Plants with Anti-Alzheimer Properties: History
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Bhupendra Koul
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Usma Farooq
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Dhananjay Yadav
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Minseok Song

Alzheimer’s disease (AD) is a neurological disorder in humans caused by complex pathophysiological mechanisms that lead to loss of memory and cognition, death of neurons, loss of synapses, and damage of the brain, which culminates in death.

  • Alzheimer’s disease
  • medicinal plants
  • ‘ginseng
  • gotu kola

1. Treatment of Alzheimer’s Disease

There are already more than 55 million cases of Alzheimer’s disease (AD) documented globally, and by 2050, the overall number of AD patients is expected to more than triple [1][2]. Even though it is a serious health issue proper and complete treatment is not available, treatment strategies used today concentrate on assisting patients in managing behavioural symptoms, sustaining mental function, and delaying or preventing the signs of illness. Two treatment strategies can be adopted as discussed below.

1.1. Chemical-Based Treatment

Despite the fact that AD is a public health problem, there are currently only two classes of medications that have been approved by the FDA to treat AD: cholinesterase enzyme inhibitors (naturally occurring, synthetic, and hybrid analogues), and antagonists to N-methyl D-aspartate (NMDA).

1.1.1. Cholinesterase Inhibitors

According to the cholinergic theory, a reduction in the synthesis of acetylcholine (ACh) causes AD. A reduction in acetylcholinesterase along with an increase in cholinergic levels is one therapy that enhances neuronal cell and cognitive function [3]. Acetylcholine breakdown in synapses is prevented by acetylcholinesterase inhibitors (AChEIs), leading to continuous ACh build up and cholinergic receptor activation. Another approach to treating AD may involve raising choline reuptake and, consequently, the generation of acetylcholine at presynaptic terminals. This might be done by focusing on the choline transporter (CHT1), which is in charge of supplying the choline required for the synthesis of ACh [3][4]. Different AChEIs are donepezil, rivastigmine, and galantamine.

Donepezil

The most effective medication for treating AD is donepezil, which is a derivative of indanonebenzylpiperidine and a member of the second generation of acetylcholinesterase inhibitors (AChEIs). Due to donepezil’s reversible binding to acetylcholinesterase, there is more ACh present at the synapses and prevents it from being hydrolysed. With transient cholinergic side effects that affect the neurological, as well as gastrointestinal systems, the medicine may be tolerated by the patient. Notably, donepezil is used to treat AD symptoms, such as improving cognition and behaviour [5][6]. Due to an imbalance in acetylcholine, unusual adverse reactions such as extrapyramidal side effects are more likely to occur when AD medication is used along with psychiatric medicines. A case of an extrapyramidal adverse response brought on by the donepezil and risperidone combination was reported [7]. The patient experienced fatigue, nausea, panic, sweating, and vomiting.

Rivastigmine

It is a butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) pseudo-irreversible inhibitor. In order to function, it binds to the two active sites of AChE which are estearic and anionic sites, which stops acetylcholine (Ach) metabolism [8]. In the healthy brain, glial cells contain BuChE and have only a 10% activity level compared to the AD brain, where it has a 40–90% activity level, while simultaneously reducing ACh activity. This implies that BuChE activity can be a sign of mild to severe AD. Rivastigmine is metabolised by AChE and BuChE at the synapses and dissociates slower than AChE, which is why it is known as a pseudo-irreversible. The drug is used for the treatment of mild to moderate AD. It ameliorates daily activities and cognitive processes [9][10]. The most common adverse effects of rivastigmine are gastrointestinal problems such as bladder pain, painful urination, etc.

Galantamine (GAL)

For mild to severe AD cases, it is regarded as a conventional first-line medication. Galantamine is a dual-mode selective tertiary isoquinoline alkaloid, which not only acts as a competitive inhibitor of AChE but also has the ability to allosterically bind to and activate the nicotinic acetylcholine receptors subunit. Like other AChE inhibitors, GAL has good efficacy and tolerability and can reduce behavioural symptoms and improve daily activities, cognitive performance, and mood [11][12]. For transporting the medicine only to the areas of the brain that were injured, it is linked to hydroxyapatite particles that contain ceria. To transport GAL hydrobromide, some researchers have used solid-lipid nanoparticles and nano emulsification techniques [13]. The results of these tests are promising for the safe administration of the drug. Nasal delivery of a GAL hydrobromide–chitosan combination of nanoparticles has good pharmacological potential, while the controlled release dose of the drug has been transported via the patch technique by another group. The common problems associated with this drug are gastrointestinal problems, headache, dizziness, insomnia, weight loss, loss of appetite, etc. [13][14].

