The original source of the amyloid plaques is the amyloid precursor protein (APP). The alpha-, beta-, and gamma secretase enzymes are in charge of cleaving APP. The non-harmful pathway involves the enzymatic decomposition of the APP by alpha- and gamma-secretase at critical junctures, which favor the generation of soluble APP and limit the formation of toxic Ab by beta-secretase [19]. The pathogenic pathway involves the enzyme beta-secretase (BACE-1), which initiates the cleavage of the amyloid precursor protein (APP) molecule at the N-terminus of the A chain. The primary secretase involved in the metabolism of APP is BACE-1, an aspartyl protease embedded in the cell membrane. Secrease then digests the last piece of APP that is attached to the neuronal cell membrane [20]. Further cleavages result in the liberation of A$\beta$, which is then released into the extracellular surroundings. Subsequently, it forms varying-sized aggregates, known as oligomers. Ever since the inception of the amyloid hypothesis, also referred to as the “null hypothesis”, over a quarter of a century ago, A$\beta$ has been widely regarded as the principal etiological factor in Alzheimer’s disease (AD) [21]. An alternative hypothesis posits that A$\beta$ is a prodromal manifestation or simply the consequence of the disease rather than a causal factor for its development and progression. However, both models agree that the A$\beta$ peptide is associated with the production of reactive oxygen species (ROS). The presence of several oxidative stress indicators in Alzheimer’s patients’ brains confirms that AD is characterized by ROS-induced oxidative stress [22]. The oxidative stress and damage is associated with a bioenergetic decline that in turn facilitates accumulation of toxic Ab.

The pathogenesis of Alzheimer’s disease (AD) is also associated with detrimental changes in the cholinergic system, characterized by the employment of the enzyme acetylcholinesterase (AChE) to convert the neurotransmitter acetylcholine into choline and the acetate anion [23]. AChE has a CAS, or catalytic site, and a PAS, or peripheral anionic binding site. Acetylcholine is thought to first bind to the PAS before quickly diffusing to the CAS. Extensive cholinesterase enzyme, butyrylcholinesterase (BuChE), exhibits increased activity as the AD state worsens while AChE activity declines. The accumulation of the Abeta peptide is related to increased BuChE activity. Cholinesterase inhibitors (ChEIs) are used to increase cholinergic neurotransmission, which is the basis of the current medication for AD patients [24]. Amyloid plaques exhibited elevated levels of Cu, Fe, and Zn when subjected to certain physical techniques, namely scanning transmission ion microscopy, Rutherford backscattering spectrometry, and particle-induced X-ray emission, with meticulous attention to detail [25]. As a result, it was discovered that the amounts of copper, zinc, and iron were approximately triple that in the surrounding tissues. An accurate evaluation of redox-active transition metals, namely iron (Fe) and copper (Cu), together with the redox-inactive metal zinc (Zn), has identified a crucial new element linked to Alzheimer’s disease (AD): The occurrence of oxidative stress induced by metallic elements [26, 27]. Acetylcholinesterase (AChE) inhibitors, including donepezil (administered at dosages ranging from 5 to 10 mg per day), rivastigmine (often prescribed at dosages ranging from 1.5 to 6 mg per day), and galantamine (suggested at dosages ranging from 16 to 24 mg per day), have been authorized as pharmacological interventions for the clinical management of Alzheimer’s disease [24]. Furthermore, memantine, an infrequently employed noncompetitive antagonist of the N-methyl-d-aspartate receptor, is suggested for administration at a dosage range of 5–20 mg/day [28]. These medications, while offering some relief, come with several unwanted side effects, including diarrhea, nausea, bradycardia, and potential liver toxicity. Furthermore, their primary limitation lies in their ability to only provide temporary symptom improvement without halting or altering the course of the disease. Despite amyloid $\beta$ accumulation being a prominent hallmark of Alzheimer’s disease, phase III trials involving anti-amyloid monoclonal antibodies such as bapineuzumab and solanezumab failed to demonstrate any significant enhancement in cognitive abilities among Alzheimer’s patients [29].

