Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder that is responsible for most cases of dementia ^[1]. Besides the environmental and genetic factors, which are presupposed to contribute to AD etiology, there are numerous hypotheses which have been elucidated to attempt to explicate AD. The most prevalent hypotheses are the Aβ cascade hypothesis, the inflammation hypothesis, the cholinergic hypothesis, the tau hypothesis, and the oxidative hypothesis ^[2][3][4]. The Aβ cascade hypothesis implicates Aβ peptides as the AD causative agent due to the extracellular deposition of the Aβ peptides as senile plaques, with the neurofibrillary tangles resulting in neuronal loss, dementia, and vascular damage ^[5]. Neurofribrillary tangles are also considered an AD hallmark and principally consist of tau, which is a microtubule-associated scaffold protein ^[6]. The aggregation of tau impairs the axons, leading to neurodegeneration ^[7]. Currently, the inflammation hypothesis has gained prominence as one of the major AD pathological factors, encompassing the immune response sustained in the brain ^[8]. Continuous activation of the brain’s immune cells, such as microglia, leads to the release and production of various proinflammatory cytokines, which aids tau and Aβ pathologies and leads to the loss of neurons ^[8]. Damage to the cholinergic neurons has also been accepted as a critical pathological chance associated with AD-related cognitive impairment ^[9]. As such, the cholinergic hypothesis proposes that cholinergic neuronal dysfunction in the brain could substantially contribute to the AD-related cognitive decline ^[9]. In general, this hypothesis is supported by the usage of cholinesterase inhibitors in the treatment of AD ^[10]. Furthermore, oxidative stress has also been determined to have a crucial role in AD pathogenesis ^[11]. In fact, a vast amount of evidence indicates that AD is perpetually accompanied by elevated oxidative cellular stress in the brain, yielded by the elevated production of free radicals, reduced polyunsaturated fatty acid, elevated protein and DNA oxidation, elevated lipid peroxidation, and the aggregation and accumulation of Aβ, which cause oxidative stress ^[12].