1.1.2. N-methyl D-aspartate Receptor (NMDAR) Antagonists

It is thought that NMDAR performs an important role in the pathophysiology of AD. Ca2+ influx brought on by NMDAR activation promotes signal transduction, and results in gene transcription that is required for the growth of long-term potentiation (LTP), which is essential for the establishment of synaptic neurotransmission, plasticity, and memory [15]. Excessive NMDAR activation overstimulates glutamate, the main excitatory amino acid in the CNS, which results in excitotoxicity, synaptic malfunction, neuronal cell death, and damage to cognitive abilities. Numerous NMDAR uncompetitive antagonists have been created and tested in clinical settings, though the majority of them were ineffective and had undesirable side effects [16]. The sole drug in this class that is approved for the treatment of moderate to severe AD is memantine.

Memantine

It is an uncompetitive, low-affinity antagonist of the glutamate receptor subtype. To treat mild to severe AD, memantine is administered alone or in combination with AChEI [12]. The drug has a low affinity and is quickly displaced from NMDAR by high quantities of glutamate. It blocks excitatory receptors without impairing regular synaptic communication, which makes it harmless, well tolerable, and avoids a long-lasting blockage. Possible adverse effects of memantine are dizziness, constipation, vomiting, hypertension, and headache [17].

1.2. Plant-Based Treatment

Currently available synthetic medicines are effective only for 1–4 years for mild to moderate AD. Synthetic medicine exhibits many negative side effects [18]. Scientific evidence related to the efficacy of phytochemicals in the prevention and treatment of AD has been accumulating which shows that they are safe and cost effective. Oxidative stress is one of the proven causes of AD. However, plants are reservoirs of antioxidants which can mitigate the effects of AD [19][20]. Several plants were examined for their ability to combat AD as listed in Table 1 and also shown in Figure 1. A diet high in plants has repeatedly been linked to a lower risk of AD. It is advised to consume fruits, vegetables, cereals, and nuts on a regular basis for overall health, to promote healthy ageing, and to reduce the risk of age-related disorders such as AD [21][22].
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Figure 1. Different plant-based foods used for the prevention of Alzheimer’s disease (AD).
Table 1. Different plants possessing anti-Alzheimer properties.
Plant Botanical Name Family Part Used Active Compounds Properties References
Ashwangdha Withania somnifera Solanaceae Roots Glycowithanolides (Withaferin A, Withasomniferin A) It has neuroprotective functions. [23][24]
Brahmi Bacopa monnieri Plantaginaceae Arial parts Brahmine, bacosides A and B, apigenin, and quercetin It works as a memory enhancer. [25]
Calabar bean Physostigma venenosum Fabaceae Seeds physostigmine It has acetylcholinesterase inhibitor activities. [26]
Coffee Coffea arabica Rubiaceae Seeds Caffeic acid, chlorogenic acid It is effective against Alzheimer’s disease. [27]
Milk thistle Silybum marianum Asteraceae Seeds Silymarin It acts as a scavenger of free radicals and protects the central nervous system against any injury and memory impairment. [28]
Guggulu Commiphora wightii Burseraceae Bark Ferulic acid, commiphoric acid, eugenol, and commophorinic acid It acts as a scavenger of superoxide radicals. [29]
German chamomile Matricaria recutita Asteraceae leaves apigenin It helps in stimulating the brain and calms the nerves. [30]
Blueberry Vaccinium corymbosum Ericaceae Fruit Antioxidants, vitamins C, B, β-carotene, lutein, and zeaxanthin It has anti-inflammatory and antidiabetic, properties, and also helps in preventing Alzheimer’s disease. [31][32]
Rosemary Rosmarinus officinalis Lamiaceae Leaves Carnosic acid, carnosol, rosemanol, rosmarinic acid, and α-pinene It has antioxidant properties and reduces the risk of AD. [33]