The pivotal event triggering the onset of Alzheimer’s disease is the enzymatic generation of the neurotoxic A$\beta$ from APP [30]. To prevent A$\beta$ synthesis, researchers developed and tested secretase inhibitors like semagacestat and avagacestat, targeting both $\beta$-secretase and $\gamma$-secretase, which play significant roles in this process [31]. However, the outcomes were not entirely conclusive, and adverse side effects emerged during these studies. Tau is a multifunctional protein crucial for stabilizing microtubules, and its significance in Alzheimer’s disease (AD) has led to extensive research into both the protein itself and its phosphorylation. However, these investigations have yielded mixed results [32]. Certain research has associated the ‘positive symptoms’ of schizophrenia with the malfunctioning of the dopaminergic system within the mesolimbic pathway. In all phases of Alzheimer’s disease (AD), there might be different degrees of dopamine insufficiency [33]. Additional investigation and rigorous clinical studies are necessary to enhance our understanding of the potential benefits of dopaminergic therapy in individuals diagnosed with AD [34]. Furthermore, it is essential to highlight the significance of dopaminergic dysfunction in the cognitive decline observed in persons with Alzheimer’s disease. The intricate underlying processes of AD need a meticulously chosen mix of drugs that may impede the first pathological alterations and perhaps influence the progression of the condition [35]. As stated before, imbalances in metal homeostasis result in metal-induced oxidative stress, a phenomenon identified in the cerebral tissue of individuals diagnosed with Alzheimer’s disease (AD). Oxidative stress represents a pivotal pathophysiological factor in several age-related ailments, including AD, cardiovascular diseases, cancer, and various neurological disorders. The efficacy of supplements in lowering oxidative stress remains uncertain due to the absence of agreement and definitive data. Nevertheless, it seems that the inherent antioxidants present in fruits and vegetables, especially when paired with various other antioxidants, might potentially alleviate the adverse effects of oxidative stress, particularly during the first phases of disease development and advancement [36]. AD impacts a significant number of individuals globally, although now, only symptomatic relief therapies are available. According to current projections, it is anticipated that around 5.8 million individuals in the United States who are 65 years old or older would be affected by AD in the year 2020 [37]. According to the predominant theory, tau and Ab proteins impair the energy supply and antioxidant defenses of neuronal cells in AD, resulting in dysfunction in both mitochondria and synapses. Neurons, due to their high energy requirements, are particularly susceptible to disruptions in mitochondrial function associated with reduced antioxidant protection and bioenergetic decline. Regulating the levels of second messengers like calcium ions (Ca²⁺) and reactive oxygen species (ROS) is among the numerous processes crucial for the survival and demise of the cell. Moreover, mitochondria are involved in the production of intracellular energy in the form of adenosine triphosphate (ATP) [38, 39]. Importantly, when mitochondrial function is impaired, it has a substantial effect on the synthesis of ATP, disturbances in calcium ion (Ca²⁺) equilibrium, and the formation of ROS. In the early stages of AD, alterations in mitophagy and mitochondrial dynamics are observed, but the underlying processes remain inadequately understood [40]. To enhance our comprehension of the development of this neurodegenerative condition and potentially advance therapeutic strategies aimed at preserving synaptic activity and, consequently, cognitive function, research must be conducted to elucidate the mechanisms underlying mitochondrial abnormalities in AD [41]. Recent research has demonstrated that indicators of oxidative stress can be detected at the initial phases of Alzheimer’s disease (AD) [42]. Similarly, an impaired bioenergetic state resulting from mitochondrial inadequacy has been associated with pre-symptomatic AD. Apart from reduced ATP production, mitochondrial insufficiency leads to an excess of ROS which has been associated with cell death, changes in the cytoskeleton and degradation of cellular membranes. The exact correlation between oxidative stress and other indicators of the degenerative progression of Alzheimer’s disease remains uncertain, despite the multitude of biochemical hypotheses that have been offered to explain their complex interaction and development [43]. Frailty’s development is influenced by various factors such as oxidative stress, inflammation, dietary habits, obesity, blood clotting, and insulin resistance, as indicated by numerous studies [2, 5]. Many of these studies involve older individuals living in communities who do not have AD but are part of population-based research with either no cognitive impairment or mild cognitive impairment [44]. Several biological components have been associated with degenerative processes in AD, such as $\beta$-amyloid and tau pathology. Interestingly, we have observed that while some AD patients experience frailty, others do not. It is worth noting that no research has delved into the biological mechanisms underlying frailty in AD patients so far. A rare case involving a 51-year-old patient who presented with symptoms including memory loss, disorientation, hallucinations, and cognitive decline was documented by Alois Alzheimer in his essay “Über eine eigenartige Erkankung der Hirnrinde” (“On an Unusual Illness of the Cerebral Cortex”) [45]. Upon the patient’s demise, post-mortem examination revealed an atrophic brain displaying conspicuous alterations in neurofibrils and tiny localized areas of damage caused by the accumulation of a distinct substance within the cortex. This event signified the commencement of what is presently recognized as AD, a disorder that continues to be the most widespread neurodegenerative ailment after a century of scholarly investigation [46].

On a global scale, the World Alzheimer Report from 2015 reported that 46.8 million individuals were living with dementia, and this number is projected to nearly quadruple every 20 years [47]. Dementia affects approximately 5–8% of people over the age of 65, 15% of individuals over 75, and 25–50% of those over 85. In terms of regional distribution, Asia has the highest incidence with 22.9 million cases, followed by Europe with 10.5 million, and the Americas with 9.4 million [48]. It is worth noting that AD constitutes a substantial proportion of dementia cases, ranging from 50 to 75 percent. AD sufferers see a gradual deterioration in cognitive ability in comparison to persons who do not have the disorder. This decline is closely linked to a significant reduction in brain volume observed in AD patients. More specifically, the hippocampus experiences atrophy due to the loss of neurons and the deterioration of synapses [49], this brain region is responsible for spatial orientation and memory. The risk of developing AD rises up to 50% in individuals aged over 85, highlighting age as the most significant risk factor. Women have a higher likelihood of developing AD than men, possibly due to their longer life expectancy and the potential impact of reduced estrogen levels during menopause, which may increase the risk of AD. Extensive research is currently focused on a neurological disorder known as AD [50]. This condition has gained notoriety due to its increasing prevalence, particularly among older individuals, with the likelihood of developing it rising significantly with age. In fact, the incidence of Alzheimer’s disease may approach 50% for individuals older than 90 years, and a European study revealed a 7.2% incidence rate among the population aged over 65 [51]. Initial indications of Alzheimer’s disease often include deficits in short-term memory, difficulties in visuospatial perception and impairments in language and executive function. The disease can be diagnosed by observing a decline in cognitive abilities. One cost-effective diagnostic tool for this purpose is the Mini-Mental Status Exam (MMSE) test, which is considered a preferred choice in many healthcare systems over expensive laboratory tests relying on biochemical markers. Despite its simplicity, the MMSE test proves to be a robust tool for detecting the disease in its initial stages [52].