2. Herbal Neuroprotective Effects

Withania somnifera, common name ashwagandha, is an evergreen shrub in the Solanaceae family ^[13][14]. W. somnifera is one of the most conspicuous herbs prescribed for AD ^[15][16]. In general, it is prescribed as a nerve tonic and energy booster ^[16]. W. somnifera, as an adaptogen, has been demonstrated to possess free radical scavenging and antioxidant and immune-boosting activities ^[13]. W. somnifera contains a plethora of bioactive compounds of medical interest, such as withanolides A-Y, withanone, withasomniferols A-C, dehydrowithanolide-R, withasomidienone, and other ergostane-type steroidal lactones ^[17][18]. The plant also includes alkaloids, beta-sitosterol, and phytosterols sitoindosides VII-X ^[18]. Some of these constituents have been demonstrated to scavenge free radicals produced during AD pathological progression ^[18][19]. Molecular modeling research studies have elucidated that withanamides A and C have the ability to bind to the active motif of Abeta-25-35 and avert the formation of fibrils ^[20]. Subsequently, these compounds have been shown to protect neuronal rat cells and PC-12 cells from Beta-amyloid-induced neuronal death ^[21][22]. Consequently, therapeutic treatments that consist of W. somnifera’s methanol extractions have been shown to trigger the outgrowth of neurites in a time- and dose-dependent approach in human neuroblastoma cells ^[23]. Another research study consisting of cultured cortical rat neurons displayed a diminishment of pre- and postsynaptic stimuli, as well as dendritic and axonal atrophy, when treated with Aβ peptides ^[24]. Consequent therapeutic treatment with withanolide A displayed significant regenerative properties of dendrites and axons, and even displayed restorative properties of the pre- and postsynapses in the cultured neurons ^[24]. Withanolide A has been shown to inhibit Abeta25-35-induced axonal and dendritic degeneration in the hippocampus and cerebral cortex, while also seemingly restoring synapses and Aβ -peptide-induced memory impairment in mice ^[25]. Additionally, the ameliorative outcomes were retained after treatment discontinuation ^[25]. Subsequently, aqueous extracts of W. somnifera elevated the activity of choline acetyl transferase and acetylcholine in rats, potentially explicating the memory- and cognition-enhancing effects ^[23][26]. Consequently, root extract treatments led to low-density lipoprotein receptor-related protein upregulation, thereby boosting Aβ clearance and ameliorating AD pathology in APP/PS1 mice ^[27]. Similarly, administering semipurified extracts of W. somnifera orally inhibited Aβ peptide accumulation and reversed behavioral impairment in APP/PS1 mice models of AD ^[27]. These ameliorative effects were mediated via the enhancement of liver low-density lipoprotein receptor-related protein. Consequently, Drosophila melanogaster models of AD have also elucidated that W. somnifera treatment could mitigate Abeta toxicity while seemingly boosting longevity ^[28]. Nonetheless, although a vast amount of literature has reported the ameliorative therapeutic effects of W. somnifera, clinical data related to its use for cognitive impairment are limited ^[29]. In a double-blind, randomized, placebo-controlled study encompassing 50 subjects with mild cognitive impairment (MCI), the subjects were treated with 300 mg of W. somnifera root extracts twice daily or with a placebo for eight continuous weeks ^[30]. At the end of the eight weeks, the W. somnifera-treated group showed significant enhancements in information-processing speed, attention span, and executive function ^[30]. As such, these two studies provide evidence for W. somnifera’s enhancing roles in memory and executive function in subjects with MCI ^[27][30]. Bacopa monnieri, common names waterhyssop or brahmi, is a perennial plant in the Plantaginaceae family ^[31]. B. monnieri is a nootropic herb with low toxicity and has been traditionally utilized as a memory booster and neural tonic in a plethora of ailments ^[31]. There have been studies that have elucidated evidence for the role of B. monnieri in epilepsy, dementia, and Parkinson’s disease attenuation ^[32][33]. Furthermore, it has also been utilized for stress, asthma, and insomnia ^[34][35]. The bioactive phytochemicals present in B. monnieri encompass sterols, polyphenols, sulfhydryl compounds, saponins, bacosides A and B, betulic acid, bacopasides II, IV, and V, and bacosaponins A, B, C, D, and E ^[36]. The neuroprotective activity of B. monnieri could potentially be due to the bioactivity of the phytochemicals, thereby explaining its usage in traditional medicine. In fact, research studies conducted in vitro and in vivo demonstrate that these phytochemicals contain free radical scavenging and antioxidant activities via the blockage of lipid peroxidation in various brain areas ^[37][38]. B. monnieri elicits its role via the reduction in divalent metals, reduction in lipid peroxide formation, inhibition of lipoxygenase, and through its scavenging activity of reactive oxygen species ^[39]. Various studies have seemingly elucidated the role of B. monnieri in terms of intellect and memory ^[40][41]. In order to illuminate the neuroprotective activities of B. monnieri in rat models of AD, researchers conducted studies examining the administration of 20, 40, and 80 mg/kg alcoholic extracts of B. monnieri on rats for 2 weeks prior to and 1 week after intracerebroventricular ethylcholine aziridinium ion administration ^[42]. The Morris water maze was utilized to test spatial memory, and histological assays were utilized to assess the density of cholinergic neurons ^[42]. In this case, the B. monnieri extract appeared to enhance the escape latency time in the Morris water maze and blocked the diminishment of cholinergic neuron density ^[42]. Another conducted study demonstrated the backtracking of colchine-induced cognitive impairments by B. monnieri extracts ^[43]. Similarly, B. monnieri extracts attenuated oxidative damage caused by colchicine via the reduction in the protein carbonyl content while also restoring antioxidant enzyme activity ^[43]. The majority of the research studies examining the cognitive enhancement elicited by B. monnieri in humans have been centered on normal geriatric individuals. In a randomized, double-blind, placebo-controlled clinical trial encompassing 35 subjects of 55 years and older, the subjects were administered a 125 mg dosage of B. monnieri extract or a placebo twice a day for an interval of 12 weeks, with a placebo period that consisted of an additional four weeks ^[44]. The researchers conducted numerous memory tests focused on logical memory, visual reproduction, paired-association learning, general information, orientation, digit forward, and digit backward subtests ^[45]. The subjects were then given a score on each subtest, with the total memory consisting of the result of all of the subtests ^[44]. Treatment with B. monnieri extract significantly improved paired-association learning, mental control, and logical memory in the subjects in comparison to the placebo groups at 8 and 12 weeks following trial initiation ^[44]. These results propose that B. monnieri extracts could be beneficial in age-associated memory deficit treatment

3. Medicinal Plants for AD with Limited Studies

Currently, there are a plethora of other medicinal plants that show preventative and therapeutic activity for AD ^[46]. Nonetheless, in vitro and in vivo studies are limited, with most data deriving from observational studies. These plants include Commiphora wightii, Tinospora cordifolia, Hypericum perforatum, Rhodiola rosea, Moringa oleifera, Convolvolus pluricaulis, Hericium erinaceus, Camellia sinensis, and others ^{[46][47][48][49][50][51]}. Similarly, there are also neuroprotective natural products that could be obtained from food. To illustrate this, Allium sativum in the Alliaceae family has shown to be a potent anti-neuroinflammatory, antioxidant, and regulator of neurotransmitter signaling when referring to aged garlic extract, which could ameliorate AD pathogenesis ^[52][53]. Likewise, juice and extracts from Punica granatum have also shown neuroprotective effects in animal models, potentially by counteracting oxidative damage, minimizing inflammation of the brain and soluble Aβ 42 and hippocampal amyloid deposition ^[54][55].