Snowdrop Galanthus nivalis Amaryllidaceae Bulbs Galanthamine, nivalidine, narwedine, and lycorine It has antioxidant and antiamyloid activities. [34]
Turmeric Curcuma longa Zingiberaceae Rhizome Curcumin, bisdemethoxycurcumin, eugenol demethoxycurcumin, zingiberene dihydrocurcumin, azulene, D-camphene, caprylic acid, cineol, and turmerone It has antioxidant properties so it helps in preventing Alzheimer’s disease. [35][36]
St. John Wort Hypericum perforatum Hypericaceae Entire plant quercetin, Hypericin, rutin quercetin, and isorhamnetin, It possesses antioxidant and antiamyloid activities. [37][38]
Black pepper Piper nigrum Piperaceae Seeds piperine It reduces acetylcholinesterase levels and shows better results in the treatment of Alzheimer’s disease. [39]
Garlic Allium sativum Lilliaceae Cloves S-allyl-cysteine, S-allyl-mercaptocysteine Biophenols: caffeic acid, and ferulic acid It shows antiamyloid and antitangle properties. [40][41]
Ginkgo Ginkgo biloba Ginkgoaceae Leaves Ginkgolides A, B, C, J and M, bilobalide, quercetin, sesquiterpene kaempferol, and isorhamnetin It has antioxidant properties. It increases the blood flow in the brain and acts as a scavenger of free radicals and shows neuroprotective properties. [42][43]
Coriander Coriandrum sativum Apiaceae Leaves Camphor, limonene, alpha-pinene, geraniol, petroselinic acid, and linalool It helps in improving memory and also helps in managing Alzheimer’s disease. [44][45]
Sesame Sesamum indicum Pedaliaceae seeds Sesaminol, sesamine It shows neuroprotective properties. [46]
Apple Malus pumila Rosaceae Fruit Quercetin, catechin, and epicatechin It improves cognitive functions. [47]
Ginseng Panax ginseng Araliaceae Roots Ginsenosides, gintonin It improves the functioning of the central nervous system, and it also shows anti-amyloid activity. [48][49]
Mulberry Morus alba Moraceae Fruit resveratrol, oxyresveratrol, chlorogenic acid, mulberroside, moracin, and maclurin It has antioxidant properties and helps in lowering the risk of AD. [50]
Gotu kola Centella asiatica Apiaceae Leaves Quercetin, myricetin, kaempferol, rutin, and apigenin It possesses anti-amyloid properties. [51]
Seneca snakeroot Polygala tenuifolia Polygalaceae Roots Tenuigenin, tenuifolin, and xanthone glycosides It acts as an acetylcholinesterase and beta-secretase 1 inhibitor. [52][53]
Golden root Rhodiola rosea Crassulaceae Roots Rosavin, salidroside, rosin, cinnamoyl alcohol, and tyrosol It has very good antioxidant activity and also acts as a cognitive enhancer. [54][55]
Lemon balm Melissa officinalis Lamiaceae Leaves Citral, protocatechuic acid, caffeic acid, and rosmarinic acid It acts as a memory enhancer. [56]
Dwarf periwinkle Vinca minor Apocynaceae Upper parts Vinpocetine, apovincaminic acid, kaempferol glycosides, hydroxybenzoic acids, and chlorogenic acid It acts as a memory enhancer and also shows antioxidant properties. [57]
Green tea Camellia sinensis Theaceae Leaves Gallocatechin, Gallic acid, epigallocatechin, epicatechin, epigallocatechin gallate, and caffeine It possesses antioxidant and antiamyloid activities. [58][59]
Grapes Vitis vinifera Vitaceae Fruit Resveratrol, quercetin, and catechins It has antioxidant and antiamyloid properties and is used in preventing neurodegeneration. [60]
Marijuana Cannabis sativa Cannabaceae Bud and leaves Tetrahydrocannabinol, cannabidiol It shows antiamyloid activity. [61]
Olive Olea europaea Oleaceae Fruit, oil, leaves Oleuropein, tyrosol, hydroxytyrosol, caffeic acid, verbascoside, and rutin It possesses antioxidant, anti-inflammatory, and antiamyloid properties. [62]
Brazil nut Bertholettia excelsa Lecythidaceae Nut Lecithin It increases the level of acetylcholine n AD patients. [63]
firmoss Huperzia serrata Lycopodiaceae Aerial parts Huperzines It possesses antiamyloid activity. [64]
