Insights on therapeutic approaches of natural anti-Alzheimer's agents in the management of Alzheimer's disease: A future perspective

Abstract

In the current scenario, Alzheimer's disease is a complex, challenging, and arduous health issue, and its prevalence, together with comorbidities, is accelerating around the universe. Alzheimer's disease is becoming a primary concern that significantly impacts an individual's status in life. The traditional treatment of Alzheimer's disease includes some synthetic drugs, which have numerous dangerous side effects, a high risk of recurrence, lower bioavailability, and limited treatment. Hence, the current article is a detailed study and review of all known information on plant-derived compounds as natural anti-Alzheimer's agents, including their biological sources, active phytochemical ingredients, and a possible mode of action. With the help of a scientific data search engine, including the National Center for Biotechnology Information (NCBI/PubMed), Science Direct, and Google Scholar, analysis from 2001 to 2024 has been completed. This article also described clinical studies on phytoconstituents used to treat Alzheimer's disease. Plant-derived compounds offer promising alternatives to synthetic drugs in treating Alzheimer's disease, with the potential for improving cognitive function and slowing down the progression of the disease. Further research and clinical trials are needed to fully explore their therapeutic potential and develop effective strategies for managing this complex condition.

Keywords

Alzheimer's disease management natural anti-Alzheimer's agents neurodegenerative diseases neurological disorders phytochemicals

Introduction

Neurodegenerative diseases are characterized by the progressive loss of both the structural and functional elements of the peripheral nervous system and the central nervous system.¹ Neuronal death leads to the onset of various neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke.² AD is the most observable form of dementia in aged people,³ characterized by the progressive deterioration of memory and other cognitive functions.⁴ Memory loss is the key symptom of AD.⁵ Major hypotheses for AD include amyloid and cholinergic hypotheses and additional risk factors like genetic problems, aging, head injuries, infections, vascular disorders, and environmental factors.⁶ Recent research has demonstrated that the genesis of AD is significantly influenced by the inhibition of oxidative stress and target enzymes like cholinesterase, β-secretase, and monoamine oxidase, as well as by the suppression of tau protein hyperphosphorylation and amyloid-β (Aβ) plaque aggregation, inflammatory responses, and unfolded protein responses.⁷ The comorbidities due to AD include hypertension, depression, osteoarthritis, diabetes mellitus, cerebrovascular disease, and others.

The FDA-approved medications for the treatment of AD are cholinesterase inhibitors (donepezil, galantamine, rivastigmine), glutamate regulators (memantine), and orexin receptor antagonists (suvorexant), and novel anti-amyloid antibodies (aducanumab).⁸ The availability of these pharmaceuticals and their potentially hazardous side effects restrict their usage. As a result, developing an effective, safe, economical, and cost-efficient drug is essential. Recent studies indicate that natural products might exert therapeutic potential against AD and recommend that herbal drugs are alternatives to synthetic drugs in managing AD.⁹ The efficacious usage of these herbal drugs will enhance anti-AD effects by acting on numerous targets associated with AD with lower side effects.¹⁰ Therefore, herbal plants and their derivatives are practical approaches to treating AD.

In recent years, researchers have found many active compounds in herbs, and such bioactives have targeted the therapeutic potential of herbal products against AD with fewer adverse effects than conventional drugs.¹¹ This review highlights the recent research contributions from different academics worldwide in herbal-based AD treatment. The present study covers the trends in epidemiological data, pathogenesis, and herbs with their phytochemicals and mechanism of action against AD. This review also discusses the country-wise research carried out from 2001 to 2021. Figure 1 depicts the workflow for the literature selection process.

Figure 1.

Flowchart of the literature selection process.

Epidemiology of Alzheimer's disease

AD is the most familiar and common type of dementia, accounting for 60 to 70% of all cases, and around 5 million new cases are found annually. Dementia affects more than 50 million people in the world today, and by 2050, the total figure of patients is expected to triple, the majority of whom have AD.^12,13 Turkey, Lebanon, Libya, and Finland have higher death rates because of AD as compared to other countries in the world.

Pathophysiology of Alzheimer's disease

AD is characterized by a complex interplay of pathological processes contributing to its pathophysiology. Key factors involved in AD include the deposition of extracellular Aβ, tau protein abnormalities, oxidative neuronal damage, intracellular neurofibrillary tangles (NFTs), neuroinflammation, genetic mutations, dysregulation of neurotransmitters, and various molecular and cellular pathways; represented in Figure 2. Deposition of the extracellular Aβ due to neurotoxicity is the main reason for AD.^14–16

Figure 2.