Oxidative stress is a condition characterized by the accumulation of reactive oxygen or nitrogen species to a level where the body can no longer effectively neutralize them. The connection between Alzheimer’s disease and oxidative stress is under extensive investigation, and it appears to hold promise as a potential target for therapeutic intervention [53]. The relationship between Alzheimer’s disease and oxidative stress has undergone thorough investigation and appears to hold significant potential as a therapeutic target. This work examines the existing body of knowledge regarding oxidative stress in AD and the broad implications of using medicine to target the molecular mechanisms and mediators of the pathways implicated in oxidative stress and damage [54].

There is a great amount of research suggesting that oxidative and nitrosative stress significantly contribute to the progression of AD, resulting in the impairment of vital cellular elements like nucleic acids, lipids and proteins [55]. Oxidative stress (OS) occurs when the generation of reactive oxygen species (ROS) exceeds the cellular antioxidant defense system capacity. Likewise, OS arises as a result of the buildup of oxidized or impaired macromolecules that are insufficiently eliminated and replenished. The assemblage of antioxidant enzymes, comprising superoxide dismutase (SOD), glutathione peroxidase (GPx), glutaredoxins, thioredoxins and catalase (CAT), in conjunction with non-enzymatic antioxidant compounds, forms a fundamental defensive mechanism within the cellular environment [56]. Within the framework of AD, there is a decline or deterioration in the operation of antioxidant enzymes, as evidenced by a decrease in their particular activity. Indeed, several investigations have verified that dysfunction in mitochondria, principally caused by the production of ROS, plays a substantial role in the pathogenesis of AD [57]. The presence of A$\beta$ peptides, in conjunction with trace metal ions like iron and copper, as well as altered mitochondrial function, have been identified as probable causes of OS. The incorporation of A$\beta$ peptides into the cellular membrane has the potential to initiate the production of ROS, resulting in the peroxidation of lipids inside the membrane [58]. This process can subsequently cause harm to intracellular proteins and nucleic acids. Proteins have a heightened vulnerability to oxidative damage, which can induce significant modifications to their secondary and tertiary conformations, so causing enduring abnormalities in their structure and, subsequently, their functionality. The modifications may encompass processes such as the dissociation of subunits, unfolding of molecular structures, exposure of hydrophobic residues, aggregation of molecules, and fragmentation of the protein backbone.

Apart from these commonly observed protein modification markers, protein oxidation and nitrosylation can lead to S-nitrosylation and methionine oxidation (sulfoxidation). S-nitrosylation is a chemical reaction involving the cysteine group and N₂O₃, resulting in the formation of S-nitrosothiol (SNO). The control of SNO levels is quite complex, including the actions of nitrosylases and denitrosylases, which add or eliminate the NO modification, but also a homeostatic system of nitrosylated proteins. SNO modification plays a critical role in intracellular signaling based on redox reactions, and alterations in the SNO profile have been observed in Alzheimer’s disease [59]. Over the course of more than thirty years of research, the Food and Drug Administration (FDA) has granted approval for only five prescription drugs for Alzheimer’s disease, and none of these medications target amyloid or tau. While these treatments do not provide a cure or a halt to the disease’s progression, they are employed to address dementia-related symptoms such as memory loss and confusion. Galantamine, rivastigmine, and donepezil are administered to mild to moderate Alzheimer’s patients, while memantine and memantine/donepezil are given to moderate to severe patients [60].

Regrettably, more than 200 phase II/III clinical trials assessing over 100 potential medications have experienced significant failures, resulting in substantial financial costs and decades of research efforts. Several methodological factors pertaining to the design of clinical trials for Alzheimer’s disease (AD) have been related to these disappointments, including issues like inadequate dosing, insufficient bioavailability, challenges in patient recruitment/selection and compliance, inconsistencies in cognitive assessment methods, inappropriate timing of interventions, and difficulties in evaluating target engagement [61]. These issues raise questions about whether the current drugs are appropriately targeting the underlying pathological elements or if a multi-target approach is needed to bring about actual changes in the disease rather than just symptom alleviation. Several therapeutic strategies for Alzheimer’s disease are currently in their preliminary or theoretical phases, undergoing experimentation in controlled laboratory settings or animal subjects, while others are now undergoing evaluation in clinical trials [62].

