Introduction

Alzheimer’s disease (AD) is a type of dementia characterized by cognitive impairment. This disease impacts brain regions especially, the hippocampus and entorhinal cortex [1]. AD is marked by extracellular plaques containing amyloid-β (Aβ-40,42) and intracellular neurofibrillary tangles(NTs) containing tau protein [2]. Aβ plaques are clumps of misshapen proteins that accumulate in the spaces between neurons. Whereas, NTs are twisted masses of tau protein that form inside nerve cells. Another hallmark of this condition is the deterioration of neural connections within the brain [3]. Furthermore, the pathology of AD is linked to both, abnormal amyloid precursor protein (APP) processing, Tau hyperphosphorylation, generating Aβ peptide and aggregation [4].

In addition to this, AD has several forms, including early-onset, late-onset, and familial AD. Early-onset AD (EoAD) is an uncommon form of illness that affects individuals below the age of 65, generally between 40 to 50 [5]. Individuals with EoAD often exhibit more Alzheimer-related brain changes, including tangles, plaques, and loss of brain volume. EoAD has been associated with a genetic defect on chromosome 14 [6]. Late-onset AD (LoAD) is the most common form, typically affecting individuals aged 65 or older. Researchers have not yet identified a specific gene responsible for LoAD. Family AD (FAD) is a less common type of AD with a known genetic link [7]. It is associated with three genes: APP located on chromosome 21, the gene for presenilin 1 (PSEN1) on chromosome 14, and the gene for presenilin 2 (PSEN2) on chromosome 1 [8].

The exact cause of AD is not fully understood. Still, some researchers suggest that dysfunction in the cholinergic system is a significant risk factor for Alzheimer’s, while others propose that changes in amyloid β-protein production and processing may be the primary trigger [9].

Moreover, genetic variances and a range of health, environmental, and lifestyle factors can play a role in the development of AD. As AD progresses, individuals may encounter memory loss, including difficulties recalling their past, diminished awareness of their surroundings, and challenges recognizing familiar individuals [10].

While there is no cure for AD, specific medications like Donepezil, Galantamine, and Rivastigmine may be prescribed to individuals in the early to mid-stages of the disease. These cholinesterase inhibitors can help mitigate some cognitive and behavioral symptoms by preventing the breakdown of acetylcholine, a crucial brain chemical for memory and cognition. In addition to medication, self-care strategies can assist in managing AD symptoms.

A report from the Alzheimer’s and Related Disorders Society of India (ARDSI) estimates that there are more than 5.3 million individuals in India living with dementia, with AD being the most prevalent form. Projections indicate that this number may increase to 7.6 million by 2030 [11]. Furthermore, according to the WHO, At present, the population exceeds 55 million individuals worldwide living with dementia, and approximately 10 million new cases are diagnosed each year [12]. Globally, AD is the most common cause of dementia, accounting for an estimated 60–70% of cases [13]. In the United States, an estimated 6.2 million people aged 65 and older are living with Alzheimer’s dementia in 2021, and this number is projected to grow to nearly 13 million by 2050 [14]. The economic impact of AD is substantial, with the global cost of dementia estimated at $1.3 trillion in 2019 and expected to rise to $2.8 trillion by 2030 [15]. This review provides a concise introduction to AD, covering its pathogenesis, biomarkers, traditional treatments, the need for novel drug delivery systems (NDDS), ongoing clinical trials, and AD-related patents.

Pathophysiology

AD is marked as the gradual accumulation of neuritic plaques (NP) & NTs [16] which are present around the brain’s meningeal, cerebral, and grey matter regions. These plaques and tangles interfere with neurotransmission by affecting neuronal cells [17]. NP is defined as round, small lesions comprised of an Aβ-peptide core. This peptide originates from a transmembrane protein called APP [18]. This is cut from APP by enzyme proteases: α, β, γ secretase [19]. This cleavage further results in the formation of Aβ 42. Furthermore, they can clump together & harm the neuronal cells [20]. In addition to this, Aβ 42 also leads to the accumulation of fibrillary amyloid protein clusters instead of normal APP degradation [21]. As, a result of this there is hyperphosphorylation of the tau protein. This further leads to tau protein aggregation & forms NTs [22]. These are twisted pairs of helical filaments that primally affect the hippocampus & cerebral cortex. As a result of this, there is an impairment in cognition functions [23].

In addition to this, in AD Acetoacetyl CoA level increases which converts into HMG-CoA with the help of HMG-CoA reductase [24]. Further, it activates the mevalonate pathway which results in the formation of Isopentenyl Pyrophosphate (IPP), Geranyl Pyrophosphate (GPP), and Farnesyl Pyrophosphate (FPP) [25]. Afterward, FPP leads to the formation of geranylgeranyl pyrophosphate (GGPP). This further promotes the formation of Ras-related C3 botulinum toxin substrate (Rac) and Ras Homologous (Rho). Finally, it leads to the oxidation of NADH [26]. This ultimately causes mitochondrial dysfunction. As a result of this, there is the formation of Reactive oxygen species (ROS) which activates microglial & causes neuroinflammation [27].

In addition to this, genetic variations are also one of the implicating reasons for the pathogenesis of AD. The genes that are mainly affected in AD include AAP on chromosome 21, Presenilin2 (PSEN2) on chromosome 1, and Presenilin1 (PSEN1) on chromosome 14 [28]. These genetic alterations result in the production and accumulation of Aβ peptide by disrupting the functioning of gamma-secretase. These mutations are responsible for approximately 5–10% of AD cases, predominantly in EoAD [29]. Besides this, the other genes that are altered in AD include Apolipoprotein E (APOE), CLU, CR1 (Complement Receptor 1), Bridging Integrator1, Sortilin-related Receptor 1, and TREM2 [30]. The genetic variation in APOE and CLU genes results in the aggregation of Aβ protein. Hence, results in impairment in the functioning of the brain [31]. Whereas, alteration in the Bridging Integrator 1 gene results inhibition of cellular processes such as endocytosis. This leads to a buildup of Aβ protein, thereby increasing the susceptibility to AD [32]. Dysregulated endocytosis contributes to the pathogenesis of AD by enhancing the production and accumulation of Aβ, disrupting cellular homeostasis, and impairing neuronal function [33]. Similarly, alterations in the SORL1 gene result from an impairment in APP processing. Hence, promotes the accumulation of tau proteins and NTs in the brain [34]. Finally, leads to an impairment in cognition functions. Whereas, alterations in the TREM 2 gene result from an impairment in the microglial function and immune response in the brain. Overall, these events result in AD (Fig. 1) [35].

Fig. 1
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Pathogenesis of AD

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Signaling Pathways

AD involves several cells’ signaling systems and metabolic pathways (Fig. 2) [36].

The Aβ aggregation pathway is a central process in AD development [37]. Decreasing Aβ production, preventing its aggregation, or promoting its clearance to change the disease’s progression [38]. It starts with APP cleavage into Aβ peptides that can aggregate into Aβ fibrils [39]. These fibrils contribute to oxidative stress, inflammation, and the formation of NTs) leading to neuronal damage [40]. Aβ plaques a characteristic of AD accumulates but smaller Aβ aggregates also play a role in disease. Aβ oligomers may interact with cell membranes or accumulate at synapses affecting synaptic proteins and glutamate receptors [41]. Microglia the brain’s primary immune cells surround these plaques forming a protective barrier and contributing to Aβ fibril clearance [42]. Additionally, degradation of acetylcholine (Ach) is accelerated leading to neurotransmitter deficiency and cognitive impairment [43]. Tau hyperphosphorylation: The tau protein when excessively phosphorylated leads to the destabilization of microtubules, a process linked to AD [44]. Tau hyperphosphorylation plays a critical role in AD by causing tau proteins to misfold and aggregate into NTs [45]. These tangles disrupt neuronal function, impairing synaptic communication and leading to cell death, which contributes to cognitive decline and memory loss characteristic of AD [46]. Alzheimer’s is marked by the buildup of amyloid plaques and tau protein clusters in various brain regions. The formation of NTs and neuropil threads results in tau phosphorylation [47]. The tau phosphorylation at Ser202/Thr205 labeling is used to determine the Braak stage based on the presence of NTs [48]. The phosphorylation of tau at Tyr18 and Thr231 in the transentorhinal region at Braak stage III/IV indicates a progressive increase with advancing Braak stages [49]. These insights imply that tau hyperphosphorylation could be a key factor in the development of AD from its early stages making it a potential target for therapeutic strategies [50].