Various pathways involved in the pathogenesis of Alzheimer's disease.

Extracellular deposition of Aβ plays a central role in AD. Aβ peptides are derived from the cleavage of amyloid-β protein precursor (AβPP) and can aggregate to form insoluble plaques. These plaques disrupt normal neuronal function and activate inflammatory responses. Aβ oligomers, intermediate forms of Aβ aggregation, are particularly toxic to neurons and contribute to synaptic dysfunction and neurotoxic cascades. Tau protein abnormalities contribute to intracellular NFT formation. Tau is a microtubule-associated protein involved in maintaining neuronal structure and transport. In AD, tau becomes hyperphosphorylated, leading to its detachment from microtubules and aggregation into NFTs. These tangles disrupt neuronal integrity, impair axonal transport, and contribute to cognitive decline.

Oxidative stress is a prominent feature of AD pathophysiology. Excessive production of reactive oxygen species overwhelms the antioxidant defense mechanisms, leading to neuron oxidative damage. Mitochondrial dysfunction, Aβ-induced oxidative stress, and inflammation contribute to reactive oxygen species generation. Oxidative stress results in lipid peroxidation, protein oxidation, DNA damage, and mitochondrial dysfunction, further exacerbating neuronal injury and synaptic dysfunction.

Neuroinflammation plays a significant role in AD. Microglial cells, the brain's immune cells, are activated in response to Aβ accumulation and NFT formation. Activated microglia release pro-inflammatory cytokines, contributing to Aβ production, tau pathology, and neuronal damage. Peripheral immune cells are also recruited, amplifying the inflammatory response and contributing to neuroinflammation.

Genetic mutations are implicated in familial forms of AD. Mutations in genes such as APP, PSEN1, and PSEN2 affect Aβ production or metabolism, directly contributing to AD pathology. Risk factors such as advanced age, the APOE ε4 allele, and lifestyle factors influence AD susceptibility and disease progression. Dysregulation of neurotransmitters is observed in AD. Cholinergic dysfunction, characterized by the degeneration of cholinergic neurons and reduced acetylcholine levels, contributes to cognitive impairment. Other neurotransmitter systems, including glutamate and serotonin, are also affected, leading to excitotoxicity, synaptic dysfunction, and behavioral and psychiatric symptoms.

AD involves various molecular and cellular pathways, including factor nuclear factor-kappa B (NF-κB), extracellular regulated kinases (ERK1/2), p38 mitogen-activated protein kinases (MAPK), AMP-activated protein kinase (AMPK)/mTOR, extracellular regulated kinases (ERK1/2), and c-Jun N-terminal kinase (JNK), along with others. Dysregulated AβPP processing leads to the production of different Aβ species with varying degrees of aggregation and neurotoxicity. Tau kinases, such as glycogen synthase kinase-3β, contribute to abnormal tau phosphorylation and NFT formation. Disrupted calcium homeostasis, impaired insulin signaling, compromised autophagy, lysosomal degradation, and altered synaptic plasticity contribute to AD pathophysiology.

Emerging pathways and mechanisms have gained attention in AD research. Mitochondrial dysfunction, vascular abnormalities, epigenetic modifications, and the gut-brain axis are emerging areas of investigation. Mitochondrial dysfunction affects energy production and increases oxidative stress. Vascular abnormalities lead to reduced cerebral blood flow and metabolic disturbances. Epigenetic modifications influence gene expression patterns and may contribute to AD development. The gut-brain axis involves bidirectional communication between the gut microbiota and the brain and has been implicated in AD pathophysiology.^17,18

Trends based upon natural anti-AD agents

The present study is based on a colossal numeral of literature gathered from scientifically authenticated sources like NCBI/PubMed, Science Direct, and Google Scholar.

Table 1 depicts some significant advancements in natural medicinal development in treating AD. It includes a list of natural anti-Alzheimer's agents and information on their biological sources, families, chemical composition, parts used, and potential mode of action.

Table 1.

Various representative herbs and their parts used, pharmacological action, and active phytoconstituents.

