Trace element alterations in Alzheimer's disease: A review

Abstract

Dyshomeostasis of trace elements have been implicated in the progression of Alzheimer's disease (AD), which is characterized by amyloid‐β (Aβ) plaques. Trace elements are particularly associated with the Aβ plaques. Metal‐protein attenuating compounds have been developed to inhibit metals from binding to Aβ proteins, which result in Aβ termination, in the hope of improving cognitive functioning. However, there are still some contradicting reports. This review aims to first establish which trace elements are increased or decreased in the brains of Alzheimer's patients, and secondly, to review the effectiveness of clinical trials with metal‐protein attenuating compounds for AD. Studies have consistently reported unchanged or increased iron, contradicting reports for zinc, decreased copper, unchanged or decreased manganese, inconsistent results for calcium, and magnesium seems to be unaffected. However, varied results have been reported for all trace elements. Clinical trials using metal‐protein attenuating compounds to treat AD have also reported varied results. Copper chelators have repeatedly been used in clinical trials, even though few studies report increased brain copper levels in AD patients. Homeostasis of copper levels is important since copper has a vital role in several enzymes, such as cytochrome c, Cu/Zn superoxide dismutase and ceruloplasmin. Dyshomeostasis of copper levels can lead to increased oxidative stress and neuronal loss. Future studies should assess a variety of trace element levels in moderately and severely affected AD patients since there are contradicting reports. This review thus provides some insight into trace element alterations in the brains of individuals with AD.

The position of geochemical variables as causal co-factors of diseases of unknown aetiology

“…The work reported in this manuscript did not involve human subjects, and informed consent to participate was not required. Grobe, 1976;Tseng, 1977;Mak, 1988;Kurklinsky et al, 2011Cold climate -Crocq, 1896Carpentier, 1998 By 2009, the global prevalence of dementia was estimated at 3.9 % in people aged 60+ years, with the regional prevalence being 1.6 % in Africa, 4.0 % in China and Western Pacific regions, 4.6 % in Latin America, 5.4 % in Western Europe, and 6.4 % in North America (Qui et al, 2009); Geographical variation (latitude) plays key role in dementia risk (e.g., Russ et al, 2016) Significantly different (ρ < 0.05) mean concentrations of Br, Cl, Ce, Hg, N, Na, P, and Rb were observed in AD bulk brain samples compared to controls - Ehmann et al, 1986; Varying trace element relationships with AD severity, with Al deposits greater in severely affected AD brain -Jagannatha Rao et al, 1999;Loef and Walach, 2012; Biometal dyshomeostasis and toxic metal accumulations -Chapman, 2008;Greenough et al, 2013;Li et al, 2017;Bagheri et al, 2018;Liu et al, 2019;Mocanu et al, 2020;Cilliers, 2021; Anomalous concentration levels of metals in metalbinding proteins have growth inhibition functions on neurons - Constantinidis, 1991;Richarz and Brätter, 2002; Trace metals and abnormal metal metabolism influence protein aggregation, synaptic signalling pathways, mitochondrial function, oxidative stress levels, and inflammation, ultimately resulting in synapse dysfunction and neuronal loss in the AD brain -De Benedictis et al, 2019;Wang et al, 2020 Air pollution, cf., Mills et al, 2015;Bikbov et al, 2020; "In 2017, the global prevalence of Chronic Kidney Disease (CKD) was 9•1% (95% uncertainty interval [UI] 8•5 to 9•8), which is roughly 700 million cases" - Cockwell and Fisher, 2020 Synergistic reaction between Cd and diabeticrelated hyperglycaemia -Edwards and Prozialeck, 2009; Consumption of (polluted) well water suggested; need for investigating role of Cd -…”

The position of geochemical variables as causal co-factors of diseases of unknown aetiology

“…It becomes worse with time (degenerative). The symptoms expressed are as a result of the damage or destruction of nerve cells (neurons) in parts of the brain involved in thinking, learning and memory (cognitive function) By 2009, the global prevalence of dementia was estimated at 3.9% in people aged 60 + years, with the regional prevalence being 1.6% in Africa, 4.0% in China and Western Pacific regions, 4.6% in Latin America, 5.4% in Western Europe, and 6.4% in North America—[ 51 ]; Geographical variation (latitude) plays key role in dementia risk (e.g., [ 52 ]) Significantly different (ρ < 0.05) mean concentrations of Br, Cl, Ce, Hg, N, Na, P, and Rb were observed in AD bulk brain samples compared to controls—[ 53 ]; Varying trace element relationships with AD severity, with Al deposits greater in severely affected AD brain—[ 54 , 55 ]; Biometal dyshomeostasis and toxic metal accumulations—[ 56 – 62 ]; Anomalous concentration levels of metals in metal-binding proteins have growth inhibition functions on neurons—[ 63 , 64 ]; Trace metals and abnormal metal metabolism influence protein aggregation, synaptic signalling pathways, mitochondrial function, oxidative stress levels, and inflammation, ultimately resulting in synapse dysfunction and neuronal loss in the AD brain—De Benedictis et al [ 65 ]; Wang et al [ 66 ] Air pollution, cf. , long-term exposure to O 3 and PM 2.5 above the current [2015] US EPA standards—[ 65 ] are associated with increased the risk of AD—[ 66 ]; Association between high altitude exposure, cognitive decline and dementia mortality rate—[ 67 – 71 ]; Associations with seasonal temperature—[ 72 ]; Global warming and neurodegenerative disorders —[ 73 ] According to Thielke et al [ 67 ] we still do not yet fully understand which environmental risk factors are associated with Alzheimer dementia; nor do we know which of these factors have links with the geological milieu In 2019 Alzheimer’s Disease International (ADI) estimated that there are over 50 million people living with dementia globally, a figure set to increase to 152 million by 2050—[ 74 ].…”

“…Significantly different (ρ < 0.05) mean concentrations of Br, Cl, Ce, Hg, N, Na, P, and Rb were observed in AD bulk brain samples compared to controls—[ 53 ]; Varying trace element relationships with AD severity, with Al deposits greater in severely affected AD brain—[ 54 , 55 ]; Biometal dyshomeostasis and toxic metal accumulations—[ 56 – 62 ];…”

Salpyran: A Cu(II) Selective Chelator with Therapeutic Potential

“…However, AD is a multiparametric disease, and other factors contribute to its etiology such as mitochondrial dysfunction, genetics, and age . At present, a large body of research suggests that metal ion dyshomeostasis plays a role in AD’s pathology; therefore, the restoration of biometal homeostasis offers a new clinical target when developing AD therapies. ,− …”

“…30−32 In the past decade, there has been an increasing interest in designing Cu-specific small molecule metal chelators (SMMCs) aiming to reduce Cu(II)-Aβ induced oxidative stress and the resulting pathogenic consequences. 6,15,[34][35][36][37][38][39][16][17][18][19][20][21][22]33 Chelation therapy aims to disrupt potential toxic interactions of metal ions and biomolecules by targeting specific metal ions and promoting redistribution or excretion. When designing a Cu-specific SMMC, both the thermodynamic properties of the metal chelate and the pharmacological properties of the ligand must be considered.…”