Neurotrophic factor signaling pathway: Brain-derived neurotrophic Factor (BDNF) a type of neurotrophic factor is pivotal for maintaining synaptic plasticity a process vital for memory and learning [51]. Dysregulation of this pathway contributes to neurodegeneration and cognitive decline, highlighting its importance in the development and progression of AD [52]. This makes it a potential therapeutic molecule and diagnostic biomarker for AD [53]. BDNF-TrkB pathway, a significant signal pathway for BDNF contributes to neurodegeneration in AD, especially in brain regions like the hippocampus where BDNF expression is reduced [54]. Furthermore, the ERK/CREB signaling pathway can increase BDNF levels mitigating Aβ-induced neuronal loss and dendritic atrophy [55]. Silencing BDNF antisense RNA can also enhance BDNF, reduce Aβ-induced neurotoxicity, and improve cell viability [52]. In AD apoptosis, or programmed cell death is a key process [56]. The build-up of Aβ and hyperphosphorylated tau proteins in AD activates apoptotic pathways causing neuronal death [57]. This process is controlled by both extrinsic and intrinsic pathways involving a variety of proteins such as Bcl-2 family proteins and caspases [58]. These apoptotic components interact with growth factors and signaling molecules which include Ras-ERK, JNK, GSK-3β, BDNF/TrkB/CREB, and PI3K/AKT/mTOR [59]. Ras-ERK signaling pathway plays a role in cell cycle progression and apoptosis, while upregulation of JNK pathway in AD leads to a decrease in anti-apoptotic proteins [60]. Additionally, the PI3K/Akt/mTOR pathway regulates the balance between autophagy and apoptosis, and GSK-3β stimulates pro-apoptotic factors, leading to a dysregulation of apoptosis [61]. Drugs that target these pathways are being developed to modulate the disease condition [62].

ER stress: ER has a significant impact on AD [63]. It performs vital cellular functions such as protein folding, calcium balance maintenance, and cholesterol synthesis [64]. In AD, the build-up of Aβ peptides triggers chronic ER stress, leading to oxidative stress, calcium ion imbalance, and mitochondrial dysfunction [65]. This cycle further induces ER stress. ER stress response includes unfolded protein response (UPR), activated by accumulation of misfolded proteins like Aβ [66]. The UPR involves three stress sensors: IRE1, PERK, and ATF6 [67]. Prolonged or severe UPR activation can lead to pathological apoptotic cell death [68]. Furthermore, ER stress can induce neuronal apoptosis, with excessive oxidative stress being an ER stress inducer [69]. Insulin signaling is a key player in cognitive functions such as memory and disrupted in AD [70]. Insulin signaling plays a critical role in AD by influencing brain glucose metabolism, amyloid-beta accumulation, and tau phosphorylation [71]. Impaired insulin signaling in the brain, often termed brain insulin resistance, is associated with cognitive decline and the pathogenesis of AD. This disruption often referred to as brain insulin resistance explains the increased AD risk in diabetic patients [72]. This insulin resistance can lead to an increase in Aβ accumulation, tau hyperphosphorylation, and inflammation [71]. In AD, there are reduction in PI3K subunits and Akt kinase phosphorylation [73]. Enhancing PI3K-Akt signaling in the central nervous system through intranasal insulin treatment can improve memory [74]. The microbiota-gut-brain axis, which is believed to play a significant role in neurodegenerative conditions has been observed to be dysregulated in AD [75]. This dysregulation can lead to changes in intestinal permeability, resulting in neuroinflammation and immune dysregulation [76]. This further contributes to protein aggregation and neuronal death in the brain [77]. Further, gut dysbiosis contributes to amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance, all of which are implicated in AD [78].

NMDA pathway: NMDARs which are vital for synaptic transmission and plasticity are implicated in AD [79]. These receptors are essential for memory and learning processes [80]. In the early stages of AD, an increase in oligomeric amyloid-beta peptide is observed, which leads to NMDAR-dependent synaptic depression and elimination of spine [81]. Notch signaling pathway is a key player in vascular development and function that has been linked to AD [82]. Dysfunctional Notch signaling could contribute to the pathophysiology of neurodegenerative diseases like AD [83]. Notch intracellular domain (NICD) is released from the transmembrane by γ-secretase in signal-receiving cells, leading to the activation of canonical Notch target genes [84]. Notch receptor genes and proteins have been associated with aging, cerebrovascular disease, and AD that have potential overlapping between age-related vascular and Alzheimer’s pathophysiology [85]. The GLUT4 is an insulin-regulated glucose transporter found in various tissues including the brain, and plays a crucial role in AD [86]. It facilitates the movement of glucose from the bloodstream to parenchymal cells for metabolism [87]. Alterations in GLUT4 lead to glucose deficiency in the brain that potentially hastens cognitive decline [88]. In the hippocampus, GLUT4 translocates to the plasma membrane post-memory training [89]. Inhibiting GLUT4-mediated glucose transport can impair memory acquisition, with long-term inhibition affecting long-term memory while enhancing short-term memory [90]. This indicates GLUT4’s critical role in hippocampal memory processes [91].

Akt-GSK-3β pathway involving Akt and GSK-3β is significant in AD [92]. This pathway is crucial for neuroprotection as it promotes cell survival by encouraging cell proliferation and inhibiting apoptosis [93]. It is particularly relevant in AD due to its role in facilitating Tau protein hyper-phosphorylation [94]. GSK-3β is instrumental in the neuronal stress response affecting transcriptional activity of the cAMP response element binding [95]. This regulates the transcription of BDNF and other neuropeptides [96]. These elements are vital for long-term memory regulation and maintenance of synaptic plasticity [97]. The mTOR pathway is a key regulator of cell growth, proliferation, and metabolism, and has been linked to AD [98]. This pathway responds to environmental stimuli such as growth factors, energy state, and nutrients [99]. Increased activity of the mTOR signaling pathway is believed to contribute to AD’s major pathological processes [100]. mTOR inhibitors have shown promise in alleviating AD-like pathology and cognitive deficits in numerous animal models suggesting the potential of reducing mTOR activity as a novel therapeutic strategy for AD [101]. Oxidative stress induced by the accumulation of Aβ in AD contributes to neuronal death by damaging lipids, proteins, and DNA [102]. It also triggers apoptosis and interferes with various signaling pathways, including ERK1/2, Nrf2, RCAN1, CREB/ERK, Nrf2, PP2A, NFκB, and PI3K/Akt, leading to changes in GSK-3β expression and PP2A activity [103].

The NF-κB pathway a family of transcription factors that regulate numerous genes associated with inflammation is implicated in AD due to chronic inflammation and overactivation of the NF-κB pathway [104]. This pathway can be activated through two distinct pathways: canonical and noncanonical, with the former playing a crucial role in inflammatory responses seen in AD [105]. Extracellular Aβ induces iNOS, leading to an oxidative stress response and activation of the NF-κB inflammation pathway [106]. The multifactorial nature of AD has led to the exploration of novel targets for AD therapeutics including NF-κB signaling pathway [107]. NLRP1/3 pathway: The NLRP1 and NLRP3 are implicated in AD due to their role in inflammation [108]. In AD, these inflammasomes are activated, leading to an increase in inflammasome components and downstream effectors [109]. NLRP3 inflammasome activated in microglia by Aβ contributes to neuroinflammation [110]. Similarly, the NLRP1 inflammasome responds to Aβ aggregates leading to the activation of caspase-1 and processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) [111]. The Wnt/β-catenin pathway is crucial for cell survival and death and is implicated in AD [112]. Its loss makes neurons more susceptible to Aβ-induced apoptosis [113]. Activation of this pathway occurs when Wnt proteins bind to the Frizzled (Fzd) receptor family and Wnt co-receptor LRP5 or LRP6, leading to GSK3β inhibition and β-catenin stabilization [114]. Stabilized β-catenin then moves into the nucleus interacts with TCF/LEF and induces the expression of specific target genes [115]. Impaired Wnt signaling pathways are linked to increased Aβ levels, reduced β-catenin levels, and enhanced GSK-3β enzyme expression [116]. Wnt/β-catenin signaling also regulates adult hippocampal neurogenesis with Wnt7a playing a critical role in neurogenesis by activating Wnt/β-catenin signaling and specific downstream target genes [117].