Sr. no.	Biological source	Family	Active constituents	Part use	Pharmacological action (mechanism)	Type of extract	Method/assay/animal model	References
1.	Abies holophylla	Pinaceae	Firmanoic acid, mangiferonic acid, and terpenoids	Trunk	Suppress JNK signaling pathway, inhibit NO production, prostaglandin E2, tumor necrosis factor, and interleukins (anti-euro-inflammatory)	Ethanol and ethanol extract (chloroform- and hexane-soluble fractions)	Murine microglial cells	^19,20
2.	Acorus calamus	Araceae	α- and β-asarone and phenylpropanoids	Rhizome	Inhibition of AChE and decreased ROS production	Hydroalcoholic extract and essential oil	96 well microplate reader (Ellman's method)	^21–23
3.	Allium sativum	Liliaceae	Allicin	Clove	Inhibit cholinesterase, decrease Aβ induced toxicity	Hydroalcoholic extract	Intra hippocampal rat model	^23,24
4.	Angelica decursiva	Apiaceae	Umbelliferone, 6-formyl umbelliferone and coumarin	Whole plant	Inhibit AChE and BChE	Methanolic extract	BACE1 and ChE enzyme Assay	^25,26
5.	Artemisia annua	Asteraceae	Artemisinin (Sesquiterpene lactone), chrysosplenetin and scopoletin	Leaves	Inhibit AChE, inhibit NO production, and decrease the oxidative stress	Ethanolic extract	264.7 macrophages cell line and Ellman's colorimetric method	^27,28
6.	Ferula assafoetida	Apiaceae	Ferulic acid and umbelliferone	Resins	Decrease Aβ-induced neurotoxicity and oxidative stress, inhibit AChE	Aqueous extract	Mice	^29,30
7.	Azadirachta indica	Meliaceae	Nimbin, salannin, limonoids, and terpenoids	Fruits	Inhibits tau aggregation, anti-inflammatory	Methanolic extract	HEK293T cell line, Thioflavin S fluorescence,	^31,32
8.	Bacopa monnieri	Scrophulariaceae	Bacopasaponi, pseudo jujubogenin, bacopaside and brahmine	Arial parts	Improve acetylcholine and cerebral blood flow, and inhibit superoxide anion formation (antioxidant)	Alcoholic extract	Male Wistar rats, Morris water maze test	³³
9.	Berberis darwinii	Berberidaceae	Berberine (alkaloid)	Stem, bark	Inhibit AChE	Methanolic extract	Anti-AChE assay	³⁴
10.	Boletinus asiaticus	Suillaceae	Asiaticusinols C, asiachromenic acid, asiaticusin A, and terpenoids	Fruits	Inhibit BACE1	Chloroform and methanolic extract	BACE1 FRET Assay	³⁵
11.	Caesalpinia crista	Leguminosae	Polyphenol	Leaves	Inhibit the Aβ-aggregation, anti-amyloidogenic	Aqueous extract	Thioflavin-T assay and Transmission electron microscopy study	³⁶
12.	Camellia sinensis	Theaceae	L-Theanine	Leaves	Inhibit NK-κB, ERK1/2 and p38 MAPK pathway, antioxidant	Pure form	Human neuroblastoma cells (dopaminergic and nondopaminergic cells)	^37,38
13.	Cannabis sativa	Cannabaceae	Cannabidiol, cannabielsoin, cannabigerol, cannabitriol, cannabinoid	Flowers	Prevent toxicity of Aβ-induced increase in [Ca²⁺], inhibit AChE and BChE, neuroprotection, antioxidant	Methanol: chloroform (9:1) extract and pure Cannabidiol	Rat pheochromocytoma PC12 cells, In vitro ChE inhibitory test	^39,40
14.	Carica papaya	Caricaceae	Carpaine (alkaloid)	Leaves	Inhibit BChE	Ethanolic extract	Ellman's microplate assay	⁴¹
15.	Cassia obtusifolia	Leguminosae	Rubrofusarin-6-O-D-gentiobioside, and Nor-rubrofusarin-6-O-D-glucoside	Seeds	Inhibit AChE, BChE, AβPP and BACE1	Methanolic extract	Ellman's colorimetric method	⁴²
16.	Catharanthus roseus	Apocynaceae	Serpentine (alkaloid)	Roots	Inhibit AChE	Aqueous extract	Male Wistar rat	⁴³