Currently, AD affects approximately 24 million individuals worldwide [63]. Magnetic resonance imaging (MRI) results often provide support for the clinical assessment of probable AD. However, a more precise pre-mortem diagnosis can be achieved through a positron emission tomography (PET) scan that examines amyloid $\beta$ deposition or diminished 18F-fluoro-2-deoxyglucose uptake. Additionally, cerebrospinal fluid (CSF) analysis, which assesses amyloid beta peptide 1-42 (A$\beta$ 42), tau, and phosphorylated tau, can provide valuable diagnostic information. Postmortem examination of brain histology demonstrates significant neuronal and synaptic deterioration, along with the existence of various amyloid plaques outside cells and the formation of neurofibrillary tangles inside neurons. These pathological features serve as confirmatory evidence for the analysis of Alzheimer’s disease [64]. Increasing evidence indicates a link between AD and several variables, including mitochondrial failure, oxidative stress, and disruptions in autophagy [40]. Mitochondria are crucial for the proper functioning of neurons and any oxidative harm occurring within these mitochondria can have significant implications for the development of AD. Oxidative stress is acknowledged as a primary factor in cellular demise in neurodegenerative disorders, arising from an inequilibrium between oxidizing agents and systems that counteract their effects. Various research studies have demonstrated that autophagy is suppressed in numerous neurodegenerative disorders, such as AD and Huntington’s disease (HD) [40, 65].

ROS and RNS are generated as a result of regular metabolic processes or in response to cellular stressors, and they gradually build up in the body [87]. Extended exposure to ROS, in addition to its cumulative effect, results in cellular harm and hindered regeneration, which are strongly linked to age-related degenerative illnesses. The aged population is more vulnerable to degenerative illnesses due to elevated levels of pro-oxidant damage and a decline in antioxidant defence systems [88]. Neurons are highly active cells with a substantial oxygen demand, accounting for approximately a quarter of the body’s total oxygen consumption [89]. Consequently, neuronal cells generate significant amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS), rendering them susceptible to free radical attacks. Neurons have relatively lower quantities of antioxidant defence molecules, such as glutathione (GSH), and a larger quantity of readily oxidizable polyunsaturated fatty acids, as compared to other types of cells. The existence of antioxidant enzymes, specifically hemeoxygenase (HO)-1 and superoxide dismutase (SOD)-1, within senile plaques provides significant evidence for the role of oxidative stress in the aetiology of Alzheimer’s disease [90]. Notably, it has been shown that oxidative stress is an early occurrence in the progression of Alzheimer’s disease. Elevated production and accumulation of ROS lead to increased levels of oxidized proteins, lipids, and DNA, which have been associated with Alzheimer’s disease [67]. ROS molecules have been demonstrated to augment the synthesis, aberrant folding, and accumulation (crosslinking) of amyloid beta. Amyloid beta peptides typically consist of 40–42 amino acid chains with the sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA. The peptides mentioned are generated by proteolysis of the amyloid precursor protein (APP) as a consequence of cleavage by beta and gamma proteases, frequently as a result of hereditary abnormalities in the APP gene. Methionine, which is located at position 35 in the Amyloid beta protein sequence, is an amino acid residue highly susceptible to oxidation. ROS can oxidize methionine side chains under physiological conditions, leading to the presence of oxidized forms of methionine in Alzheimer’s disease brain tissue [91]. Methionine can be oxidized either by the addition of two electrons to form methionine sulfoxide or by the loss of one electron, resulting in a sulfuranyl free radical. The oxidative changes have the potential to induce harm to neighbouring neuronal proteins and lipids [92].

AD is linked with the occurrence of lipid oxidation in the brain tissue, which is a degenerative characteristic [93]. The brain contains highly susceptible polyunsaturated fatty acids, including arachidonic and docosahexaenoic acids, which are prone to oxidation. Lipid peroxidation causes the degradation of neuronal membranes and produces several secondary substances including 4-hydroxy-2-nonenal, acrolein, isoprostanes, and neuroprostanes. A specific investigation found elevated levels of the lipid peroxidation biomarker called thiobarbituric acid reactive substances (TBARS) in the synaptosomal membrane portion of neurons impacted by Alzheimer’s disease [94]. Alzheimer’s disease is linked to oxidative damage of DNA, along with the oxidation of amyloid beta and lipid peroxidation. Reactive oxygen species (ROS) can damage DNA by causing uncontrolled alterations to nucleic acid bases [95]. Hydroxyl radicals have the ability to alter guanine nucleotides, resulting in the creation of 8-hydroxy guanine. This altered guanine has a propensity to form base pairs with adenine rather than cytosine. The oxidation of thiamine may lead to the creation of hydrogen bonds between 5-hydroxymethyluracil and adenine, enabling their coupling. In addition, reactive nitrogen species (RNS) and peroxynitrous acid have the ability to interact with nucleic acid bases, resulting in oxidative deamination by substituting NH₂ groups with OH groups. The uncontrolled process can convert adenine, cytosine, and guanine into hypoxanthine, uracil, and xanthine, respectively. Hypoxanthine and uracil can both create erroneous base pairs with cytosine and adenine. The occurrence of oxidised DNA bases in the brains of individuals with AD, such as 8-hydroxyadenine, 8-hydroxyguanine, thymine glycol, Fapy-guanine, 5-hydroxyluracil, and Fapy-adenine, strongly emphasises the important contribution of DNA damage to the development of AD [96]. Researchers have discovered a much greater quantity of damaged DNA in neurons that have been exposed to A$\beta$ peptides in individuals with AD [97]. Various metal ions, such as copper, iron, aluminium, lead, mercury, manganese, and zinc, are essential for maintaining cellular homeostasis. Nevertheless, heightened concentrations of toxic metals have been identified in the cerebral tissue of patients afflicted with Alzheimer’s disease. Multiple studies have confirmed that interactions between metal ions and APP and amyloid beta peptides lead to an increase in the generation of ROS, which, in turn, results in the overproduction and accumulation of amyloid beta peptides and heightened neurotoxicity [54, 58, 62, 98]. Heavy metal ions behave as potent pro-oxidants and facilitate redox processes that generate free radicals that are highly reactive, such as hydroxyl radicals. Lead and mercury, in particular, have been associated with increased expression of APP, heightened reactivity of glial cells, neuronal inflammation, and oxidative stress [99].