AMPK pathway: The AMPK is a crucial controller of energy balance within cells and has significant role in managing glucose and lipid metabolism [118]. It has been proposed that AMPK may be involved in AD [119]. AMPK influences the generation of Aβ protein is a key factor in AD by adjusting neuronal cholesterol and sphingomyelin levels and controlling APP distribution in lipid rafts [120]. Furthermore, AMPK activity, which is linked to mitochondrial biogenesis and function, is found to be reduced in AD brains [121]. AMPK activation also facilitates autophagy and promotes lysosomal degradation of Aβ [122]. However, AMPK activation can also lead to non-neuroprotective outcomes, including increased Aβ generation and tau phosphorylation [123]. mTOR pathway: mTOR is a serine/threonine kinase that is integral to various cellular processes such as growth, proliferation, metabolism, protein synthesis, and autophagy [124]. mTOR activation is thought to increase Aβ generation and deposition by influencing APP metabolism and upregulating β- and γ-secretases [125]. It also inhibits autophagy, leading to a decrease in Aβ clearance [126]. Furthermore, mTOR is implicated in the pathogenesis of AD by inhibiting insulin signaling and affecting neuronal growth and plasticity as a nutrient sensor [127]. However, mTOR activation also has harmful effects, including inhibiting insulin signalling and autophagic removal of Aβ and tau aggregates [128].

Sirtuin 1 (Sirt1) pathway: SIRT1 a member of the Sirtuin family, plays a crucial role in AD by regulating processing of APP [129]. It enhances the production and activity of α-secretase, an enzyme that prevents the formation of toxic Aβ species [130]. Additionally, regions of the brain with high Aβ deposition also show increased aerobic glycolysis, which can reduce NAD+ levels and potentially affect the Sirtuin pathway [131]. Therefore, therapeutic strategies that increase SIRT1 could potentially reduce AD neuropathology by inhibiting the formation of Aβ [132]. PGC-1α pathway: PGC-1α is a key regulator of mitochondrial biogenesis which is involved in various metabolic processes and could potentially protect against AD [133]. It activates survival pathways such as the MEK/ERK and PI3K/AKT signalling pathways which prevent apoptosis in hippocampal neurons [134]. PI3Ks are a group of enzymes vital for cellular functions that have a significant role in AD through the PI3K/Akt signalling pathway [135]. This pathway regulates numerous biological processes and can inhibit several neurotoxic mechanisms, making it a potential therapeutic target for AD [136]. It influences Tau phosphorylation and amyloid cascade both crucial in Alzheimer’s progression [137]. The pathway is also linked to oxidative stress, neuroinflammation, insulin signalling alterations, and autophagy changes in Alzheimer’s [138]. HIF-1α pathway: HIF-1α is a key regulator that manages cellular reactions to low oxygen levels [139]. It has a crucial role in AD. When oxygen levels are low HIF-1α stabilizes and moves to nucleus to form a complex with HIF-1β [140]. This process is controlled by enzymes like prolyl hydroxylase (PHD) and HIF prolyl hydroxylase (HPH) which modify HIF-1α enabling it to associate with Von Hippel-Lindau (VHL) [141]. Any disruption in the autophagy process can lead to neuroinflammation and neuronal cell death, causing hypoxia and triggering various transcription factors, including HIF-1α [142].

The NRF2-ARE pathway is crucial in AD [143]. NRF2 is a transcriptional regulator that responds to oxidative stress [144]. When oxidative damage is high NRF2 moves to nucleus and binds to Antioxidant Response Element (ARE) which triggers transcription of antioxidant protector genes [145]. This pathway is involved in AD due to its dysfunction and altered localization [146]. It triggers genes that protect cells and detoxify enzyme genes which can prevent AD pathology [147]. However, in AD, buildup of Aβ and tau decreases NRF2 levels, reducing the antioxidant response [148]. This decrease in NRF2 levels leads to further accumulation of Aβ and tau by disrupting their autophagy-mediated turnover [149]. Therefore, NRF2-ARE pathway is considered a potential therapeutic target for AD [150]. PKC pathway: PKC is a group of enzymes that is essential for various cellular functions [151]. In AD, PKC enhances the production of a secretory form of amyloid precursor protein (sAPP α) by activating α-secretase activity, which decreases buildup of harmful Aβ levels in brain [152]. PKC isoforms like PKCα and -ε signalling pathways are closely linked with pathological damage in AD [153]. Activating these PKC isoforms can reduce Aβ production and related dementia in AD by enhancing APP α-processing pathways and Aβ degradation [154]. TGF-β pathway: TGF-β a transcriptional regulator is crucial in AD [155]. Under low oxygen conditions, TGF-β stabilizes and forms a complex with Smad proteins key molecules in TGF-β signalling [156]. This pathway is involved in AD due to its dysfunction and altered localization [157]. It triggers genes that protect cells and detoxify enzyme genes which can prevent AD pathology [158]. However, in AD the buildup of Aβ and tau decreases TGF-β levels reducing the antioxidant response [159]. This decrease in TGF-β levels leads to further accumulation of Aβ and tau by disrupting their autophagy-mediated turnover [160]. Therefore, the TGF-β pathway is considered a potential therapeutic target for AD [161].

JAK-STAT pathway is crucial in neuroinflammatory diseases like AD [162]. It initiates innate immunity, manages adaptive immune mechanisms, and controls the neuroinflammatory response [163]. This pathway transmits signals from receptors on cell membrane to nucleus, regulating cellular activities such as growth, differentiation, and apoptosis [164]. Any imbalance in this pathway leads to severe immunodeficiencies and malignancies, and it also plays a role in neuro-transduction and pro-inflammatory signalling mechanisms [165]. Ras/ MAPK pathway: It transmits signals from receptors on the cell membrane to the nucleus that regulates cellular activities such as growth, differentiation, and apoptosis [166]. In AD, all MAPK pathways, including ERK, JNK, and p38 pathways, are activated in vulnerable neurons, indicating their involvement in the disease’s pathophysiology and pathogenesis [167]. Oxidative stress can trigger intracellular signalling pathways including p38 MAPK signalling pathway which contributes to aggregation of Aβ and hyperphosphorylated tau protein in brain [168]. CDK5 pathway: CDK5 is a crucial member of the cyclin-dependent kinases, playing a significant role in development of a central nervous system and various neuronal activities [169]. In AD, CDK5 is closely linked with the disease’s pathogenesis [170]. When neurons are exposed to pathological stimuli, CDK5 activity increases leading to abnormal hyperphosphorylation of several CDK5 substrates like APP, tau, and neurofilament resulting in AD [171]. The imbalance of CDK5 contributes to numerous pathological events in AD from the creation of senile plaques and NTs to synaptic damage, mitochondrial dysfunction, cell cycle reactivation, and neuronal cell apoptosis [172].

Fig. 2
figure 2

Signaling pathways related to AD

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Biomarkers

A biomarker, which is also called a biological marker, is a detectable sign that gives us information about alterations occurring inside our body. These changes can be detected by measuring the increase or decrease in the level of biomarkers present in the blood, urine, or soft tissues. These studies help us to diagnose disease at an early stage [173]. The different biomarkers which are essential in the diagnosis of AD are given in Table 1.

Table I Biomarkers of AD
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Conventional Treatments

Conventional treatments for AD mainly concentrate on managing the symptoms of the condition. There is currently no cure or synthetic medication available to halt or reverse the disease’s progression [193]. The two main classes of synthetic drugs used for AD are cholinesterase inhibitors and NMDA receptor antagonists [194]. Cholinesterase inhibitors, including medications like Donepezil, Rivastigmine, and Galantamine. They work by elevating acetylcholine levels, a neurotransmitter associated with memory and cognition, in the brain [195]. These drugs aim to enhance communication between nerve cells and temporarily reduce cognitive and behavioral observed in individuals with Alzheimer’s. [196].