17.	Centella asiatica	Apiaceae	Asiatic acid (triterpenoids), asiaticoside (saponins glycoside)	Leaves	Decreases Aβ, decreases lipid peroxidation, inhibits AChE and BChE	Aqueous extract	B103 cell cultures, rat embryonic cortical primary cell culture hippocampal slices	⁴⁴
18.	Chrysanthemum indicum	Asteraceae	Acaciin, 3,5-diarylpyrazole, acacetin-7-O-beta-D-galactopyranoside (Flavonoid)	Flowers	Inhibits AChE, reduces Aβ aggregation	Ethanolic extract	96 well microplate reader (Ellman's method)	^45,46
19.	Cinnamomum zeylanicum	Lauraceae	Cinnamaldehyde	Barks	Inhibit AChE and antioxidant	Aqueous extract	Male Wistar rats	⁴⁷
20.	Cissampelos sympodialis	Menispermaceae	Phanostenin, aporphine (Alkaloids)	Roots	Inhibit AChE, antioxidant	Methanolic extract	96-well plates	⁴⁸
21.	Citrus limon	Rutaceae	Neoeriocitrin, isonaringin, naringin, hesperidin, neohesperidin, limonin	Peels	Inhibit AChE, antioxidant	Pure form	PC12 cell cultures, 96-well plates	^49,50
22.	Commiphora whighitti/ C. berryi/ C. caudata/ C. pubescens	Burseraceae	Guggulsterone, myrrhterpenoids K, Myrrterpenoid N (Terpenoid)	Barks and leaves	Inhibit AChE, lipid peroxidation, and neuroprotective effect against MPP⁺-induced neuronal cell death (antioxidant)	Ether extract	Ellman's assay, 96-well plates, human neuroblastoma cell line SH-SY5Y	⁵¹
23.	Convolvulus pluricaulis	Convolvulaceae	Not clear	Roots	Decrease AβPP, tau, Aβ and activate PI3K/Akt signaling pathway	Aqueous extract	Male Wistar rats	^52,53
24.	Coptidis rhizoma	Ranunculaceae	Berberine, jateorrhizine palmatine, epiberberine, coptisine, and groenlandicine	Rhizomes	Inhibit cholinesterase and Aβ development, antioxidants, reduce Aβ accumulation and tau phosphorylation.	1-Butanol fraction of extract	BACE1 enzyme assay, 96-well plates, male Wistar rats	^54,55
25.	Coptis chinensis	Berberidaceae	Berberine, palmatine, jatrorrhizine	Rhizomes	Inhibit monoamine oxidase A and B	Methanolic extract	Rat brain mitochondrial fraction	^56,57
26.	Coreopsis lanceolata	Asteraceae	Caffeic acid, cinnamic acid	Flowers	Antioxidant, neuroprotective, and anti-inflammatory effects	Ethanolic and aqueous extracts	PC12 neuronal cells and mice	⁵⁸
27.	Coriandrum sativum	Apiaceae	Caffeic acid, protocatechuic acid, and glycitin	Aerial parts	Antioxidants	Aqueous ethanolic extract	Diphenylpicrylhydrazyl radical, 15-lipoxygenase, and Fe²⁺ induced porcine brain phospholipid peroxidation assay	⁵⁹
28.	Corni fructus	Cornaceae	Ursolic acid, p-coumaric acid	Fruits	Inhibit BACE1	Ethanolic extract	α- and β-secretase, chymotrypsin, and trypsin enzyme assay	⁶⁰
29.	Cornus officinalis	Cornaceae	Cornuside (tannin)	Fruits	Inhibit cholinesterase and BACE1	Not clear	Cholinesterase (Ellman's) and BACE1 enzyme assay	⁶¹
30.	Corydalis cava	Fumariacea	Corycavamine, corynoline, protoberberine (alkaloid)	Tubers	Inhibit BACE1	Ethanolic extract	BACE1 fluorescence resonance energy transfer, glycogen synthase kinase-3β, and casein kinase-1δ assays	⁶²
31.	Corydalis tuber	Papaveraceae	Berberine, pseudo dehydrocorydaimine, pseudocoptisine (Alkaloid)	Tubers	Inhibit AChE and BuChE	Ethanolic extract	Ellman's assay	⁶³
32.	Crocus sativus	Iridaceae	Crocin (Carotenoid)	Stigma	Inhibit Aβ-aggregation, inflammatory process, apoptosis, beta-amyloid aggregation, tauopathy, and antioxidant.	Hydroalcoholic extract	Trolox equivalent antioxidant capacity (TEAC), thioflavin T, DNA binding shift assay	^64,65