ROS are endogenously generated as a result of normal metabolic processes within cells in living organisms [100]. ROS play a crucial role in preserving cellular balance and are implicated in several physiological processes, such as immunological responses and inflammation. The overproduction of ROS may be harmful, leading to oxidative harm to cell components, particularly the delicate mitochondrial structures that are highly susceptible to ROS-induced injury [101]. Given its substantial oxygen demand for proper functioning, the brain is particularly susceptible to the deleterious effects of ROS. In addition, the brain contains a limited number of enzymes and other antioxidant molecules, a substantial amount of iron (a potent catalyst for reactive oxygen species), and peroxidation-sensitive polyunsaturated fatty acids. Therefore, oxidative stress plays a substantial role in the advancement of neurodegenerative diseases, including AD. The biomolecules that experience the highest levels of oxidation in AD are the ones present in neuronal membranes, such as lipids, fatty acids and proteins. Changes in biomarker levels can function as prognostic indicators of AD, where oxidative stress is a pivotal contributor to its development and progression [102]. ROS are amphiphilic compounds distinguished by their unpaired electron that gives them their exceptionally high reactivity and short lifetime. Upon oxidation of biomolecules, the resultant species exhibit enhanced stability compared to the initial molecules and can serve as indicators of oxidative damage. Nucleic acids, proteins, and oxidised lipids are a few examples of these biomarkers. Biomarkers may also consist of variations in the concentrations of antioxidant enzymes such as glutathione peroxidase, superoxide dismutase, and catalase, in addition to other antioxidant compounds. Due to their properties, antioxidant molecules hold promise in preventing and treating disorders related to oxidative stress, including neurodegenerative diseases [103]. Antioxidants consist primarily of compounds that possess the capacity to scavenge free radicals, thereby preventing the chain reaction of the radical propagation and reinstating the stability of the molecules involved.

Iron is a vital constituent of the human body, and its iron (II) forms, such as iron (II) ions or iron (II)L complexes (where L is a coordinated ligand), can engage in chemical processes referred to as Fenton or Fenton-like reactions. These reactions involve the combination of iron with H₂O₂ to produce hydroxyl radicals ($\cdot$OH). The hydroxyl radical, possessing a substantial electrode potential has remarkable reactivity and may swiftly engage with diverse biomolecules via mechanisms such as hydrogen abstraction and hydroxyl addition which leads to oxidative adverse effects on DNA, proteins, and cells. Oxidative damage to biomolecules takes place inside a living organism when the body’s antioxidant defences, such as enzymes and natural antioxidants, are unable to cope with the excessive creation of ROS, thereby disturbing the balance between prooxidation and antioxidation (Fig. 1). Multiple studies have presented compelling data establishing a significant connection between oxidative stress and neurodegenerative illnesses, namely AD and Parkinson’s disease (PD), particularly in the specific areas of the brain that are afflicted [8, 27, 36, 64, 104]. Iron, being the transition metal most abundant in a healthy brain, is essential for optimal brain function. Copper and zinc, among other transition metals associated with AD pathology, are present in trace quantities. However, the initial phases of AD progression are distinguished by the existence of iron accumulation and oxidative stress.

Fig. 1.

Amyloid beta plaques, neurofibrillary tangles, and heavy metals all contribute to the production of reactive oxygen species (ROS) and, ultimately, Alzheimer’s disease. Antioxidants can inhibit the formation of ROS and protect against neurodegeneration in Alzheimer’s disease.