Whereas, NMDA receptor antagonists include Memantine which helps to regulate the activity of glutamate, an excitatory neurotransmitter [197]. It is typically used in moderate to severe Alzheimer’s cases and can provide some relief from symptoms. It is important that these medications do not modify the course of the disease [197]. Their effects can vary among individuals. While they may offer temporary improvement in cognitive function and behavior, the progression of AD continues [198]. The various Synthetic drugs used in the management of AD are discussed below in the table (Table II):

Table II Synthetic Drug Used in the Management of AD
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In addition to this, there is currently no approved herbal medication or therapy that is commonly accepted as a standard treatment for AD. Hence, the majority of the medications used in traditional treatment of the condition are synthetic. The majority of traditional methods focus on drugs such as NMDA receptor antagonists and cholinesterase inhibitors, which are designed synthetically to target particular components of Alzheimer’s symptoms [203]. Additionally, the use of herbal medicines and other complementary and alternative therapies as possible supplements to traditional medical care is the subject of the remaining research. In small-scale studies, certain herbs and compounds, such as Ginkgo biloba, Curcuma longa, Papaya, Blueberry, and Colostrinin have shown potential for maintaining cognitive function and reducing inflammation, which is linked to AD. The various herbal drugs used in the management of AD are described below in Table III.

Table III Therapeutic Products Used in the Management of AD
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The drawbacks of current and conventional treatments for various medical conditions include issues related to pharmacokinetics, bioavailability, patient compliance, and toxicity or side effects [217]. Conventional treatments often suffer from poor pharmacokinetics, leading to inadequate absorption and distribution of the drug within the body. This results in suboptimal bioavailability, where only a small fraction of the administered dose reaches the target site in an effective form [218]. Additionally, the difficulty of patient compliance is a significant concern, as many traditional therapies require frequent dosing or have inconvenient administration routes, making it challenging for patients to adhere to their treatment regimens. Moreover, toxicity and adverse side effects are common problems associated with conventional treatments, which can cause harm to patients and reduce the overall effectiveness of the therapy [219]. These limitations highlight the need for novel delivery systems that can enhance pharmacokinetics, improve bioavailability, simplify administration, and minimize toxicity, thereby offering more effective and safer treatment options.

Need for a Novel drug Delivery System and Their Mechanism of Penetration

There are several conventional treatments which have been explored by the researchers for the management of AD [220]. However, they have some limitations. For instance, they have difficulty crossing the Blood-brain barrier (BBB), which prevents them from reaching the target site [221]. Additionally, conventional treatments are associated with side effects due to their non-specific targeting or toxicity to healthy cells. Furthermore, a major limitation of herbal drugs is their low solubility and metabolism, which can limit their bioavailability and efficacy [222]. In addition, the quality and purity of herbal drugs can vary depending on the sources and preparation methods, which also affects their safety and efficacy. Also, the active ingredients in herbal drugs can interact with other medications or cause side effects such as gastrointestinal upset, dizziness, or headache [223]. Most importantly, At present, the options for treating AD are quite restricted and have shown only modest efficacy. The main classes of drugs used to treat AD are cholinesterase inhibitors and NMDA receptor antagonists [224]. However, these drugs have several limitations that make them less effective in treating AD. Cholinesterase inhibitors have limited efficacy and can cause side effects such as diarrhea, nausea and vomiting. Whereas, NMDA receptor antagonists can cause side effects such as dizziness, headache, and confusion [225]. Furthermore, these drugs do not address the underlying pathophysiology of AD, which involves different pathophysiological events such as buildup of amyloid and tau, neuro-inflammation, and neuronal injury [226].

The aforementioned limitations of the conventional treatments can be addressed by using NDDS. Advantages of using NDDS include enhanced drug efficacy, reduced side effects, prolonged drug action, better patient compliance, targeted drug delivery, protection of sensitive drugs from degradation, and overcoming biological barriers [227]. The different mechanism that helps the nanocarriers to cross BBB include the paracellular pathway, adsorption-mediated transcytosis, receptor-mediated transcytosis, and carrier-mediated pathway [228]. In passive diffusion, Nanoparticles (NPs) with high lipophilicity and small size can diffuse through BBB. This is facilitated by the lipid bilayer of the BBB’s endothelial cells, which allows lipophilic substances to dissolve and cross BBB [229]. In adsorption-mediated transcytosis, NPs with a positive charge or hydrophobic surface can adsorb to the luminal surface of the endothelial cells and induce endocytosis, followed by exocytosis at abluminal side [230]. In receptor-mediated transcytosis, NPs are conjugated with ligands that bind to specific receptors on endothelial cells which trigger receptor-mediated endocytosis and exocytosis across the BBB (Fig. 2) [231]. In carrier-mediated transport, NPs are conjugated with molecules that are substrates for transporters on the endothelial cells that utilize carrier-mediated transport to cross the BBB (Fig. 3) [232]. The various nanocarrier explored to treat AD includes VDDS, Nanoparticle (Gold NPs, Silver NPs, Copper NPs), Intranasal, Liposome, Nanoemulsion, Nano Suspension, in situ gel, Nanoparticle and SLN, and PLGA Nanoparticle.

Fig. 3
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Mechanism of drug transport

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Vesicular Drug Delivery System (VDDS)

Liposomes

Liposomes are defined by the presence of at least one lipid bilayer. This lipid bilayer forms a closed sphere that houses a cavity filled with drug. This arrangement is due to the amphipathic characteristics of phospholipids, which have hydrophilic heads and hydrophobic tails. They are being investigated as a potential method for delivering drugs to treat AD. They can carry various therapeutic molecules and cross the blood-brain barrier. Recent developments have led to liposomes that can better penetrate the blood-brain barrier, enhancing the effectiveness of Alzheimer’s drugs are discussed below [233].

Andrade et al., prepared transferrin-functionalized VB12 liposomes (VB12-Tf-LIP) by thin film hydration technique. Results of the study showed that the prepared formulation exhibited particle size below 200 nm. Thereby helping the liposomes to cross the BBB. This further helped the VB12-Tf-LIP to exhibit a 1.6-fold increase in Aβ1−42 fibril disaggregation as compared to the VB12 alone treated group. In addition to this, the prepared formulation exhibited anti-AD activity by inhibiting the Aβ fibrillation and disaggregation of preformed fibrils [234].

Similarly, Mutu et al., prepared rivastigmine liposomes by thin film hydration technique. Their activity was evaluated in the Balb-C-type mice model. The results of the study showed that rivastigmine liposomes exhibited an increase in anti-cholinesterase activity by 2.8-fold and 2.2-fold as compared to negative control and rivastigmine alone treated group, respectively. Hence, they exhibited better anti-AD activity as compared to other groups [235].

In another study, Vasileva et al., prepared α-tocopherol and donepezil co-loaded liposomes by solvent evaporation technique. Their activity was evaluated in a transgenic AD mice model. The prepared formulation showed a decrease in the number of Aβ plaques by 1.5-fold as compared to the untreated group [236].

Kuedo et al., explore the potential of ethanolic extract shrimp shells (EESS) loaded liposomes against AD. Their activity was evaluated on a thiopental-induced Wistar rat model. The result demonstrated that the prepared formulation exhibited a neuroprotective effect by modulating BDNF/TrkB, GAP-43, and PSD-95 signaling pathways. In addition, upregulated synaptic proteins. Thereby, improved cognition in the AD model [237].

Li et al. prepared Galanthamine hydrobromide-loaded liposomes against the AD model by the thin-film homogenization method. Their in vivo activity was checked on the Male Sprague–Dawley rats. The result of the prepared formulation showed a 7-fold decreased in the acetylcholinesterase activity in the diseased group [238].

Niosomes

Niosomes are vesicles formed by non-ionic surfactants and cholesterol for targeted drug delivery. They are structurally similar to liposomes but offer greater stability. They can encapsulate both water-soluble and fat-soluble drugs making them ideal for various applications in drug delivery systems. They can encapsulate various therapeutic agents and cross the blood-brain barrier [239]. Various niosomes that are being studied as a potential delivery system for AD treatments are mentioned below.

Kulkarni et al., formulated N-Acetyl Cysteine niosomes by ethanol injection method. Their activity was evaluated on Male Wistar rats. Results showed that the prepared formulation exhibited a 1.2-fold increase in nasal permeation as compared to unprocessed N-Acetyl Cysteine. Furthermore, the prepared formulation exhibited a 1.3-fold decrease in AChE level as compared to untreated group [240].