33.	Cullen corylifolium	Leguminosae	Isobavachalcone, bavachromene (chalcone) and kanzonol B	Seeds	Block I-kBa and NF-kB pathway, inhibit NO, PGE2 (anti-inflammatory and antioxidant)	Methanolic extract	BV-2 microglial cells	⁶⁶
34.	Curcuma longa	Zingiberaceae	Curcumin (curcuminoids)	Rhizomes	Inhibit Aβ deposition	Methanolic extract	PC12 rat pheochromocytoma and usual human umbilical vein endothelial (HUVEC) cells	^67,68
35.	Dioscorea bulbifera	Dioscoreaceae	Diosgenin, stigmasterol, (saponin glycoside)	Tubers	Neuroprotective, antioxidants	Not clear	HT-22 mouse hippocampal cells	⁶⁹
36.	Emblica officinalis	Euphorbiaceae	3,6-di-O-galloyl-d-glucose, myricetin (flavonoid), chebulagic acid (tannin)	Fruits	Inhibit AChE, BuChE, cytosolic cytochrome c, pTau, GSK-3β, and pAkt, antioxidant	Methanolic extract	2,2-diphenyl-1-picrylhydrazyl scavenging activity, AChE, and BuChE assay, rodents	⁷⁰
37.	Esenbeckia leiocarpa	Rutaceae	Leptomerine, galanthamine, skimmianine (Alkaloid)	Stem	Inhibit cholinesterase	Ethanolic extract	96-well microplate method	⁷¹
38.	Eucommia ulmoides Oliv	Eucommiaceae	Geniposidic acid (glucoside)	Bark, leaves, and seeds	Prevent Aβ-induced Ca²⁺ intake and protective effect against Aβ-induced cytotoxicity, anti-inflammatory.	Aqueous extract	Rat pheochromocytoma PC-12 cell line, cell number TCR 3	^72,73
39.	Eugenia aromatica	Mytraceae	Eugenol	Buds	Enhance learning-memory ability and antioxidant effect	Pure form	Sprague Dawley rats	^74,75
40.	Evolvulus alsinoides	Convolvulaceae	β-Sitosterol (aglycone), kaempferol (flavonoid)	Aerial parts	Acts against tau-proteins	Aqueous extract	Not mentioned	⁷⁶
41.	Ficus racemosa	Moraceae	Racemosic acid, quercetin, kaempherol	Bark	Inhibit AChE, antioxidant, anti-inflammatory	Aqueous extract	Male Wistar rats	^77,78
42.	Pinus pinaster	Pinaceae	Not clear	Bark	Decrease amyloid plaques, antioxidant	Not clear	APP-transgenic mice	^79,80
43.	Galanthus nivalis	Amaryllidaceae	Galanthamine (alkaloid)	Bulb	Inhibit AChE	Methanolic extract	TLC bioautographic method, Ellman's assay	⁸¹
44.	Garcinia mangostana	Guttiferae	α-Mangostin, 8-deoxy gartanin, garcinone C, garcinone D, gartanin, garciniafuran, and xanthones	Pericarp	Inhibits Aβ agglomeration, glutamate-induced cell damage, BACE1, and AChE, and reduces NF-κB.	Ethanolic extract (xanthones are purified from the extract)	Thioflavin T, DPPH radical scavenging, Cu21-chelating ability assay, HT22 murine hippocampal neuronal cells	^82,83
45.	Gardenia jasminoides	Rubiaceae	Geniposide (glycosides)	Fruits	Inhibit AChE, ChAT expression, blocking of RAGE-MAPK over-activation, Aβ accumulation.	Pure form	mPrP-APPswe/PS1dE9 doubly transgenic mice and littermate wild-type mice	^84,85
46.	Ginkgo biloba (L)	Ginkgoaceae	Ginkgolide B, quercetin (glycosides)	Leaves	Modulate phosphorylation of tau protein, restrict Aβ peptide-induced mitochondrial dysfunction, activation of ERK1/2, JNK, and Akt pathway.	Acetone extract	Embryonic brain tissue was harvested from E15 NMRI mice	^86,87
47.	Glycine max	Leguminosae	Genistein (isoflavones)	Seeds	Inhibit pro-inflammatory mediators ICAM-1, TNF-α, MCP-1, IL-1β (cytokines), IL-8 (chemokines), (anti-inflammatory), inhibit AChE.	Ethanolic extract	Ellman's method, male Wistar rats	^88,89
48.	Glycyrrhiza glabra	Leguminosae	Glabridin (flavonoid)	Roots	Inhibit cholinesterase, anti-inflammatory, antioxidant, and stimulate PI3K-Akt signaling pathway.	Acetone extract (Glabridin isolated in pure form)	Male Kunming mice	^90,91