Increased concentrations of redox-active iron have been suggested as possible catalysts for the clumping together of amyloid-$\beta$ (A$\beta$) and the occurrence of oxidative harm in the brain [105]. Ferroptosis, an iron-dependent pattern of cell death that has recently been identified, is thought to be induced by the buildup of ROS composed of lipids. It is also considered to be a major cause of cell death in neurological disorders including AD and PD. Hence, in order to progress the pharmaceutical therapies for neurodegenerative disorders, it is imperative to acquire a more profound comprehension of the functions of iron and the resulting oxidising species [106]. Significantly occurring primarily within mitochondria, ROS are generated by mitochondrial enzymes. Single-electron leakage is a process by which the electron transport chain (ETC) within mitochondria generates superoxide radicals; this occurs primarily during respiratory phases I and III of the oxidative phosphorylation (OXPHOS) pathway [107]. Nevertheless, it is crucial to acknowledge that the rate of reactive oxygen species (ROS) production in complex I is comparatively lower than that of Flavin-dependent enzymes present in the mitochondrial matrix. Under normal physiological circumstances, researchers have extensively examined five distinct antioxidant enzymes that are found within cells: (i) Cu/Zn-SOD or SOD1, which is located in the cytosol, (ii) Mn-SOD or SOD2, located in the matrix of the mitochondria, (iii) CAT, (iv) GPx and (v) additional secondary antioxidant and cellular detoxification systems.

