The Association of Essential Metals with APOE Genotype in Alzheimer’s Disease

Abstract

Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. Objective: To test the association of essential metals with APOE genotype. Methods: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. Results: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. Conclusion: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

What can 7T sodium MRI tell us about cellular energy depletion and neurotransmission in Alzheimer's disease?

“…Our study therefore points at a TSC imbalance accompanying the neurodegenerative process in AD in vivo. This finding confirms observations from post mortem studies 18,26 and the recent detection of sodium increases in AD patients and subjects at risk 19,20 . Interestingly, TSC can be highly discriminative between control subjects and only mildly affected patients in temporal regions such as the fusiform gyrus and is predictive for cognitive state.…”

“…In the context of AD, baseline studies have indeed shown a close interplay between the pathological hallmarks of AD, that is, amyloid beta (Aβ) deposits and tau tangles with the NKA in disease models 13–16 . Correspondingly, sodium and potassium concentration imbalances have been detected in post mortem brain tissue, and increased sodium concentrations have also been found in blood plasma of AD patients and in cerebrospinal fluid (CSF) of those at risk 17–20 …”

3T sodium MR imaging in Alzheimer’s disease shows stage-dependent sodium increase influenced by age and local brain volume

“…This more widespread discriminative power of TSC outside the hippocampus could be due to the fact that disturbances in tissue homeostasis might precede the onset of significant atrophy. An increase in TSC has already been confirmed in post mortem examinations of brain tissue of AD patients ( Graham et al, 2015 , Vitvitsky et al, 2012 ) and in AD patients at risk ( Babić Leko et al, 2021 , Souza et al, 2020 ).…”

“…We did not choose e.g. the ventricles, since CSF sodium values have also recently been detected to change in AD-pathology and those at risk for it ( Babić Leko et al, 2021 , Souza et al, 2020 ).…”

Metals in Alzheimer’s Disease

“…Previous studies have revealed that the homeostasis of essential metals is altered in AD [ 26 , 27 , 28 ], where iron (Fe), zinc (Zn), and copper (Cu) are the essential metals most commonly associated with AD pathological changes. Heavy metal concentrations have also been found to rise in AD brains [ 29 ].…”