Table 1. Biometals and their effects.

AβPP: Amyloid-β Protein Precursor; MT3: Metallothionein 3; Cu²⁺: Cupper;  Zn²⁺: Zinc; Mg²⁺: Magnesium; Ca²⁺: Calcium; Fe²⁺: Ferritin 

Metal	Iron-Binding Protein	Effect
Cu2+	Amyloid-β (Aβ) peptide	Harmful:  Interaction between Cu2+and Aβ is correlated with a metal reduction from Cu(II) -> Cu(I) along with the formation of H2O2, leading to hydroxyl free radicals [6]. Aβ promotes oxidative stress in the presence of redox metals, copper, and iron [6].
Cu2+	Metallothionein 3 (MT3)	Harmful: Defects in MT3 pathway lead to increased aggregation of Aβ as MT3 is involved with the homeostasis of Zn2+ and Cu2+ by increasing soluble amyloid precursor proteins (sAPPα) [6].
Zn2+	Amyloid-β (Aβ) peptide	Beneficial [at low levels]: Competes with iron/copper to bind to Aβ to prevent Cu-Aβ induced formation of H2O2 and toxic free radicals [6]. Harmful [in excess]: Oxidants releasing excess zinc can trigger neuronal death that may be related to the toxic effect of Aβ [6] Studies found that high concentrations of zinc-binding to Aβ force Aβ to participate over a wide range of pH [16], and preserve the highly ordered conformation of Aβ, producing toxic, fibrillar Aβ aggregates [6].
Zn2+	Tau Protein	Harmful [in excess]: The pathological concentration of Zn2+ dramatically accelerated the abnormal aggregation of full-length human Tau [in Sh-SY5Y cells] [17], in addition to enhancing Tau aggregation in neuronal cells and Tau aggregation-induced apoptosis and toxicity. Contributes to hyperphosphorylation of tau [6], and lead to the formation of tau-paired helical filaments (PHF) that gather into neurofibrillary tangles (NFT).
Mg2+	Amyloid-β Protein Precursor (AβPP)	Beneficial: Decreased intracellular Ma2+ levels impair cell viability; magnesium modulates AβPP processing as follows [18]. High Mg2+ promotes non-amyloidogenic AβPP cleavage through α-secretase while demoting amyloidogenic processing by β-secretase [18], which is typically associated with the formation of amyloid plaque [19]. Lowering Mg2+ concentration sees the opposite, detrimental effects [18].
Ca2+	AβPP & Presenilins	Beneficial: Both Ca2+ and Mg2+ stabilize γ-secretase (which cleaves AβPP), enhancing its activity and decreasing Aβ secretion [6]. Mutations in presenilins downregulate Ca2+ channels and Ca2+ dependent mitochondrial transport proteins, which is seen in familial forms of AD [6]
Fe2+	Amyloid-β peptide	Harmful: Increased iron deposition leads to oxidative stress, contributing to early Aβ deposition [8]. Excess of iron leads to annular protofibrils, slowing formation of ordered cross-β fibrils and resulting in disordered, toxic aggregates [6]. In short, excess iron is linked to neuron loss in AD brain [20], iron enhances the toxicity of Aβ in cultured neural cells [21]. Iron in reduced Fe2+ state accelerates cell damage through toxic hydroxyl radical formation catalyzation [10].
Fe2+	Tau protein	Harmful: Fe3+ induces aggregation through tau-binding  Reduction of Fe2+ can reverse this aggregation Iron dyshomeostasis can contribute to AD neuroinflammation by causing oxidative stress and tau hyperphosphorylation [similar to zinc] [6].
Fe2+	Divalent metal transport 1 (DMT1) and Ferroportion 1 (FPN1)	Harmful: Expression of these iron metabolism-associated proteins could affect iron load in the brain negatively [13].
Selenium	Endogenous sulfhydryl groups	Harmful [in excess]: In high concentrations, Se can oxidize endogenous sulfhydryl groups, increasing free radical formation [22].   Beneficial [in moderation]: Acts as an antioxidant component  Deficiency results in glutathione peroxidase (GSH-Px) impairment, resulting in oxidative stress [23].