Alzheimer’s disease (AD) is a progressive age-related neurodegeneration that represents the most common cause of dementia and cognitive decline in the elderly [1]. According to statistics, the true prevalence is unknown; however, it is the leading cause of death in the UK, surpassing cardiovascular diseases [2], and the fifth leading cause in individuals aged > 65 in the United States [3]. Additionally, it is twice as common in women compared to men [4]. Unfortunately, AD leads to a high level of health loss and mortality worldwide, with limited treatment options. Approximately 10–15% of AD patients are misdiagnosed by specialists, and the diagnosis can only be confirmed post-mortem. Early symptoms include cognitive deterioration, memory loss, and confusion.
The etiology of Alzheimer’s remains unknown; however, most cases present sporadically with late onset (≥65 years), while 5–10% of cases have a familial component, characterized by early onset (<65 years) and commonly associated with specific genetic mutations. The neuropathogenesis of AD is marked by the misfolding and aggregation of two proteins, amyloid precursor protein (APP) and tau protein (responsible for microtubule stabilization) [5]. APP leads to the formation of Aβ monomers, which aggregate to form Aβ fibrils and plaques, which are particularly toxic and damaging. On the other hand, hyperphosphorylation of tau protein leads to the formation of neurofibrillary tangles (NFTs) [6], associated with cognitive decline and the neurodegeneration typical of AD. Other genetic factors contributing to neurodegeneration are related to apolipoprotein E (apoE), which influences cytoskeletal integrity and neuronal repair efficiency. Studies have shown that other factors, such as hypertension, diabetes, dyslipidemia, smoking, hormonal changes, and metal exposure, can increase the risk of developing AD [6].
Metals are natural components of the Earth’s crust and can be inhaled or ingested through food, water, and air. Some heavy metals such as copper (Cu), zinc (Zn) and selenium (Se) can be detected in the body at low concentrations as trace metals. Metal ion homeostasis is essential in regulating certain brain functions. However, variations in concentration and form can make them toxic to the body. In particular, metals like Cu can promote the maturation of Aβ monomer aggregation and tau protein hyperphosphorylation. Evidence suggests that dysregulation of essential metal homeostasis and exposure to non-essential metals significantly impact AD pathogenesis [7].
Copper is a redox-active essential metal normally found in blood [8]. It is essential for the functioning of numerous enzymes, such as cytochrome C oxidase (CcO), copper-zinc superoxide dismutase (SOD1), dopamine-β-hydroxylase, tyrosinase, and lysyl oxidase, which respectively regulate the processes of energy metabolism, antioxidant activity, dopamine synthesis, melanin production, and tissue formation [9]. Cu is an important catalyst for iron absorption and heme synthesis. It is the third-most abundant transition metal in the liver, after iron (Fe) and zinc [3]. In the brain, Cu concentrations of approximately 60~110 μM can be detected, especially in the frontal lobe, brain, and hippocampus [8]. Usually, about 85–95% of total copper is found bound to ceruloplasmin (CP), a blue-looking copper glycoprotein. CP is mainly synthesized by the liver, brain, kidney, and fat. It plays important roles in Cu transport, Fe regulation, and antioxidant processes. Its structure is composed of 6 domains that can bind to six Cu atoms; when all six domains are bound to Cu, CP becomes unstable [10].
The remaining 5–15% of Cu is represented by loosely bound Cu to albumin and other little molecules, also known as “free copper” or “non-Cp-Cu”. Free copper, due to its loose binding, is freely available to meet tissue needs in the body.
The moment this 5–15% pool expands, copper becomes toxic; this is in line with what occurs in the case of Wilson’s disease [11]. Moreover, Cu is considered to be a pro-oxidant factor [12]: an increase in its serum levels may lead to feeding of the brain’s copper reservoir, which can enter oxidative stress (OS) cycles [12,13]. Neuronal damage caused by Cu homeostasis failure could be attributed to its numerous roles in processes essential for normal brain function, including catecholamine synthesis, activation of neuropeptides and hormones, antioxidant defense, connective tissue production, immune function, and synaptic transmission.
Considering the strong evidence of copper’s essential roles in the brain, it is not surprising that several studies have proposed that an imbalance in its homeostasis is associated with neurodegenerative disorders such as AD.
In this review, we will examine the role of copper in the pathophysiology of AD, as well as the mechanisms involved in neurotoxicity and cognitive decline, through a careful synthesis of literature published in the last 10 years, to identify new evidence.
2. Materials and Methods
2.1. Protocol
A draft protocol was written according to the Cochrane Handbook for Systematic Reviews of Interventions [14] for an updated systematic review on the role of the Cu in AD etiopathogenesis. The protocol is presented in the Supplementary Materials (S1).
2.2. Eligibility Criteria, Search Method, Information Sources, and Study Selection
The study adopted inclusion and exclusion criteria. These criteria were designed to ensure the selection of relevant studies while excluding those that did not meet the specified criteria.
The search was conducted in PubMed, Google Scholar, and across all databases available to us. We included only original research articles in full text, those published in a peer-reviewed journal, those in English and Italian languages, and those published from January 2013 up to January 2023. All case–control studies that addressed the analysis of Cu and AD were considered, following the combinations of keywords: “Alzheimer disease”, “blood”, “copper”, “risk”. We did not use any AND or OR in our research, thanks to the use of Boolean operators that read the space between words as an implied AND.
We considered only late onset Alzheimer’s disease; so, the population consisted in only over 60 years old people. Both sexes were taken into account. The nationality in which the study was conducted and/or where the samples were from was not a cause of exclusion.
After the initial screening of the title and abstract, the full texts of potentially eligible studies were examined independently by the authors and the discrepancies at all stages of study selection were resolved through discussion and consensus among the author group.
Finally, the studies included in the review, accompanied with the reasons for exclusion, are presented in the flow Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) [15] diagram (Figure 1). For data extraction, a standardized form is used (https://www.ncbi.nlm.nih.gov/books/NBK355732/ accessed on 17 November 2023) and screening of the data was performed using Excel spreadsheets.