Similarly, Moulahoum et al., prepared carnosine-loaded niosome Against AD. The prepared formulation exhibited a neuroprotective effect by exhibiting antioxidant and anti-AOPP activity. In addition, it was observed from the study that the carnosine-treated group exhibited a 2.1-fold decrease in AoPP level as compared to the carnosine-treated group [241].

In addition, study Ansari et al., explore the potential of Artemisia absinthium loaded niosomes against AD. The formulation was prepared by thin hydration techniques. The result of the study showed that Artemisia absinthium noisome exhibited a neuroprotective effect by decreasing aggregation of Aβ proteins and neurofibril tangles at the desired site [242].

Exosome

Exosomes are tiny vesicles ranging from 30 to 150 nm in diameter. They can carry genetic material and proteins from their parent cells. They are particularly useful in cancer detection as they can contain relevant information from cancer cells. As potential drug delivery tools, exosomes offer low immunogenicity, the ability to cross the blood-brain barrier, and the flexibility to encapsulate various therapeutic agents, thereby extending their half-life and stability [243]. Studies related to exomes for the management of AD are given below.

Chen et al., isolated exosomes from mesenchymal stem cells (MSC-exosomes). Their activity was examined on the J20 mouse model. The result of the study showed that the prepared formulation exhibited a 2-fold improvement in cognition as compared to the disease group. Also, reduce the Aβ plaque to 5-fold in Tg- exosome treated group as compared to the diseased group animals [244].

Similarly, Zaldivar et al., isolated exosomes from Mesenchymal stem cells, and their activity was examined in the C57BL/6 AD mice model. The result of the study showed that the prepared formulation exhibited a 1.6-fold increase in novel object activity as compared to the negative control group. Overall, the results of the aforementioned activity revealed improvement in learning and memory in the MSCs exosome-treated group [245].

Cui et al., isolated rabies viral glycoprotein (RVG) exosomes from the Mesenchymal stem cells (MSCs), and their activity was examined on the APP/PS1 double transgenic mice. The result of the study showed that the prepared formulation exhibited a 1.4-fold increase in the Morris water maze test as compared to the diseased group. Overall, the result showed a 2-fold decrease in the formation of plaques in MSC-RVG-Exo treated group [246].

In another study, Sheykhhasan et al., isolated Q10-loaded exosomes from adipose-derived stem cells (ADSCs-Exo) and their activity was examined on the STZ-induced Wistar rats. The result of the study showed that the prepared formulation exhibited improvement in cognition by learning and memory as compared to the untreated. In addition, exosomes, exhibited anti Amyloid beta effect, antioxidant and anti-inflammatory action in the brain, and produced a neuroprotective effect [247].

Similarly, Jahangard et al., isolated exosomes from the Mesenchymal stem cells that contain miR-29, and their activity was examined in the male Wistar rats. The result shows that the prepared formulation showed a decrease of 1.5-fold in the Aβ as compared to the diseased group. Overall, the study showed increased learning and memory in the AD model [248].

Transferosome

Transferosomes are unique, deformable vesicular structures composed of phospholipids and an edge activator, which allow them to navigate through small pores. They are used for both local and systemic drug delivery due to their high encapsulation efficiency, ability to act as a reservoir for gradual drug release, and protection of the drug from metabolic breakdown. They can also deliver drugs through the nasal route, bypassing the blood-brain barrier and enhancing bioavailability [249]. The several studies reported for the management of AD are discussed below.

Raj et al., prepared curcumin-loaded transferosome-based In-Situ Gel by the thin film hydration method. The in vivo study was performed on the Swiss albino mice. The result of the study showed that the prepared formulation increased the 2-fold concentration of the drug in the brain as compared to the curcumin IV formulation. This study showed that the prepared In-situ gel formulation increased BA in the brain. Hence, transfersome can be used in the management of the AD [250].

In another study, Mishra et al., prepared Berberine and curcumin co-loaded transferosomes by film hydration method against the AD model. Their activity was checked on the Swiss albino mice. The result of the study showed that the prepared formulation decreased the 4-fold AChE in the BBR-CUR-TRANS treated group as compared to the control group. Overall, the study showed an improvement in memory in the AD mice model [251].

Similarly, Nojoki et al., prepared chitosan-transfersulin (CTI) transfersome by the film hydration method against the AD model. An in vivo study of the prepared formulation was performed on the STZ-induced Wistar rats. The result of the study showed that the prepared formulation-treated group exhibited a 1.5-fold increased in latency as compared to the diseased group. Additionally, the Histopathological evaluation of the study indicated a decrease in the level of CA1, CA3, and DG in CTI treated group by 2-fold, 3.6-fold, and 2.5-fold respectively as compared to the control group [252].

Ethosomes

Ethosomes are nanoscale carriers composed of phospholipids, ethanol, and water, designed for delivering substances through the skin. They can encapsulate and deliver both lipophilic and hydrophilic drugs efficiently. They are stable, approved for pharmaceutical use, and can be incorporated into different formulations like gels and creams [253]. Studies that have explored the use of ethosomes as a type of nanoscale carrier in Alzheimer’s treatment are mentioned below.

Shi et al., prepared ligustrazine phosphate-loaded Ethosomes (LP-Ethosomes), and examined its activity in the male Sprague–Dawley rats. The result of the study showed that the LP-Ethosomes treated group indicated a decrease in escape time by 2.5-fold as compared to the control group. the ethosomal-treated group exhibited an increased in MDA activity by 0.93-fold as compared to the control group. Overall, the study showed that prepared formulation is effective in treating AD [254].

Phytosomes

Phytosomes are a type of advanced drug delivery system that encapsulates plant-based bioactive compounds with phospholipids, forming a cell-like structure. This unique structure enhances the pharmacokinetic and pharmacodynamic properties of the herbal extracts leading to increased bioavailability. Phytosomes enhance the potency, quality, and precision of treatments. Additionally, it shields the components of herbal extracts from degradation by digestive fluids and gut bacteria [255]. Studies reported so far for the AD treatment are given below.

Wattanathorn et al., prepared mulberry fruit and ginger (PMG) loaded Phytosome. Their activity was evaluated on the male Wistar rats. The result of the study showed that the prepared formulation decreased 1.5-fold in the Morris Water Maze test which resulted the improved memory as compared to the diseased treated group. Also, PMG Phytosome increased 1.4-fold in the locomotor as compared to the induced group. Thus, the study showed that the prepared formulation will be effective in the neuroprotectant effect [256].

Similarly, Ullah et al., prepared curcumin-loaded phytosomes. Their activity was examined on the GFAP-IL6 mice AD model. The result of the study showed that the prepared formulation decreased 1.4-fold Iba-1 + microglia in the hippocampus as compared to the normal food-fed GFAP-IL6 group. Furthermore, it also decreased 1.3-fold of TSPO + microglial cells in the hippocampus as compared to the normal food-fed group. This indicated the neuroprotective effect of the prepared formulation [257].

in vitroCubosomes

Cubosomes are lipid-based NPs that form a 3D cubic lattice. They can encapsulate and deliver a wide range of therapeutic agents, including both hydrophobic and hydrophilic drugs. Their unique structure provides stability, controlled drug release, and protection against degradation. By adjusting the lipid composition and surface modifications, drug release kinetics can be modulated, enhancing therapeutic efficacy and reducing side effects [258]. Studies related to cubosomes for the management of AD are given below.

Elnaggar et al., prepared monoolein cubosomes co-loaded piperine which are modified by the Tween (T-cubs). Their in vivo activity was examined in male Wistar rats. The result of the study showed that the prepared formulation showed an increase of 4.7-fold in the latency test as compared to the positive group. Further, T-cubs also decreased 3.8-fold in the AChE activity as compared to the diseased group. Overall, the result showed that the prepared formulation is effective against AD [259].

Wu et al., prepared cubosomes which are modified by Odorranalectin (OL-Cubs) against the AD, and examined their anti-AD activity on the Sprague-Dawley rats. The result of the study showed that the prepared formulation showed an improved in escape latency by the 2-fold as compared to the AD group in the water maze learning test. The overall study concluded that the OL-Cubs was effective for the improved learning impairment in AD [260].

