APOE-ε4 and brain iron (ferritin) levels paper

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BrianR
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APOE-ε4 and brain iron (ferritin) levels paper

Post by BrianR »

Open access paper explores a mechanism by which APOE4 may contribute to AD.

https://www.nature.com/articles/s41380-022-01568-w

Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy
Abdel Ali Belaidi, Shashank Masaldan, Adam Southon, Pawel Kalinowski, Karla Acevedo, Ambili T. Appukuttan, Stuart Portbury, Peng Lei, Puja Agarwal, Sue E. Leurgans, Julie Schneider, Marcus Conrad, Ashley I. Bush & Scott Ayton
Molecular Psychiatry (2022). Published 28 April 2022


I'll quote the Abstract below [emphasis mine], but if you're interested, I suggest jumping first to the Discussion which is relatively readable. This bit from the Discussion on fatty acids was intriguing: "... This agrees with observational studies where increased dietary intake of n-3 PUFAs (ferroptosis-resistant), and decreased dietary intake of n-6 PUFAs (ferroptosis-fueling), was associated with reduced AD risk in people without APOE ε4, but not with the risk allele"
Abstract
Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer’s disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC50 ≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer’s disease was stronger among those with the adverse APOE-ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele’s heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.
I also just saw, but was not able to read, this paywalled paper which seems to link the blood brain barrier, brain iron levels, and APOE ɛ4 - which may also be of interest to those who have access and want to dive deeper into the topic of iron levels.: APOE ɛ4 dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction
Plumster
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Re: APOE-ε4 and brain iron (ferritin) levels paper

Post by Plumster »

Thanks, BrianR.

Does cerebrospinal fluid ferritin level match up with body ferritin levels? I read that a study of Restless Leg Syndrome with low body ferritin did correspond with low brain ferritin. But can we actually use body levels to predict?

I am postmenopausal, my ferritin is about 34 and I have an underactive thyroid. My doctor wants my ferritin to be at least 60, so I am taking iron bisglycinate 25 mg.
e3/4 MTHFR C677T/A1298C COMT V158M++ COMT H62H++ MTRR A66G ++ HLA DR
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