49.	Hizikia fusiformis	Sargassaceae	Glycyrrhizin (saponin), 18a-glycyrrhetinic acid, 18b-glycyrrhetinic acid	Seaweed	Inhibit BACE1	Methanolic extract	Ellman's method, FRET assay	⁹²
50.	Huperzia serrate	Huperziaceae	Huperzine A (alkaloid)	Whole plant	Inhibit AChE, neuroprotective activity against hydrogen peroxide, Aβ and glutamate (antioxidant)	Pure form	Rat and human model	^93,94
51.	Hypericum perforatum	Hypericaceae	hyperforin, tetrahydrohyperforin, hypericin, chlorogenic acid	Aerial parts	Inhibit AChE, BuChE, and DPPH radical scavenging activity (antioxidant)	Acetate, methanol, and aqueous extract	Ellman's method, dopachrome method, DPPH, N,N-dimethyl-p-phenylene-diamine, superoxide, Nitric oxide radical scavenging assay, ferric-reducing antioxidant power assay, Phosphomolibdenum-reducing antioxidant power assay	⁹⁵
52.	Ilex paraguariensis	Aquifoliaceae	Chlorogenic acid caffeine, theophylline, and theobromine (alkaloid)	Leaves	Reduce AChE activity, reduce Aβ-induced toxicity	Hydroalcoholic extract	Transgenic worms CL2006	⁹⁶
53.	Juglans regia	Juglandaceae	Phenol and flavonoid contents	Leaves and fruits	Neuroprotective, antioxidant, inhibits BChE	Dichloromethane, ethyl acetate, acetone, methanol, and aqueous extract	AChE and BuChE, DPPH, DMPD, superoxide, NO, and hydrogen peroxide radicals ferric ion-chelating capacity assay	⁹⁷
54.	Juniperus chinensis	Cupressaceae	α-methyl artoflavanocoumarin, 5,7,4′-trihydroxy-2-styrylchromone, vanillic acid, taxifolin	Heartwood	Inhibit BACE1	Methanolic extract	Ellman's and BACE1 enzyme assay	⁹⁸
55.	Lavandula angustifolia	Lamiaceae	Linalool and linalyl acetate	Leaves and flowers	Increase clearance of Aβ plaque, antioxidant	Aqueous extract	Rats	⁹⁹
56.	Lepidium meyenii	Brassicaceae	Quercetin (anthocyanins)	Hypocotyls	Inhibit AChE and antioxidant	Aqueous extract	Female mice	¹⁰⁰
57.	Liriope platyphylla	Asparagaceae	Spicatoside A, (saponin)	Roots	Stimulate PI3-kinase/Akt and ERK1/2 pathways, decrease production and aggregation of Aβ₄₂ peptides, increase nerve growth factor, anti-inflammatory	Aqueous extract	Tg2576 mice	^101,102
58.	Maclura pomifera	Moraceae	Osajin, pomiferi (isoflavones)	Fruits	Inhibit cholinesterase	Methanolic extract	Ellman method	¹⁰³
59.	Magnolia obovate	Magnoliaceae	Obovatol (lignan)	Fruits	Inhibit NF-kB pathway, Aβ generation, BACE1, and AChE	Methanolic extract (Obovatol isolated in pure form)	Mice	¹⁰⁴
60.	Magnolia officinalis	Magnoliaceae	4-O-methylhonokiol (lignan)	Bark	Decreased activity of AβPP, BACE1, inhibits cytokine release and NF-kB pathway, decreases Aβ toxicity.	Ethanolic extract	Transgenic C57BL/6 mouse model	^105–107
61.	Melia toosendan	Meliaceae	1-O-Tigloyl-1-O-deacetyl-nimbolinin B, limonoids	Fruits	Suppress NF-κβ and JNK pathway, iNOS, TNF-α, IL-1β, and COX-2 (anti-inflammatory)	Pure form	BV-2 microglia cells	¹⁰⁸
62.	Melissa officinalis	Lamiaceae	Rosmarinic acid, gallic acid, isomenthone, ε-caryophyllene, neral/geranial, citronellal, ursolic acid	Leaves	Inhibit AChE, matrix metalloproteinase-2, antiagitation properties, antioxidant	Aqueous and ethanolic extract	AChE and DPPH assay	¹⁰⁹
63.	Morinda Officinalis	Rubiaceae	Alizarin-1-methyl ether, scopoletin, b-sitosterol, 1-hydroxy-3-hydroxymethyl (anthraquinone)	Roots	Inhibit AChE, BChE, and BACE1	Methanolic extract	AChE, BChE, and BACE1 inhibition assay	¹¹⁰