Nanoparticles (NPs)

NDDS utilize NPs to enhance the delivery and effectiveness of therapeutic agents. These systems aim to control the size, surface properties, and release of active pharmaceutical ingredients for optimal therapeutic effect. NPs can reduce side effects and are prepared using various techniques. The field of nanomedicine is advancing rapidly, with nano-delivery systems serving as diagnostic tools and delivering therapeutic agents to targeted sites. These nanoparticle-based systems could potentially address the challenges of conventional therapies and contribute to improved clinical outcomes [261].

Gold NPs (AuNPs)

AuNPs are increasingly being used in NDDSs due to their biocompatibility and adaptable surface. These properties allow for the addition of bioactive ligands, enhancing drug stability and efficacy, and enabling drugs to cross the blood-brain barrier [262]. Recent studies showing promises in treating AD are described below.

Zhang et al., prepared tetrapeptide-anchored gold NPs and analysed their effect on the Kun Ming (KM) mice model against the AD. Results of the study showed that the prepared formulation of AuNPs exhibited an antioxidant effect by increasing the level of SOD, GSH, and catalase and increased the level of AChE in the brain. Hence, improved cognition and managed AD [263].

Hou et al., prepared AuNPs of chiral L- and D-glutathione and examined their activity on the KM mice model against the AD. Results of the study showed that prepared formulation improved memory by 2-fold as compared to AD group. Furthermore, the prepared formulation decreased Aβ plaque deposition in the brain. This indicated the effectiveness of the AuNPs against AD [264].

Tramontin et al., prepared AuNPs for the treatment of AD. They examined their activity in the Okadaic acid (OA) induced male Wistar rats model. Results of the study showed that the prepared formulation improved memory by 1-5-fold as compared to the diseased group. Overall, the Study showed that prepared formulation improved cognition and decreased oxidative stress. Hence, effective against the AD mice model [265].

Poly (lactic-co-glycolic acid) NPs (PLGA NPs)

PLGA NPs are a promising area of research in NDDS, particularly for neurodegenerative diseases. Their biocompatibility, non-toxicity, and various benefits such as improved drug solubility, protection from enzymatic digestion, increased targeting efficiency, and enhanced cellular internalization make them an attractive option. Despite their potential, no PLGA NPs are currently on the market or in clinical trials for neurodegenerative diseases and are only at the preclinical stage [266]. Some of the preclinical studies supporting PLGA for management of AD are mentioned below.

Lopez et al., prepared Memantine polylactic-co-glycolic nanoparticle (MEM–PEG–PLGA) NPs and examined its in vivo activity on the Male APPswe/PS1dE9 (APP/PS1) and C57BL/6 mice. Results of study showed that the MEM–PEG–PLGA NPs treated group exhibited an increased in the latency by 2.5-fold as that of the untreated group. Additionally, the prepared formulation exhibited a decreased in the level of Aβ plaques and Tau proteins in the brain as compared to the untreated group. Overall study, indicated the anti-AD potential of the developed formulation in the diseased mice [267].

Abreu et al., prepared PGZ-loaded NPs (PGZ-NPs) by the solvent displacement technique against the AD. They examined their activity in the male APP/PS1 mice. Results of the study showed that the prepared formulation decreased 2.5-fold of the Aβ burden as compared to the diseased group. This indicated that the PGZ-NPs improved cognition and were effective against the AD in mice model [268].

Jeon et al., prepared Vitamin D-binding protein (DBP) PLGA NPs by the emulsion diffusion method and investigated its in vivo activity on a 5XFAD AD mice model. The result of the study showed that the prepared formulation exhibited improvement decreased by 1.3-fold in a cognition-treated group compared to the disease group. Additionally, the DBP-PLGA NPs exhibited treated group decreased Aβ aggregation and reduced neurodegeneration. The overall study indicated that the prepared formulation is effective against AD [269].

Xu et al., prepared rhynchophylline-loaded mPEG-PLGA NPs coated with Tween 80 (T80-NPS-RIN) by nanoprecipitation method against the AD model. They investigate their in vivo activity on the C57BL/6 mice and male Sprague-Dawley rats. Results of the study showed that prepared formulation has a neuroprotective effect against AD by decreasing inflammation, oxidative stress, and tau protein in the brain [270].

Vilella et al., fabricated the Polymeric NPs (g7-NPs-Zn) against the AD model and evaluated their anti-AD activity on the APP23 mice. Results of the study showed that the prepared formulation decreased the Aβ plaques by 1.2-fold as compared to the saline group. Furthermore, g7-NPs-Zn reduced the IL-6 by 3-fold as compared to the diseased group. Thus, the study concluded that the prepared formulation was an effective formulation against AD [271].

Silver NPs (AgNPs)

AgNPs are gaining attention for their potential role in AD treatment. Produced through environmentally friendly methods, these NPs exhibit properties that enable them to cross the blood-brain barrier, a significant hurdle in brain disease treatment. They have demonstrated an ability to improve drug stability and efficacy, making them suitable carriers for Alzheimer’s drugs. Additionally, their antioxidant and anti-diabetic properties could also be beneficial in managing Alzheimer’s [272]. Studies related to AgNPs for the management of AD are given below.

Zhang et al., prepared N. khasiana leaf extract-based (AgNPs) and evaluated its Anti- AD activity in the male Wistar rats. Result of study showed that prepared formulation decreased the Barnes Maze Task by 1.2-fold as compared to the negative control group which improved memory. Finally, this study indicated that the AgNPs will be effective in cognition impairment and managing AD [273].

Ittiyavirah et al., prepared an Ethanolic extract based Boerhaavia diffusa AgNPs (AgNPsBD) against the AD mice model and investigated their anti-AD activity in the male Wistar albino rats. Result of the study showed that prepared formulation exhibited an increase of 1.5-fold Morri’s water maze test activity as compared to the diseased induced group. This indicated the Enhancement in the ability to learn and remember spatial information in rodents. Also, AgNPsBD increased GSH level by 1.4-fold as compared to the AD group. Overall, the study showed that the formulation is effective against AD [274].

In another study, Ramshini et al., explored the AgNPs against the AD in Wistar rat model. Result of the study indicated a decrease in the escape latency by 2.2-fold & and 2.4-fold as compared to scopolamine & and lysozyme-treated group. In addition to this, AgNPs also exhibited improvement in memory and spatial learning by inhibiting amyloid fibrils-induced neurotoxicity. Overall event, indicated the potential of AgNPs against AD [275].

Cerium Oxide NPs (CNPs)

CNPs are a type of nanomaterial with significant potential in various fields. They are known for their biomimetic activities, including acting as superoxide dismutase, catalase, and more. Two forms exist: CeO2 and Ce2O3, with CeO2 being more stable and commonly used. CNPs have antioxidant properties due to the self-regeneration of their surface which involves redox-cycling between cerium’s 3+ and 4+ states. They are used in biomedical applications, such as treating bacterial infections, and have potential in biology and medicine [276].

Danish et al., synthesized Cerium oxide NPs (CNPs) by homogenous precipitation method against the AD and investigated their anti-AD activity on the female Wistar rats. Result of study showed that prepared formulation improved memory in the MWT escapes latency by 1.4-fold as compared to AD-induced group. Also, CNPs increased SOD and GSH activity by 2.7-fold and 4-fold as compared to Scopolamine group respectively [277].

Similarly, Hu et al., synthesized cerium dioxide NPs (LMC) and loaded them with Resveratrol (LMC-RES) against the AD mice model and explored their activity on the 5xFAD mice. Result of study showed that prepared formulation increased GSH level by 3-fold and SOD level by 4-fold as compared to Aβ induced group. LMC-RES also decreased the Aβ 1–42 concentration by 1.3-fold as compared to diseased group. Overall, study concluded that LMC-RES have antioxidant properties, reduced ROS, protected neurons, and improved cognition in AD [278].

In another study, Wahle et al., synthesized cerium dioxide (CeO2 NPs) against the AD and examined their anti-AD activity on the 5xFAD transgenic mice. Result of study showed that prepared formulation decreased the plaque load percentage by the 1.3-fold as compared to control group in hippocampus. Overall study concluded that CeO2 NPs was effective against the AD [279].

Zinc Oxide NPs (ZnO NPs)

ZnO NPs are unique nanomaterials with diverse applications. They are known for their distinct optical and chemical properties, which can be adjusted by changing the NPs’ morphology. ZnO NPs are commonly used in electronics and optoelectronics. They also have potential in biomedicine and biotechnology, including enhancing plant growth and productivity, managing diseases, and serving as an antimicrobial agent [280].