Pomegranate Punica granatum Punicaceae Fruit Ellagic acid, gallagic acid punicalagin, and punicic acid It possesses antioxidant and antiamyloid activities. [65][66]
Marapuama Ptychopetalum olacoides Olacaceae Roots Ptychonal, muirapuamine, and theobromine It possesses antiamnesic, anticholinesterase, and neuroprotective properties. [67][68]
Fennel Foeniculum vulgare Apiaceae Seed Estragole, limonene, fenchone, and β-myrcene It shows an inhibitory effect against acetylcholinesterase and butyrlcholinesterase. [69]
Papaya Carica papaya Caricaceae Fruit Quercetin, β-sitosterol It possesses radical scavenging activity. [70]
Saffron Crocus sativus Iridaceae Stigma Crocin, crocetin, picrocrocin, safranin, and safranal, It possesses antioxidant and antiamyloid activities. [71]
Ginger Zingiber officinale Zingiberaceae Rhizome Shagol, gingerol, zingerone It shows antioxidant properties. [72]
Sage Salvia officinalis Lamiaceae Leaves Rosmarinic acid, thujone, cineol, and camphor It shows antioxidant properties. It has cognitive-enhancing properties and helps in preventing age-related problems. [73]
Camb Caryocar brasiliense Caryocaracea Leaf Gallic acid, quinic acid, quercetin, and quercetin 3-o arabinose It has neuroprotective effects. [74]
Coconut Cocos nucifera Arecaceae Seed Caproic acid, Caprylic acid, Capric acid, Lauric acid, and Myristic acid It helps in preventing Alzheimer’s disease. [75]
Gouteng Uncaria rhynchophylla Rubiaceae Stem Rhynchophylline, isorhynchophylline, and hirsuteine It shows free radical scavenging activity and also exhibits protection against kainic acid-induced neuronal damage. [76]
Aloe vera Aloe barbadensis miller Aloaceae Juice Aloin, β-secretase, aloe-emodin It improves brain functioning. [77]
Wuzhuyu Tetradium ruticarpum Rutaceae Fruit Evodiamine, rutaecarpine, evocarpine, and quinoline It increases the blood flow in the brain and also inhibits the effect of acetylcholinesterase. [78]
Moringa Moring oleifera Moringaceae Leaves Glycoside niazirin, niaziminim A and B, It maintains the monoamine level in the brain and helps in treating Alzheimer’s disease. [79]
Walnut Juglans regia Juglandaceae Kernel α-tocopherol, ellagic acid, and juglone It reduces the risk of Alzheimer’s disease by reducing oxidative stress and it also shows amyloidogenic activity. [80][81]
Cinnamon Cinnamomum verum Lauraceae Extract of bark Cinnamaldehyde, eugenol, and trans cinnamaldehyde It promotes the disassembly of tau filaments and also shows anti-inflammatory activity. [82]
Tahitian gooseberry Phyllanthus acidus Phyllanthaceae Fruit Terpine It lowers oxidative stress, decreases lipid peroxidation, and helps in increasing the level of antioxidant enzymes in the brain. [83]
Fig Ficus carica Moraceae Fruit Quercetin, C-Sitosterol It has antioxidant activity, exhibits memory-enhancing effects and better learning abilities. [84]
Pumpkin Cucurbita maxima Cucurbitaceae seeds Ferulic acid, caffeic acid, and coumaric acid It has antioxidant properties and helps in relieving stress. [85]
Shankhpushpi Convolvulus pluricaulis Convolvulaceae Whole plant Flavonol glycosides, anthocyanins, and triterpenoids It is consumed as a tonic for enhancing memory and it calms the nerves. [86][87]
Strawberry Fragaria ananassa Rosaceae Fruit Pelargonidin It has antioxidant properties. [88]
Butterfly pea Clitoria ternatea Fabaceae Root and leaf extract Myricetin, quercetin It shows antioxidant properties and AChE inhibitor activities. [89]
Broccoli Brassica oleracea var. italica Brassicaceae Floret Kaempferol, sulforaphane It possesses antioxidant activities and reduces cerebral oedema. [90]
Spinach Spinacia oleracea Amaranthaceae Leaves Ferulic acid, coumaric acid, quercetin, spinacetin, and myricetin, It reduces the neuronal death and production of ROS. [91]
Date palm Phoenix dactylifera L. Arecaceae Fruit Cinnamic acid, caffeic acid, protocatechuic, gallic acid, dactylifiric acid, and epicatechin It has antioxidant properties and helps in enhancing memory [92]