64.	Moringa oleifera	Moringaceae	β-carotene, kaempferol, rutin	Leaves, seeds, roots, flowers, and bark	Antioxidant	Methanolic extract	Rats	¹¹¹
65.	Morus alba	Moraceae	Quercetin (flavonoid), Artoindonesianin flavone	Root bark, fruits, and leaves	Inhibit BACE1, AChE, attenuates Aβ-induced toxicity, blocks oligomer Aβ4	Methanolic extract	BACE FRET assay	^112,113
66.	Murraya koenigii	Rutaceae	Mahanimbine, koenimbine, mahanine, bispyrayafoline	Leaves	Improve the level of acetylcholine, inhibit BACE1, and nootropic effect	Methanolic extract	Male Swiss Albino mice	^114,115
67.	Myrica pensylvanica	Myricaceae	Myricetin, myricitrin (Flavonol), myricanol	Berry	Decrease level of tau proteins	Aqueous extract	M17 neuroblastoma cells, HeLa cell line, human IMR32 cell line, H4 neuroglioma cells, IMR32 cells	¹¹⁶
68.	Myristica fragrans	Myristicaceae	{[(7S)-8-(4-hydroxy-3-methoxyphenyl)-7-hydroxypropyl]benzene-2,4- diol}, [(8R,8S)-7-(3,4-methylenedioxyphenyl)-8,8-dimethyl-7- (3,4-dihydroxyphenyl)-butane]	Seeds	Inhibit AChE and BACE1	Methanolic extract	Ellman method	¹¹⁷
69.	Nelumbo nucifera embryos	Nelumbonaceae	Cycloartenol, p-hydroxybenzoic acid, vanilloloside, nuciferoside, and 5-O-methyladenosine	Stamen	Inhibit AChE and BChE	Methanolic extract	Ellman method, BACE1 enzyme assay	¹¹⁸
70.	Nicotiana tobaccum	Solanaceae	Anatabine (alkaloid)	Leaves	Inhibit NFκB pathway, Aβ production, BACE-1, decrease Aβ	Pure form	Transgenic mice, HEK293 cells, SHSY-5Y cells, 7 W CHO cells overexpressing wild-type human APP	^119–121
71.	Ocimum sanctum	Lamiaceae	Ursolic acid and oleanolic acid	Leaves	Inhibit AChE, immunostimulant property	Alcoholic and aqueous extract	Male albino Wistar rats	^122,123
72.	Olea europaea	Oleaceae	Oleuropein (glucoside)	Leaves	Prevents Aβ aggregation, reduces amyloid aggregates, and modulates the AMPK/mTOR pathway	Pure Oleuropein extracted from olive oil	Mouse brain endothelial cells	^124,125
73.	Paeonia lactiflora	Ranunculaceae	Paeoniflorin (glycoside)	Roots	Decreases ROS production and mitochondrial membrane potential and upsurges Bax/Bcl-2 ratio, activation of caspases, and cytochrome c release	Pure form	Rat model, SH-SY5Y cell	¹²⁶
74.	Passiflora edulis	Passifloraceae	C dideoxyhexosyl (flavonoid)	Stem and leaves	Antioxidant	Acetone extract	PC12 cells	^127,128
75.	Physostigma venenosum	Leguminosae	Physostigmine (alkaloid)	Seeds	Inhibit AChE and BuChE	Pure form	Human and animal models	^129,130
76.	Pimpinella brachycarpa	Apiaceae	Quinic acid derivatives	Aerial parts	Anti-neuroinflammatory, inhibits NO production (antioxidant)	Methanolic extract	Murine microglial cell line	¹³¹
77.	Pistacia atlantica	Anacardiaceae	Digallic acid, trigallic acid and depsidones	Leaves	Inhibit AChE, antioxidant	Aqueous extract	TLC bioautography and DPPH assay	¹³²
78.	Pistacia integerrima	Anacardiacea	Pistagremic acid, terpene	Galls	Inhibit BACE1	Methanolic extract	BACE1 inhibition assay	¹³³
79.	Pongamia pinnata	Leguminosae	Pongaglabol methyl ether, lonchocarpin, and glabrachromene II	Seeds and stems	Neuroprotective, anti-inflammatory, decrease NO production	Dichloride methane extract	BV-2 cells	¹³⁴
80.	Psoralea corylifolia	Leguminosae	Bakuchiol, psoralen, neocorylinbavachromen, isobavachromene, bavachalcone, isobavachalcone	Seeds	Inhibit BACE1 and decrease NO production	Methanolic extract	FRET assay	^135,136