Abdulmalek et al., prepared zinc oxide NPs (ZnONP), and evaluated their activity on the male Wistar rats. Result of study showed that the prepared formulation decreased Aβ-42 by 4.2-fold as compared to the STZ-induced group. Also, it improved AChE activity by 7.4-fold as compared to diseased group. Overall study indicated the effectiveness of ZnOPN against neurodegenerative disorders [281].

Similarly, Kesmati et al., explored cognitive potential of ZnO NPs was evaluated on male NMRI mice. Results of study showed that prepared formulation exhibited improvement in locomotor activity by 1.2-fold as that of the untreated group. In addition to this, the ZnO NPs treated group also showed an increase in step-down latency time by 1.3-fold as compared to untreated group. Hence, it indicated the effectiveness of the developed formulation against AD [282].

Selenium NPs (SeNPs)

SeNPs are nanomaterials that have attracted attention due to their biocompatibility, bioavailability, and minimal toxicity. They are derived from selenium salts using reducing agents. SeNPs are recognized for their distinct optical and chemical properties and have applications in electronics and optoelectronics. In biomedicine and biotechnology, they show potential in promoting plant growth, disease management, and as antimicrobial agents [283].

Gholamigeravand et al., prepared Selenium NPs (SeNPs) by chemical Precipitation method against the AD model. They examined their activity on the male Wistar rats. Result of study showed that prepared formulation decreased Aβ plaques in brain by 1.1-fold as compared to STZ-induced group. Furthermore, SeNPs improved memory by 1.2-fold as compared to diseased group. Thus, the study concluded that prepared formulation was effective against AD [284].

In another study, Ji et al., prepared Se-loaded chondroitin sulphate (CS@Se) NPs against the AD and evaluated their anti-AD activity on the SPF-grade male C57BL/6 mice. Result of study showed that prepared formulation improved memory by 1.5-fold in MWT as compared to AD model group. Furthermore, CS@Se NPs treated group showed an increase in GSH level by 13-fold as compared to the diseased group [285].

Sun et al., prepared chiral penicillamine Se-NPs (L-/D-Pen@Se NPs) against AD and investigated their in vivo activity on the APP/PS1 transgenic mice. Result of study showed that prepared formulation improved memory in MWT by 1.4-fold as compared to AD group. Overall, study showed that the L-/D-Pen@Se NPs improved the cognitive impairment in AD [286].

Micelles

Micelles are colloidal particles formed from surfactant molecules in a liquid. They are typically spherical, with hydrophilic heads facing the solvent and hydrophobic tails in the center. This formation occurs spontaneously when the surfactant concentration exceeds the critical micelle concentration. Micelles have diverse applications, including in electronics, optoelectronics, and biomedicine. They can enhance plant growth, manage diseases, and serve as antimicrobial agents [287].

In another study, Hagl et al., evaluated anti-AD effect of curcumin-loaded micelles (CMI) on Male C57BJ/6-Thy1-APP751SL mice. Result of the study showed a decrease in Aβ40 level in the CMI-treated group by 2.8-fold as that of placebo group. Further, CMI treated group exhibited an increase in the level of ATP by 1.2-fold as compared to placebo group [288].

Yang et al., prepared the micelles that targeted the neuronal mitochondria (CT-NM) against AD and investigated their anti-AD activity on the ICR mice, nude mice, and SD rats. Result of study showed that CT-NM decreased the level of Aβ by 3-fold as compared to the diseased group. Further, the prepared formulation increased the level of the SOD and GSH by 2.1-fold and 2-fold respectively. Hence, the prepared formulation was a potential method for the treatment of AD [289].

Dendrimers

Dendrimers are highly structured, branched polymers with a typically spherical 3D shape. They are symmetric around the core and are also known as arborols or cascade molecules. Dendrimers are unique due to their structural perfection, usually being monodisperse and highly symmetric. They have diverse applications, including in biomedicine and biotechnology, where they can enhance plant growth, manage diseases, and serve as antimicrobial agents [290].

Gothwal et al., prepared rivastigmine (RIV) loaded dendrimeric (PAMAM-Lf-RIV) against the AD mice model. Their activity was examined on the Wistar rats. Result of study showed that prepared formulation improved memory by 1.2-fold as compared to control group. Overall, the study concluded that PAMAM-Lf-RIV was an effective formulation against AD [291].

In another study, Gothwal et al. prepared PAMAM-LF-loaded memantine (MEM-PAMAM-Lf) dendrimers. Their in vivo activity was evaluated against AD-induced mice. The result of study showed that prepared formulation decreased 1.4-fold AChE activity as compared to AL-induced group. Overall, the study concluded that the MEM-PAMAM-Lf improved memory, and a promising approach against AD [292].

Klementieva et al., prepared Poly (propylene imine) (PPI) glycodendrimers against AD mice model and investigated their anti-AD activity in APP/PS1 transgenic mice AD model. Result of study showed that G4mDS treated group exhibited a decreased in total amyloid burden, fibrillar amyloid burden, aggregation index, and soluble Aβ level by 1.5-fold, 1.3-fold, 1.7-fold, and 1.8-fold of that of untreated group, respectively [293].

Nanoemulsion

Nanoemulsions, also known as mini emulsions, are stable dispersions of liquid within another liquid, with droplet sizes around 100 nm. Their small size results in properties such as high surface area, stability, transparency, and adjustable rheology. They are formed by shearing a mixture of two immiscible liquids (like oil and water), surfactants, and possibly co-surfactants. They can be oil-in-water or water-in-oil, depending on the core particle. Nanoemulsions are used in areas like drug delivery, food, cosmetics, pharmaceuticals, and material synthesis [294].

Song et al., prepared the Osthole loaded nano emulsion (OST-NE) against the AD mice model. Their anti-AD activity was examined in the Scopolamine-Induced Kunming mice. The result of study showed that prepared formulation improved memory by 3.7-fold as compared to the diseased group. The OST-NE also increased the SOD activity by 1.1-fold as compared to the Scopolamine-induced group. Thus, OST-NE was an effective AD [295].

Furthermore, Alaqeel et al., prepared the quercetin-loaded nano emulsion (QCNE) against the AD. They investigated their anti-AD activity against the albino male rats. The result of study showed that prepared formulation increased SOD and GSH activity by 1.4-fold and 1.9-fold as compared to AD group respectively. Furthermore, QCNE decreased the level of IL-1β & TNF-α by 1.8-fold and 2-fold as compared to the diseased group. Thus, QCNE indicated the potential against neuronal disease [296].

Ismail et al., prepared the thymoquinone-rich fraction nano emulsion (TQRFNE) against the AD. They examined their anti-AD activity on the Sprague-Dawley rats. Result of study showed that prepared formulation decreased the BACE1 and RAGE levels by 2-fold and 1.7-fold in hippocampus respectively. This indicated the reduction of Aβ secretion in brain. Furthermore, TQRFNE also decreased the level of Aβ40 and Aβ42 in hippocampus and was effective against AD [297].

Beniwal et al. fabricated the citral Nanoemulsion (N-Citral) against the AD model and examined their anti-AD activity on the male rats model. The result of study showed that prepared formulation improved memory by 4-fold as compared to the AD-induced group. While N-Citral decreased the level of MDA by 1.2-fold as compared to diseased group. It indicated that the N-Citral was effective against the neurodegenerative disease [298].

Nanostructured Lipid Carriers (NLCs)

Nanostructured Lipid Carriers (NLCs) are lipid NPs made from a blend of solid and liquid lipids. They remain solid at room and body temperatures. As the second generation of lipid NPs, NLCs were developed to address the limitations of the first generation, such as restricted drug loading and drug leakage during storage. NLCs have diverse applications due to their unique properties. They have potential in biomedicine and biotechnology, including enhancing plant growth, disease management [299].

Shehatae et al., prepared Donepezil and Astaxanthin co-loaded NLCs (DPL/AST–NLCs) by the hot high-shear homogenization technique against AD rats model examined their anti-AD activity on the male albino rats. Result of the study showed that prepared formulation improved memory in the MWT by 3.6-fold as compared to the AD group. Furthermore, DPL/AST–NLCs decreased Aβ1–42 by 4.3-fold as compared to diseased group. In addition to this, DPL/AST–NLCs also decreased inflammation, and oxidative stress, and improved cognitive impairment [300].