The regulation of these secondary systems is predominantly carried out by Kelch-like erythroid-derived cap‘n’collar homolog (ECH)-associated protein 1 (Keap1) and NF-E2-related factor 2. Keap1 typically acts as an actin-binding protein that keeps Nrf2 in the cytoplasm. It functions as a protein that binds to a substrate and facilitates its interaction with the Cullin3-containing E3-ligase complex [108]. This intricate molecule specifically targets Nrf2 for the process of ubiquitination and subsequent destruction by the proteasome. Crucially, Keap1 is responsive to changes in redox state and can be altered by different oxidising agents and electrophiles. Oxidative stress (OS) hinders the breakdown of Nrf2 by Keap1, resulting in the buildup of Nrf2 in the nucleus [109]. Within the nucleus, Nrf2 combines with a small musculoaponeurotic fibrosarcoma (Maf) protein to create heterodimers, which then attach to antioxidant response elements (AREs). This relationship is responsible for the stimulation of the synthesis of phase II antioxidant enzymes, which include glutamate-cysteine ligase, glutathione S transferases (GSTs), NAD(P)H quinone oxidoreductase 1 (Nqo1) and heme oxygenase 1 (Hmox1). In addition, Nrf2 is involved in maintaining cellular proteostasis via controlling the expression of molecular chaperones and different subunits of the proteasome [110]. Aside from antioxidant enzymes, the cellular components are shielded from reactive oxygen species (ROS) by small molecules and non-enzymatic antioxidants, such as natural flavonoids, vitamins, thiol antioxidants and carotenoids. Antioxidants play a crucial role in protecting cellular components against oxidative injury [111]. While adequate level of ROS are critical for the proper functioning of physiological systems, elevated levels have been associated with oxidative damage to various cellular components and compartments. The oxidative damage manifests as structural and functional anomalies in macromolecules, specifically lipids and proteins, distributed throughout many brain areas. For instance, elevated levels of oxidative stress linked to cell membranes have been identified in brain tissue from individuals with AD. The elevated levels of oxidative stress detected are correlated with the buildup of cholesterol and ceramides in clustered microdomains within samples of brain tissue affected by AD [112]. Notably, antioxidants like vitamin E and ceramide inhibitors have been shown to prevent the formation of these microdomains. The formation of such microdomains has been extensively studied, with one significant finding being that the aggregation of extracellular A beta at the cell membrane leads to oxidative damage associated with the membrane. The oxidative stress occurring at the membrane level is distinguished by the process of lipid peroxidation, which leads to the formation of the neurotoxic compound known as 4-hydroxynonenal (HNE). Hydroxynonenal (HNE) has been identified in the first phases of AD advancement and exhibits a clear correlation with the extent of neuronal damage and degeneration [113]. Furthermore, it has been observed that oxidative stress has the ability to stimulate pathways that are associated with the pathogenesis of AD. An example of this is the activation of the mitogen-activated protein kinase (MAPK) p38 in response to oxidative stress induced by A beta. One of the many roles of p38 is to stimulate the phosphorylation of tau in primary neuronal models. This process can be blocked by administering a p38 inhibitor or vitamin E before the therapy [114]. The veracity of these findings has been validated in vivo by the utilisation of an APP/PS1 transgenic mice model for AD. Oxidative stress associated with Alzheimer’s disease leads to significant deterioration of nucleic acids through oxidation. This damage leads to alterations in the structure of DNA. Mitochondrial DNA and RNA have also been found to be oxidized in various diseases, not just Alzheimer’s disease [113]. One specific aspect of DNA/RNA oxidation is the conversion of guanosine to 8-hydroxyguanosine (8-oxoG). Autopsy study of brain tissues from Alzheimer’s disease patients have revealed high levels of 8-oxoG in neurons in regions such as the hippocampus, subiculum, entorhinal cortex, and various neocortical areas [115]. Furthermore, RNA oxidation in the frontoparietal cortex, hippocampus, cortical neurons, and white matter of aged rats has increased significantly. These findings indicate that the damage caused by oxidative stress to DNA and RNA adds to the progress of neurological disorders and the ageing process. Additionally, both amyloid beta (A$\beta$) and tau proteins exhibit various alterations in response to oxidative stress. Tau is involved in the organization of microtubules by dynamically interacting with newly formed microtubules [116]. In AD patients, intracellular dynamics related to microtubule structure have been found to be disrupted. Exposure to substances like hydrogen peroxide (H₂O₂) or 4-hydroxynonenal (HNE) has been shown to reduce microtubular network growth in numerous cell lines, including ventricular myocytes, neuro-2A cells, rat pheochromocytoma PC12, and the pancreatic epithelial cell line AR42J [113]. This reduction is primarily mediated by Michael addition reactions. On one end of the spectrum, there is full acceptance of the role of oxidative stress as the causative pathological process initiating diseases like Alzheimer’s disease. On the other end, there is skepticism about the physiological relevance of oxidative stress. In between these extremes, there are balanced views and hypotheses. Some propose that oxidative stress is a co-factor that exacerbates the progression of Alzheimer’s disease but doesn’t necessarily initiate it. In its mildest form, oxidative stress is considered to constitute a sole marker without a causal impact. The presence of several viewpoints results in different understandings of oxidative stress in AD. Due to the ambiguous nature of the actual cause of AD, it is difficult to properly evaluate the impact of oxidative stress. With the production of significant quantities of ROS and utilisation of more than 20% of the total ambient oxygen supply, the brain is among the most metabolically active organs in the body. In healthy conditions, mitochondria produce ROS, including superoxide anion (O₂), hydroxyl radical (OH), and hydrogen peroxide (H₂O₂), as well as reactive nitrogen species (RNS) like nitric Oxide (NO) and peroxynitrite (ONOO) [117]. The negative effects of free radicals are mitigated by antioxidant enzymes, including as SOD, GPX, CAT and different chelating proteins that lie within the antioxidant system, which combat these reactive species. Presently, it is postulated that the occurrence of oxidative stress in individuals with AD might be initiated by one or more causative factors. The most widely recognized factors include the presence of amyloid plaques, elevated levels of heavy metals, and mitochondrial dysfunction [118]. A recent investigation has demonstrated that the dysregulation of redox state significantly worsens AD and activates numerous cellular pathways implicated in the pathogenesis and progression of this neurodegenerative condition [119]. Consequently, oxidative stress should now be considered a critical player in AD and many other forms of dementia. Several empirical observations now demonstrate a strong correlation between oxidative stress (OS) and cellular mechanisms that result in neuronal damage, such as the generation of beta-amyloid, formation of Neurofibrillary Tangles (NFTs), inflammation of the brain and aberrant mitochondrial activity. These elements collectively form a complex cycle of events in which OS plays a pivotal role. Therefore, simultaneously modulating OS and suppressing other characteristics of Alzheimer’s disease (AD) could potentially lead to more promising treatment approaches compared to currently available options [120]. Recent evidence suggests that attempts to decrease the overall levels of reactive oxygen species (ROS) in the body may be futile because of the dual function of ROS. On one hand, increased ROS production contributes to the development of age-related chronic illnesses and neurodegeneration. Conversely, oxidants like superoxide and hydrogen peroxide can function as signaling molecules in numerous vital redox-dependent signaling pathways crucial for an organism’s survival. These pathways encompass epidermal growth factor receptor signaling, inactivation of the tumor suppressor Phosphatase and tensin homolog (PTEN), regulation of circadian rhythms, modulation of the inflammatory response, and the hormetic stress response. Hence, maintaining redox balance with precise control over ROS production levels is essential to safeguard cells against oxidative stress while ensuring the availability of vital electrophilic signaling molecules that act as endogenpous messengers that enable and orchestrate hormetic adaptation and synaptic plasticity. Understanding how ROS’s dual role is maintained throughout the aging process and during different stages of disease is of paramount importance for the development of therapeutic strategies targeting ROS generation and detoxification [121]. The brain is particularly vulnerable to oxidative stress due to its high concentration of polyunsaturated fatty acids, limited antioxidant capacity, and elevated oxygen requirements [122]. Oxidative stress is associated with certain neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease. Oxidative stress is caused by the disparity between ROS and RNS, which encompass radicals such as H₂O₂, OH, O₂, Nitrogen dioxide radical (NO₂), and others. Several studies have reported imbalances in trace elements such as Al, Si, Zn, Cu, and Fe in Alzheimer’s disease. Oxidative stress is a pathological process associated with aging, including Alzheimer’s disease. It has been observed that oxidative stress occurs early in AD and is a major contributor to the formation of NFTs in AD [26, 54, 62, 123].

Nitric oxide synthase catalyses the conversion of arginine to citrulline, resulting in the synthesis of nitric oxide (NO). NO has the tendency to interact with O₂, resulting in the formation of peroxynitrite (ONOO). In the presence of reduced transition metals (Fe^+2⁣/+3), H₂O₂ is converted into the harmful hydroxyl radical (HO) through Fenton and/or Haber-Weiss reactions [124]. The HO radical has the potential to cause oxidative damage to lipids, proteins, DNA, and carbohydrates. Impairment of the electron transport chain (ETC) results in the failure of the antioxidant system to counteract reactive oxygen species (ROS), causing an elevation in ROS generation and subsequent neuronal damage. The coexistence of okadaic acid and oxidative stress in AD results in an upregulation of tau protein phosphorylation and neuronal demise. It is important to mention that ROS and RNS can exert either harmful or advantageous impacts on biological systems [125].