Consequently, natural products, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), have also shown to be effective in vitro and in vivo ^{[56][57][58][59]}. In PC12 neuronal cells, CBD has shown protection against oxidative stress, Aβ-induced neurotoxicity, inhibition of tau hyperphosphorylation, prevention of proinflammatory gene transcription, and inhibition of Aβ-induced tau hyperphosphorylation ^[60][61]. In vivo, CBD has shown attenuation of Aβ-induced neuroinflammatory responses by minimizing proinflammatory gene and mediator expression, as well as minimized reactive gliosis ^[59][62]. In vivo studies using CBD and THC have shown enhanced memory in the active avoidance and two-object recognition tasks ^[58]. Additionally, it has been shown to reduce soluble Abeta42 levels and alter the plaque composition ^[58].

4. Future Directions in Herbal Medicine

Currently, approximately 6.2 million Americans aged 65+ are suffering from Alzheimer’s dementia ^[63]. Additionally, that number is expected to grow to 13.8 million Americans by 2060 if effective therapeutics are not developed and utilized to halt, prevent, or slow AD-related pathogenesis ^[63]. Consequently, AD has an astoundingly high economic burden, with an approximated USD 305 billion having been spent on AD treatment in 2020 ^[64]. As such, finding effective therapeutic treatments are necessary to enhance patient outcomes. Even though various novel approaches have been found for symptomatic treatment and numerous disease-modifying therapies are under development, most clinical trials related to AD have not been successful ^[65]. Due to this, a significant deviation from monotherapeutic treatments has taken place to favor multitherapeutic, individualized, and comprehensive approaches since AD is a highly heterogeneous disorder ^[66][67].

Tau and Aβ have been shown to boost the loss of blood–brain–barrier (BBB) integrity ^[68]. Thus, a critical challenge in AD drug delivery relies on circumventing the BBB, which averts the entry of a plethora of possible therapeutic agents ^[68]. In general, the most common administration route is oral, but it has not been clearly elucidated whether herbal components can access the central nervous system from systemic circulation. Furthermore, rapid metabolism, limited solubility in aqueous environment, and incomplete distribution in the CNS are further limits that must be overcome. Thus, intranasal administration is an efficient and noninvasive administration route that could bypass the BBB and directly target the central nervous system ^[69]. Utilizing this method of delivery, herbs in medicated oil or dry powder forms could be administered directly to the subject. Medicated oils could also contain a mixture of lipid-soluble and lipophilic molecules to warrant the synergistic interactions between the varied herbal components. The benefits of intranasal delivery comprise brain injury avoidance, surmounting the requirement of implanting delivery devises, and reducing the systemic-administration-associated side effects ^[69][70]. Utilizing the intranasal administration technique, researchers have successfully treated memory loss in transgenic mice models of AD ^[71]. However, this method also has some limitations, such as a particularly small volume of administrated drugs, the limited surface area in the olfactory epithelium, and a relatively short retention time for drug absorption ^[72][73]. Thus, further research is required to support and enhance the usage of intranasal administration for herbal delivery.

In general, a large amount of evidence has shown that various herbs and natural bioactive products could be effective in AD treatment while having minimal severe adverse effects ^[74]. Even though it is not fully understood, the AD pathological process is proposed to be multifactorial ^[75]. As such, neuroprotective techniques encompassing a plethora of mechanisms of action are crucial for AD treatment and prevention. Natural product extracts and mixtures, with various bioactive compounds and neuroprotective mechanisms, are advantageous in drug discovery for AD. However, more research is necessary to address the concerns associated with herbal medicine and natural medicine for AD. Consequently, although the use of some herbs, such as those of C. longa and B. monnieri, have demonstrated slight clinical improvements, many natural products such as polyphenols remain of interest in the treatment of neurodegenerative disorders ^[76]. Additionally, some limitations include chemical instability, since curcumin and resveratrol are chemically unstable ^[77]. Likewise, low bioavailability, such as that observed with curcumin, is also a major issue ^[78]. Therefore, it has been challenging to translate effective preclinical results. Nonetheless, numerous studies have attempted to improve bioavailability by employing nanocarriers and nanotechnology, which could potentially enhance clinical efficacy and therapeutic response ^[79]. One notable example has been that of nanolipid epigallocatechin-3-gallate particles, which have demonstrated the ability to increase α-secretase, enhancing their ability in vitro and increasing epigallocatechin-3-gallate’s oral bioavailability by greater than two-fold ^[80]. As such, more comprehensive quality control and practical guidelines, in addition to novel strategies and approaches to promote central nervous system access of the herbal neuroprotective agents, could potentially allow natural product therapy to play an essential role in AD preventative and therapeutic measures.