2. Differen Plants with Anti-Alzheimer Properties

Different plants belonging to the families Solanaceae, Plantaginaceae, Fabaceae, Rubiaceae, Asteraceae, Ericaceae, Amaryllidaceae, Zingiberaceae, Pedaliaceae, Hypericaceae, Piperaceae, Lilliaceae, Ginkgoaceae, Apiaceae, Araliaceae, Polygalaceae, Crassulaceae, Lamiaceae, Apocynaceae, Theaceae, Vitaceae, Cannabaceae, Oleaceae, Lycopodiaceae, Punicaceae, Iridaceae, Lamiaceae, Caryocaracea, Arecaceae, Aloaceae, Rutaceae, Moringaceae, Juglandaceae, Lauraceae, Phyllanthaceae, Moraceae, Convolvulaceae, Halymeniaceae, Rosaceae, etc., have anti-Alzheimer properties and have been used for the treatment of AD.

2.1. Ginseng

Panax ginseng (family: Araliaceae), commonly known as ‘ginseng’ is one of the well-known herbs in China, Japan, and Korea used to treat AD. It consists of phytochemicals such as ginsenosides (saponins), a derivative of the triterpenoid dammarane, and 20(S)-protopanaxadiol, which prevents β-amyloid from aggregating and clears it from neurons, relieves mitochondrial dysfunction, and boosts the secretion of the neurotrophic factor [44][45]. According to a molecular enzyme study, ginsenosides have substantial AChE inhibitory activities, which is an efficient strategy for lowering the symptoms of AD [93][94]. Through the stimulation of phosphatidic acid receptors involved in hemolysis, the bioactive glycoprotein gintonin lowers the production of Aβ and enhances learning and memory. Additionally, it reduces AD symptoms by promoting autophagy, anti-inflammatory mechanisms, antiapoptosis, and management of oxidative stress, as proven by comprehensive in vivo and in vitro investigations [95]. Gintonin modulates the G protein-coupled lysophosphatidic acid receptors which affect the cholinergic system and neurotrophic factors, reducing the level of plaque formation. In a clinical experiment with a limited sample size of 10 people who had mild cognitive impairment or early dementia, gintonin intake (300 mg/day, 12 weeks) significantly enhanced Korean mini mental state test scores at 4 and 8 weeks compared to baseline scores. In contrast, gintonin consumption (300 mg/day, 4 weeks) significantly raised the ADAS-Cog-K and ADAS-non-Cog-K scores on the Korean cognitive subscale of the Alzheimer’s disease assessment scale after 4 weeks compared to the baseline scores. When it comes to gintonin toxicity in humans, none of the patients reported any negative side effects during the 12-week dose of gintonin. Hence, gintonin administration to older subjects with cognitive impairment was safe and well tolerated [96].

2.2. Gotu Kola

Centella asiatica (family: Apiaceae) is commonly called ‘gotu kola’. It is a widespread persistent herbaceous climber in Asia. It is used in traditional medicines for the purpose of regenerating brain cells and enhancing memory, lifespan, and intellect [51]. Animal studies have shown that Centella asiatica has an impact on neuronal structure, learning ability, and memory-retaining ability. It has been shown to improve cognitive performance by reducing phospholipase A2 (PLA2) activity, suppressing acetylcholinesterase activity, preventing the formation of amyloid, and preventing brain damage [97][98]. In preclinical studies, Centella asiatica was also discovered to have antidepressant, anxiolytic, antistress, and seizure-prevention properties [99][100]. It has been shown to affect metabolic pathways connected to AD when administered to 5xFAD mice [101]. In rats overexpressed with β-amyloid, Centella asiatica extract has been demonstrated to enhance memory and decision-making, while it lowers hippocampus mitochondrial dysfunctioning. In a clinical investigation, a 70% water-ethanol extract of C. asiatica demonstrated promising anxiolytic properties by reducing anxiety and stress in patients [101].

