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

Article type: Research Article

Authors: Babić Leko, Mirjana^a | Jurasović, Jasna^b | Nikolac Perković, Matea^c | Španić, Ena^a | Sekovanić, Ankica^b | Orct, Tatjana^b | Lukinović Škudar, Vesna^d | Bačić Baronica, Koraljka^e | Kiđemet-Piskač, Spomenka^f | Vogrinc, Željka^g | Pivac, Nela^c | Borovečki, Fran^h | Hof, Patrick R.ⁱ | Šimić, Goran^{a; *}

Affiliations: [a] Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia | [b] Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia | [c] Ruđer Bošković Institute, Division of Molecular Medicine, Zagreb, Croatia | [d] Department of Physiology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia | [e] University Department of Neurology, Clinical Hospital “Sveti Duh“, Zagreb, Croatia and Neurology Clinic, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia | [f] Department of Neurology, General Hospital Varaždin, Varaždin, Croatia | [g] Laboratory for Neurobiochemistry, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia | [h] Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb Medical School, University Hospital Center Zagreb, Zagreb, Croatia | [i] Nash Family Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Correspondence: [*] Correspondence to: Goran Šimić, Šalata 12, HR-10000, Zagreb, Croatia. Tel.: +38514596807; Fax: +38514596942; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, apolipoprotein E, copper, metals, mild cognitive impairment, zinc

DOI: 10.3233/JAD-210158

Journal: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 661-672, 2021