In another study, Shehata et al., fabricated Astaxanthin loaded NLCs (AST–NLCs) by the hot high-pressure homogenization (HPH) technique against AD rat model. They investigated their activity on male albino rats. The result of study showed that prepared formulation improved memory in MWT by 2.6-fold as compared to AD group. Furthermore, the prepared formulation decreased Aβ1–42 content by 3-fold as compared to the diseased group. Overall, the study concluded that AST–NLCs indicated the potential against AD [301].

Anand et al., prepared NLC loaded with the rivastigmine hydrogen tartrate (RHT-NLCs). They examined their In-vivo activity on the albino Wistar rats. The result of study showed that prepared formulation improved memory by 2.9-fold as compared to the negative control group. Overall, study concluded that RHT-NLCs were an effective formulation against AD [302].

Solid Lipid NPs (SLNs)

Solid Lipid NPs (SLNs) are lipid NPs composed of a solid lipid core that can encapsulate both water-soluble and fat-soluble active pharmaceutical ingredients. Typically spherical, their size ranges from 10 to 1000 nm. SLNs have unique properties that make them useful in various fields. They have potential in biomedicine and biotechnology, including enhancing plant growth, disease management [303].

Shivananjegowda et al., prepared Memantine Hydrochloride (MeHCl) and Tramiprosate (TMPS) co-loaded solid lipid NPs (SLNs) against the AD. Their activity was examined on the Albino Wister Rats. Result of study showed that prepared formulation improved memory by 3-fold in escape latency test as compared to AlCl3-induced group. Also, M + T SLN reduced the Aβ level in AD mice model as compared to diseased group. Overall, study shows the M + T SLN was effective the AD [304].

Similarly, Saini et al., demonstrated ferulic acid SLNs coated with chitosan by the hot homogenization technique against AD and investigated their activity in the STZ-induced Wistar rats. The result of the study showed that prepared formulation promoted an increase in level of GSH, SOD, and Catalase. Furthermore, it reduced the level of AChE. Thereby managed the neurodegeneration and cognition in the AD [305].

Dara et al., fabricated Erythropoietin SLN (EPO-SLN) by the double-emulsion method and examined the activity on the Albino Wistar male rats. Result of study showed that prepared formulation exhibited a reduction in Aβ plaques by 6.5-fold as compared to diseased Aβ induced group. Also, EPO-SLN decreased ROS by 1.5-fold as compared to the diseased group. Overall, study shows that EPO-SLN was effective against neurodegenerative disorders [306].

In another study, Campisi et al., prepared the curcumin SLNs-loaded (SLNs-CUR) by solvent evaporation method against the AD model and examined their activity on the TgCRND8 (Tg) mice. The result of the study showed that the prepared formulation improved memory by 9-fold in Morris water maze test as compared to untreated group [307].

Carbon Nanotubes (CNTs)

Carbon nanotubes (CNTs) are minuscule tubular structures made of carbon atoms, with a diameter much smaller than a strand of human hair. Their small size, strength, and ability to be functionalized with various biomolecules make them ideal for targeted delivery to specific cells or tissues. They possess a high surface area and robust adsorption capabilities, which allow for high drug-loading capacity. This makes them a key component in nano-drug delivery systems. They can also penetrate cells, delivering drugs directly to the cytoplasm or nucleus. In the case of neurovascular disorders, CNTs can potentially deliver drugs across the blood-brain barrier [308].

Yang et al., evaluated the potential of single-walled carbon nanotubes (SWCNTs) against AD in the Kunming mice. Result of study showed that prepared formulation exhibited improvement in memory by 1.1-fold as compared to AD group. Furthermore, it reduced level of AChE and effective against AD [309].

Xue et al., evaluated potential of single-walled carbon nanotubes (SWNT) against AD and examined the activity on the CRND8 mice. Result of study showed that prepared formulation decreased p-ULK1/t-ULK1 by 1.7-fold as compared to untreated group. Overall, the study shows that SWNT has a neuroprotective effect against AD therapy [310].

Ranjan et al., evaluated potential of carbon nanotubes (CNTs) against AD model and examined their activity in Male Wistar rats. The result of study showed that the prepared formulation decreased the level of Ascorbic Acid by 2.1-fold, 1.8-fold, and 1.3-fold in brain which enhanced memory. Thus, CNTs are an effective approach for the treatment of the animal model of AD [311].

Hydrogel

Hydrogels are three-dimensional polymeric networks capable of absorbing large amounts of water and biological fluids are increasingly used in drug delivery due to their unique properties and biocompatibility. They can encapsulate a wide range of drug molecules and control their release over time. Their responsiveness to specific triggers such as pH, temperature, or enzymes allows for targeted drug delivery, reducing potential systemic toxicity. Hydrogels can be formed into various shapes and sizes, enhancing their versatility [312].

Ribeiro et al., prepared Curcumin-loaded mesoporous silica NPs (MSN-CCM) Hydrogel (HG@MSN-CCM) against the AD and examined their anti-AD activity on the STZ-induced mice female Swiss albino mice. Result of study showed that prepared formulation showed that prepared formulation improved memory in open field test by 4.5-fold as compared to negative control group. Thus, Study shows the HG@MSN-CCM improved cognition and acted as a potential formulation against AD [313].

Similarly, Ou et al. examined the therapeutic effect of Timosaponin BII-loaded hydrogel (ISGs) on scopolamine-induced AD mice. Result of the study showed that ISGs treated group increased cholinergic M1 receptor in hippocampus of mice by 2-fold as compared to untreated group [314].

Chen et al., prepared timosaponin BII loaded in situ hydrogel (ISG) against the AD and evaluated their in vivo activity against the C57BL/6J mice. Result of study showed that prepared formulation improved memory in the platform crossing test by 1.4-fold as compared to model group. Further, T BII-ISG improved the distance covered in open field test by 1.1-fold as compared to AD model group. Thus, study concluded the effectiveness of the developed formulation against AD [315].

In another study, anti-AD effect of galantamine loaded hydrogel (Gal) was evaluated on streptozotocin-induced AD Wistar rats. The result of study showed increased in the body weight of rat in Gal treated group by 1.4-fold as that of untreated group. Further, increased escape latency was also observed in Gal treated group by 1.3-fold as compared to untreated group [316].

Few other NDDS formulation studies for the management of AD are discussed in Tables IV and V. Industrial applications and clinical applications for the treatment of AD for various delivery systems are discussed in Table IV. Additionally, Clinical trials, ongoing clinical trials, and patents related to AD are mentioned in Tables VI and VII, and Table VIII, respectively.

Table IV Industrial Applications and Clinical Applications for the Treatment of AD for Various Delivery Systems
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Table V Nano-Drug Delivery Systems for AD
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Table VI Clinical Trials Studied for the Treatment of AD
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Table VII Ongoing Clinical Trials for the Management of AD
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Table VIII Patents Related to AD
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Future prospective

Research on AD is advancing across multiple fronts. In terms of early detection and diagnosis, ongoing efforts are focused on developing more accurate and accessible methods, including biomarkers, imaging techniques, and blood tests, to identify signs of the disease before symptoms appear. Researchers are exploring the concept of precision medicine, tailoring Alzheimer’s treatments based on individual genetic and molecular profiles to optimize effectiveness and minimize side effects. In drug development, numerous trials are underway with a focus on medications capable of decelerating or stopping the progression of disease by targeting specific biological processes such as accumulation of beta-amyloid plaques and tau tangles. Non-pharmacological studies, such as lifestyle modifications, cognitive training, and physical exercise, are being investigated for their potential in preventing or delaying Alzheimer’s onset and managing symptoms. Technology, such as wearable devices and smartphone apps, is being explored to monitor and assess cognitive function, providing valuable data for early detection and disease management. Global collaboration among researchers, healthcare professionals, and organizations is deemed crucial, fostering initiatives and partnerships to pool resources, share data, and accelerate progress. There is a growing emphasis on public awareness and advocacy to reduce the stigma associated with AD with governments and organizations working on policies to support research funding, caregiver support, and improved healthcare access. Staying updated on the latest research findings and breakthroughs is essential, given the dynamic and continuously evolving nature of the field, with reliable sources like scientific journals, health organizations, and research institutions recommended for the most current information.