2.3. Ginkgo

Ginkgo biloba (family: Ginkgoaceae) is commonly known as ‘ginkgo’. It is the most well-known herb for treating Alzheimer’s and its symptoms. Terpene lactones and flavone glycosides are both present in plant extracts. The terpene lactones include bilobalide A, B, and C, and ginkgolides, while the flavone glycosides include kaempferol, quercetin, and isorhamnetin [38]. Through the control of glutathione peroxidase, catalase, and superoxide dismutase (SOD) activity, this herbal extract shields against Aβ generated neurotoxicity by preventing apoptosis of neurons, reactive oxygen species (ROS) collection, glucose assimilation, mitochondrial dysfunctioning, and activation of the extracellular signal-regulated kinase (ERK) pathway [42][43]. Numerous studies have connected astrocytosis, microgliosis, and the presence of proinflammatory substances to the deposition of Aβ peptides [102]. G. biloba extracts demonstrated therapeutic advantage in AD, compared to donepezil, with few unfavourable side effects. It is most recognized for its capacity to improve circulation (vasorelaxing effect) throughout the body. G. biloba can thus reduce blood pressure and prevent platelet aggregation [103]. In an experiment involving 18 randomized clinical trials (RCTs) with 1642 individuals, 842 of them were in the experimental group (donepezil hydrochloride plus G. biloba formulations) and 800 were in the control group (donepezil), it was observed that donepezil with G. biloba can enhance clinical efficacy rates and verbal memory. However, to validate this, more stringent trials will be required in the future [104].

2.4. Turmeric

Curcuma longa (family: Zingiberaceae) is commonly known as ‘turmeric’. Curcuminoids, such as curcumin, demethoxycurcumin, and bis-demethoxycurcumin, are the phytochemicals present in turmeric. The primary curcuminoid is curcumin, which gives turmeric roots their characteristically yellow colour. According to research, curcumin may be a potential drug for treating AD [105]. The level of oxidative damage in the brain can be reduced by curcumin. It has been shown that curcumin can reverse β-amyloid pathology in a mouse model with AD [106]. The antioxidant and anti-inflammatory properties of curcumin also facilitated in alleviating of some AD symptoms [35][36]. The capacity of the Early Growth Response-1 (Egr1) protein to bind DNA is inhibited by curcumin, which reduces inflammation. Activated microglia and astrocytes produce chemokines which are known to cause monocyte chemotaxis and are also inhibited by curcumin at the CNS. Effective ways to stop proinflammatory cytokine activation include decreasing the production of ROS by stimulating neutrophils and suppressing the tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1) inflammatory cytokine expression [107][108]. Curcumin inhibits the activity of the activator protein (AP-1), a transcription factor involved in the synthesis of amyloid. The capacity of curcuminoids to prevent the generation and spread of free radicals is proof that they possess potent antioxidant effects. It also prevents the oxidation of free radicals and low-density lipoproteins which causes the destruction of neurons in AD and other neurodegenerative diseases.

2.5. Brahmi

Bacopa monnieri (family: Plantaginaceae) commonly known as ‘brahmi’ is a persistent creeper that is indigenous to the swamps of eastern and southern India, together with Australia, Europe, Africa, Asia, North and South America, and the Middle East. In traditional medicine, it is frequently used as a cardiotonic, diuretic, and nerve tonic [109][110]. The main phytochemicals of Brahmi are Brahmine, bacosides A and B, apigenin, quercetin, bacosaponins A, and bacosaponins B. Protein kinase activity is increased by B. monnieri extracts, which has a nootropic effect. Rats administered Brahmi extract displayed reduced cholinergic degradation and an improvement in cognition. Additionally, it also shields neural cells from the harm done by β-amyloids [110]. B. monnieri extract treatment resulted in decreased ROS levels in neural cells, indicating that it reduces intracellular oxidative stress. Cognitive abilities significantly increase with regular use of Brahmi, which also reduced their levels of inflammation and oxidative stress [111]. In addition, a team of researchers found that an extract of standardised B. monnieri corrected the cognitive abnormalities brought on by the intracerebroventricular administration of colchicines and ibotenic acid into the nucleus basalis magnocellularis. In the same study, Bacopa monnieri also restored acetylcholine depletion, choline acetyltransferase activity reduction, and reduction of muscarinic cholinergic receptor binding in the frontal cortex and hippocampal regions [112]. By suppressing cellular acetylcholinesterase activity, Brahmi extracts prevent beta-amyloid-induced cell death in neurons. In a study (randomized, double-blinded trial) involving 81 persons of the age group 55 and above, a 12-week cycle of Bacopa considerably improved memory acquisition and retention [113].

