals because of the health risks.)
4. Consume coffee or tea with meals as they impede iron absorption.

I think giving blood regularly is by far the most important step you can take. And since the donation center will check your hemoglobin and/or hematocrit levels before accepting your donation, you are not likely to become anemic as a result.

To put this in personal perspective, the only ferritin test I have had, in 2013, was 186. Because it was in the middle of the lab reference range, I thought it was fine - oops. I donated blood in December and am scheduled to donate again next month.

[MAC]

"The study found that in cognitively normal people who express the APOE ε4 risk allele, high CSF ferritin almost perfectly predicted whether the individual will experience cognitive decline in the subsequent 7 years," said Dr Bush.

The effect of ferritin "was far greater than the most established biomarkers — tau and amyloid β," he said.

Their results also showed that APOE ε4 carriers who have low iron levels were protected from cognitive decline."

Will see if I can find the article but if someone else does, feel free to comment. Note this is CSF iron. I do not know how this compares to blood levels.

Here is the paper: http://www.nature.com/articles/ncomms7760

Abstract

Brain iron elevation is implicated in Alzheimer’s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apoE levels and was elevated by the Alzheimer’s risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

"The association between ApoE and brain iron status will warrant further investigation."

http://www.moh.gov.my/images/gallery/rni/15_chat.pdf

Iron in excess may lead to health problems. The deleterious effects of excess iron is related to its ability to generate reactive oxygen species via the Fenton reaction (McCord, 1998). The net effects are DNA damage, impaired synthesis of proteins, membrane lipids and carbohydrates, induction of proteases and altered cell proliferation. Excess free iron can react directly with unsaturated fatty acids and induce lipid hydroperoxidases to form alkoxyl and/or peroxyl radicals which in turn, impair severely cellular integrity leading to cell death. This destructive potential of iron has led to the suggestion that excess iron might play a role in the multi-step processes of carcinogenesis, pathogenesis of atherosclerosis, or neurodegerative disorders such as Parkinson’s or Alzheimer’s diseases (Connor et al., 1992).

See table below re diet and iron bioavailability...yet another high meat intake, negative AD association?

Combine with methionine/mTor/SIRT1, homocysteine methylation, and T2D/IR* > an overall potent AD association risk factor, especially for E4+?. [MAC conjecture/speculation]

* http://ajcn.nutrition.org/content/94/4/ ... l.pdf+html
2011 American Society for Nutrition

Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis

"In conclusion, we showed that a greater consumption of unprocessed and processed red meat is consistently associated with a higher risk of T2D. Compared with red meat, other dietary components, such as nuts, dairy products, and whole grains, wereassociated with lower risks. Therefore, from a public health point of view, reduction of red meat consumption, particularly processed red meat, and replacement of it with other healthy dietary components, should be considered to decrease T2D risk"

[KatieS]

Marc, thanks for the reminder to add-on ferritin to my upcoming labs. Although I'm heterozygous for hemochromatosis, my ferritin was 21 in 2014. Now I'm off curcumin and have forever been too underweight for blood donations. It appears that the serum ferritin does correlate with the CSF ferritin and possibly is increased by the Apoe4.

[ERK]

I guess I should not worry then about my level (it's 17). Good to know.

[Greenie]

It looks like checking our HFE gene would be especially important.


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[marty]

It's hard to know where to begin. But this is an important study.

First, I don't see the value of checking the serum ferritin level. It does not tell you the brain iron status. Period. The only value it may have is if you were not sure it would be safe to decrease your iron intake. If the serum ferritin is normal, it's a clue that it could be okay to drop your dietary iron. If you really wanted to know, you'd like a transferrin saturation. We generally need both.

Second, while brain iron can cause cellular injury, low brain iron levels clearly do harm also. Restless legs syndrome almost always is related to low brain iron levels and can be reversed by boosting the brain iron. Dopamine and, indirectly, endorphin function requires brain iron. Fatigue, depression, and frontal lobe dysfunction are documented casualties of low brain iron. In restless legs syndrome, which does have low iron in the brain, the risk of cardiovascular disease and suicide is significantly elevated.

Third, we don't know whether the higher iron levels in the brain cause the brain injury or whether iron transport into the brain is enhanced due to injury.

Fourth, presumably a very high portion of those E4 positive don't have high brain iron levels.

This will be sorted out in time. And the good news is that there are other ways to get a handle on brain iron besides a spinal tap. In our research on restless legs syndrome, there are three others. The first is not helpful- autopsy. But there is an ultrasound technique and a form of MRI that tracks iron in the brain. These are research tools. To my knowledge, they've not been applied to Alheimer's.

Personally, I don't eat iron rich food any way and haven't for quite some time for the theoretical concerns of iron toxicity as well as other reasons. If you tend to avoid iron supplements and meats, you may be better off. But on the other hand, we do iron infusions in a small number of patients who do have low brain iron levels.

Just a note of caution.

Sorry I've been on break from the forum. Life has been demanding lately.

[MAC]

Marty, here is a paper referencing actual brain & serum iron and AD.

The full paper (10.3233/JAD-140396) is behind a paywall. Members in jurisdictions for which access to is legal may want to search http://sci-hub.bz/ for the paper there

Perturbed Iron Distribution in Alzheimer’s Disease Serum, Cerebrospinal Fluid, and Selected Brain Regions: A Systematic Review and Meta-Analysis

"In conclusion, from our current study we provide convincing and extended evidence that AD is accompanied by iron overload in specific brain regions and iron deficiency in serum. We can reaffirm previous concerns also relevant to amyloid-
amyloidosis, as to whether the perturbed iron distribution can be considered the result of the pathogenesis of AD or caused by the mismanagement of body iron metabolism. These models need more experimental data although iron certainly appears to have biomarker potential, and it is important to establish if the changes evident post-mortem are present at an earlier stage in AD."

So lower serum iron is associated with AD? Again, could be biomarker of disease progression. You'd think someone would have already made some observational connection between iron and AD by now, so I'm guessing iron might be a biomarker of disease progression?

The original paper clearly makes NO CNS ferritin level causation association with AD.

[circular]

Perturbed Iron Distribution in Alzheimer’s Disease Serum, Cerebrospinal Fluid, and Selected Brain Regions: A Systematic Review and Meta-Analysis

"In conclusion, from our current study we provide convincing and extended evidence that AD is accompanied by iron overload in specific brain regions and iron deficiency in serum."

So lower serum iron is associated with AD? Again, could be biomarker of disease progression.

But I'm not sure we can assume that low serum iron necessarily means iron overload in brain regions? Maybe there are low irons stores in serum and brain? In which case cutting iron could lead to brain iron deficiency symptoms?

[MAC]

Will go back and re read but conclusion clearly says AND.