In addition to their antioxidant properties, natural substances have shown other crucial attributes in countering the advancement of AD through anti-inflammatory responses, warding off A$\beta$ aggregation, suppression of tau protein accumulation and enhancement of cholinergic signal transmission. NF-$\kappa$B inhibitors, including alkaloids like cryptolepine and tetrandrine, are therefore classified as anti-inflammatory pharmaceuticals [135]. Flavonoids, known for their capacity to inhibit inflammatory reactions, exhibit potential in countering the progression of AD. In research conducted with animal models of AD, compounds known as terpenoids, including artemisinin, parthenolide, and carnosol, have been investigated to block the NF-$\kappa$B and p38 MAPK pathways. Ginsenoside Rg1, extracted from the roots of the Ginseng plant, has demonstrated a notable capacity to effectively reduce A$\beta$ peptide levels in mice afflicted with Alzheimer’s disease (AD) [136]. Natural botanical substances, including crocin, $\alpha$-cyperone, chrysophanol, and aloe-emodin, have demonstrated the ability to inhibit the development of tau proteins and slow down the development of AD [137].

Fish Oil

Several clinical investigations have demonstrated favourable results in elderly adults with moderate cognitive impairment when they receive supplementation of long-chain omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) [179]. It’s certainly promising to see evidence of a link between higher PUFA levels and improved cognitive performance in older individuals. This aligns with a growing body of research suggesting potential benefits of PUFAs for brain health. Higher concentrations of EPA + DHA have also been linked with a decreased likelihood of developing dementia [180]. In a meta-analysis, the consumption of these fatty acids was shown to have a positive impact. Polyunsaturated fatty acids (PUFAs) are mostly incorporated into phospholipids, sphingolipids, and plasmalogens. They have a significant impact on the physical characteristics of cell membranes, including fluidity, shape, thickness, and permeability. Additionally, they influence the functioning of transmembrane proteins [181]. Research has shown that adding fish oil to the diet can be advantageous for persons suffering from most likely Alzheimer’s disease. Supplementing with this substance decreases the amount of lipoperoxides and breakdown products of nitric oxide in the blood, while hovering the ratio of reduced glutathione to oxidised glutathione. The concurrent decrease in the omega-6/omega-3 ratio in erythrocytes alongside increased GSH/GSSG and improved cognitive function adds another layer of complexity and intrigue to this puzzle. It has been observed that patients who maintain a consistent intake of DHA and EPA, both types of PUFAs, experience reduced oxidation of plasma proteins and lipids. This favourable result is significant due to the increased production of ROS linked to AD, which negatively impacts mitochondrial activity, metal equilibrium, and the degradation of antioxidant defences [182]. These factors directly affect neurotransmission and synaptic activity, which eventually leads to cognitive impairment. The production and accumulation of tau proteins that are hyperphosphorylated and amyloid are influenced by the aberrant cellular metabolism seen in AD. These factors can independently itensify mitochondrial dysfunction and further amplify ROS production, thereby maintaining a detrimental cycle that harms cognitive function (Table 1, Ref. [131, 147, 158, 172, 178, 183, 184]). The ingestion of omega-3 polyunsaturated fatty acids in individuals with AD was found to reduce the oxidation of proteins and lipids. This reduction is associated with an increase in catalase activity [183].

Table 1. Role of antioxidants in Alzheimer’s disease.

Antioxidants	Structure	Functions	References
Vitamin A		Development of brain cells.	[147]
		Strengthen of long term memory.
		Protects brain from free radicals.
		Shows therapeutic efficacy via its anti-amyloid/Tau, antioxidant, and pro-cholinergic effects.
Vitamin E		Fights against peroxyl radicals.	[131]
		Vitamin E prevents the development of hyperphosphorylated tau, a well recognised indicator of Alzheimer’s disease, via inhibiting p38MAPK.
Vitamin D3		Prevents neurodegeneration.	[158]
		Adequate amount helps to slow down ageing process.
		It induces phagocytosis to remove amyloid plaques and lowers primary cortical neurone cytotoxicity, apoptosis, and inflammatory responses.
Caffeine		Exerts its neuroprotective effects by binding to A2A receptors, that are triggered by the endogenous nucleoside adenosine.	[184]
Curcumin		It is anti-inflammatory.	[172]
		It increases the phagocytosis of amyloid-beta, effectively clearing them from the brains of patients with AD.
Ginger		Reduces inflammation.	[178]
		Shows anti-amyloidogenic potential, and cholinesterase inhibition.
Fish oil		Shows protection against beta-amyloid production, deposition in plaques and cerebral amyloid angiopathy in Alzheimer’s disease.	[183]

MAPK, mitogen-activated protein kinase; AD, Alzheimer’s disease.