2.6. Ashwagandha

Withania somnifera (family: Solanaceae) is commonly known as ‘ashwagandha’ and is regarded as a Rasayana (rejuvenating). It possesses antioxidant properties, characteristic of free radical scavengers. The chemical composition of ashwagandha root includes alkaloids, anolides, many sitoindosides, and flavonoids [114][115]. According to a molecular study, ashwagandha root helps in treating AD by preventing nuclear factor B activation, promoting nuclear factor erythroid 2-related factor 2 (Nrf2) migration to the nucleus, where it enhances the expression of antioxidant enzymes, to reduce the formation of amyloid, decrease apoptotic cell death, restore synaptic function, and boosts the immune system [116]. In certain research, ashwagandha root methanolic preparations were used to treat human neuroblastoma SK-N-SH cells, which led to an increase in dendritic extension, neurite outgrowth, and synapse formation. Researchers have hypothesised that the ashwagandha root extracts are effective in treating neurodegenerative illnesses and also promote neurite growth, and have anti-inflammatory, antiapoptotic, and anxiolytic effects. Moreover, they have the capacity to minimise mitochondrial dysfunctioning, boost antioxidant defence levels, reduce glutathione levels, and can cross the blood–brain barrier and reduce inflammation in the brain [117]. In a double-blind, randomized, placebo-controlled study, 50 participants with moderate cognitive impairment (MCI) were treated with a 300 mg dose of W. somnifera root extract twice daily for an eight-week period. After eight weeks, the W. somnifera-treated group displayed considerable improvements in their ability to process information, concentrate, and use executive functions [118].

2.7. Saffron

Crocus sativus (family: Iridaceae) commonly known as ‘saffron’, possesses antioxidant, anticancer, and aphrodisiac properties and also improves memory in adults. Numerous studies have shown that saffron possesses antioxidative, anti-inflammatory and antiamyloidogenic properties. Additionally, saffron is said to be helpful in reducing acetylcholinesterase and protecting against toxins (AChE). AChE is connected to the neurofibrillary tangles and beta-amyloid plaques that are characteristic of AD [119].
To analyse the effect of saffron on learning abilities, and the prevention of oxidative stress, each rat was administered five and ten grams of saffron extract, twice a week. Oxidative stress markers were assessed seven days later. The group that received saffron treatment was found to have a reduced memory deficit along with enhanced spatial learning and antioxidant activity of enzymes [120]. The main bioactive compound of saffron is crocin. It has the ability to bind to the hydrophobic region of Aβ and thus inhibits its aggregation [121]. A double-blinded/phase II study using the AD assessment scale, cognitive subscale, clinical dementia rating scale, and sums of boxes scores was conducted on a total of 54 patients who were 55 years of age or older with AD. These patients received saffron extractive (30 mg) or donepezil (10 mg) as a positive control once daily for 22 weeks. As a result, donepezil and saffron extractives had similar effects on patients with mild to moderate AD, suggesting that saffron extractives have a therapeutic effect [71].

2.8. Ginger

Zingiber officinale (family: Zingiberaceae) commonly called ‘ginger’ is a spice having both culinary and therapeutic uses. It is frequently used as a nutritional supplement, in ginger tea preparation, or as an extract. The primary bioactive components in ginger include gingerols, shagols, volatile oils such as bisabolene and zingiberene, and monoterpenes. In vitro research has been done on the AChE inhibitory activity of red and white ginger [122]. Inhibition of AChE causes acetylcholine to accumulate in synapses, which is followed by an increase in the cholinergic pathway activity and results in better cognitive performance in AD patients.
Ginger’s ability to decrease lipid peroxidation is vital for the prevention of AD. Pro-oxidants such as quinolinic acid (QUIN) and sodium nitroprusside (SNP) are utilised to cause lipid peroxidation in the rat-brain homogenate. Due to the overstimulation of NMDA receptors and the significant rise in malondialdehyde level brought on by the incorporation of SNP and QUIN, free radicals are produced [72]. Ginger extract was demonstrated to boost brain SOD and CAT expression, decrease NF-ĸB, interleukin-1 beta (IL-1β), and malondialdehyde (MDA) levels and improve behavioural impairment in a rat model of AD caused by oral AlCl3 and injection of intracerebroventricular β-amyloid protein [123]. In a similar study, the fermented ginger extract had more bioavailability and has been shown to greatly reduce synaptic dysfunction and neuron cell loss, compared to the fresh extract, in a mouse model of AD produced by injection of β-amyloid plaques [124].

2.9. Rosemary

Rosmarinus officinalis (family: Lamiaceae) is commonly called ‘rosemary’. Other than its native Mediterranean region, several other countries are known to use the plant in traditional medicine.
It possesses antioxidant and anti-inflammatory properties. To learn how drinking rosemary tea affects the working of the brain, an investigation on adult male mice was done. The testing revealed that rosemary tea consumption for four weeks had a favourable effect (anxiolytic- and antidepressant) without changing the memory or learning [29]. Other researchers have shown that it possesses antidepressant properties and is able to reverse ACHE changes despite spatial learning impairment [125]. Carnosic acid has also been found to have neuroprotective effects on cyanide-induced brain damage in cultured rodent and human-induced pluripotent stem cell-derived neurons in vitro and in vivo in several brain locations in a non-Swiss albino mouse model [126]. In vitro, the intercellular adhesion molecule (ICAM-1) expression is suppressed and tumour necrosis factor (TNF)-induced monocyte adherence to endothelial cells is inhibited by carnosol and rosemary essential oils [127]. Carnosol decreases the activity of the nuclear factor kappa-B inhibitor and increases the production of heme oxygenase-1 (HO-1), both of which block the signalling pathways triggered by TNF-α [128]. According to a study conducted on 68 students in Kerman, Iran, using 500 mg of rosemary twice daily for a month improved students’ prospective and retrospective memory [129].

2.10. Date Palm

Phoenix dactylifera (family: Arecaceae) is commonly called ‘date palm’. They have been used since Mesopotamian civilization, and their historical, theological, and medicinal significance is well known [130][131]. Three to four date fruits per day were recommended for improving memory in Palestine [131]. Turkish people drink “Hurma coffee,” an herbal brew made from date fruit seeds, to improve their memory. It reduces glutathione, glutathione reductase, and glutathione peroxidase levels [132]. In addition, mice with AD were fed diets supplemented with 2 and 4% acetone-extracted date fruit, for 14 months, and the results were compared to mice receiving a control diet. When mice were fed dates at 2 and 4% levels, oxidative stress markers such as protein carbonyl levels, lipid peroxidation, and the restoration of anti-oxidative stress enzymes were all considerably reduced [133].

2.11. Pumpkin Seeds

Cucurbita maxima (family: Cucurbitaceae) is commonly known as ‘pumpkin’. Pumpkin seeds are included in the category of nuts. Despite their significant nutritional content and therapeutic qualities, pumpkin seeds are typically seen as agricultural waste and are thrown away. In addition to being added to food preparations, they can be eaten in their fresh or roasted form. Pumpkin seeds are rich in choline (63 mg/100 g) and L-tryptophan (576 mg/100 g) [11]. L-tryptophan is frequently used to treat a variety of medical disorders, including anxiety, sleeplessness, and depression [134][135]. The body can convert tryptophan to serotonin, which in turn may control a number of cognitive functions. It is known that choline serves as a precursor for the synthesis of the neurotransmitter acetylcholine in cholinergic synapses, which deliver stimulatory signals to nerve cells. Moreover, choline promotes brain growth [136]. In adult male Wistar rats, oral treatment of pumpkin-seed oil (100 mg/kg and 200 mg/kg for 5 days) is reported to have antiamnesic benefits against scopolamine-induced amnesia. It suppresses acetylcholine esterase, reduces TNF expression in the hippocampus, and raises glutathione levels in the brain [136].

2.12. Garlic

Allium sativum (family Liliaceae) is commonly known as ‘garlic’. It is widely used in traditional medicines for the treatment of numerous diseases, including AD. The most popular garlic preparation used is called AGE, and it is often made by keeping slices of garlic in a solution of water and ethanol for more than 10 months at ambient temperature. Aggregation of unusually folded Aβ and tau proteins in amyloid plaques and neuronal tangles are the main pathologies of AD. The two primary types of Aβ are Aβ40 and Aβ42. AGE at dosages of 250 and 500 mg/kg BW can improve short-term memory deficits in humans [40][41]
It has been discovered that raw garlic has strong antineuroinflammatory capabilities, and this is due to organosulfur compounds (OSCs) that are produced from alliin (such as allicin, diallyl trisulfide, and diallyl disulfide). In lipopolysaccharides (LPS)-activated microglial cells, these substances, particularly diallyl trisulfide and diallyl disulfide, reduce the generation of TNF-α, lipopolysaccharide (LPS) induced nitric oxide, monocyte chemoattractant protein-1, and interleukin-1 (IL-1) [137]. Similar to this, glial cell activation caused by LPS and inflammatory mediators that are implicated in amyloidogenesis is reduced by the sulphur-containing substance thiacremonone [138].

This entry is adapted from the peer-reviewed paper 10.3390/life13040999

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