81.	Psoralea fructus	Leguminosae	Bavachin, bavachinin, bavachalcone, and isobavachalcone (flavonoid)	Fruits	Inhibit amyloid -peptide 42, glycogen synthase kinase 3β, β-secretase, and AChE.	Ethanolic aqueous extract	BV-2 microglial cell line, BACE-1, AChE and GSK-3β assay	^137,138
82.	Pteridium aquilinum	Dennstaedtiaceae	Pteroside N (Glycoside), Pterosinone (terpene)	Whole plant	Inhibit cholinesterase enzymes	Aqueous extract	BACE1, FRET assay, and Ellman method	¹³⁹
83.	Pterocarpus santalinus	Leguminosae	Pterostilbene (stilbenoid)	Heartwood, bark	Down-regulate NF-kB, JNK pathway, inhibit cholinesterase	Methanolic extract	Swiss Albino mice and Ellman method	^140,141
84.	Ptychopetalum olacoides	Olacaceae	Not clear	Roots	Inhibit AChE	Ethanolic extract	Male adult Albino mice, Ellman method	^142,143
85.	Pueraria lobata	Leguminosae	Lupeol, Lupenone, genistein, biochanin A, triterpenoids, and polyphenol	Roots	Inhibit BACE1, reduce Aβ induce toxicity	Aqueous extract	BACE1, FRET assay	^144,145
86.	Punica granatum	Punicaceae	Punicalgin, quercetin, gallic acid, cyanidin-3-glucoside	Leaves	Inhibit BACE1, 5-lipoxygenase (5-LOX), AChE, and BuChE	Hexane, dichloromethane, ethyl acetate, ethanol, methanol, and hydroalcoholic extract	Recombinant human BACE assay, DPPH, 2,20-azinobis-3-ethylbenzothiazoline-6 sulphonate, and Ellman's method	^146,147
87.	Rabdosia japonica	Lamiaceae	Glaucocalyxin A	Aerial parts	Suppress NF-κB, anti-inflammatory	Methanolic extract (Glaucocalyxin A further isolated from this extract)	Primary microglia and BV-2 cell	¹⁴⁸
88.	Rabdosia rubescens	Lamiaceae	Oridonin (terpenoid)	Leaves	Inhibited the NF-kB pathway, decreased the release of inflammatory cytokines, and Aβ deposition	Pure form	Transgenic mice	¹⁴⁹
89.	Rauvolfia reflexa	Apocynaceae	Isoresrpiline and rescinnamine	Bark	Inhibit cholinesterase	Methanolic extract	Ellman's microplate assay	¹⁵⁰
90.	Reseda luteola	Resedaceae	Luteolin	Aerial part	Suppress BACE1, NF-κB, MAPK pathway interleukin (anti-inflammatory), and antioxidant	Aqueous extract	Sprague–Dawley rats	^151,152
91.	Rhodiola rosea	Crassulaceae	Salidroside, gossypetin-7-O-L-rhamnopyranoside, rhodioflavonoside	Roots	Activation of PI3K/Akt, decreased Aβ deposition and inhibited AChE.	Ethanolic extract (Salidroside is in pure form)	Transgenic Drosophila AD model, Ellman's method	^153,154
92.	Rosa damascene	Rosaceae	Docosahexaenoic acid, polyunsaturated fatty acid	Buds	Decrease Aβ-induced atrophy and cell death	Chloroform extract	Embryos of Sprague-Dawley rats	^155,156
93.	Salix alba	Salicaceae	Salicin (glucoside), procyanidins	Bark	Inhibit AChE and shows the antioxidant effect	Hydroalcoholic extract	2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid, DPPH test, Ellman's method	^157,158
94.	Salvia miltiorrhiza	Lamiaceae	Tanshinone	Roots	Protect from Aβ-induced toxicity, antioxidant, inhibit ROS, inhibit PTP1B generation, prevention of lipid peroxidation, decrease the release of cytochrome c	Alcoholic extract	Sprague Dawley rats, cell viability assay	^159,160
95.	Salvia officinalis	Lamiaceae	Isorosmanol, 7a-methoxy rosmanol, terpenoid glycosides	Aerial parts	Inhibit AChE	Methanolic extract	Ellman's method	¹⁶¹
96.	Schisandra chinensis	Schisandraceae	Gomisin A, C, D & G schisandrol B, (lignan)	Fruits	Inhibit AChE	Hexane extract	Ellman's method	¹⁶²
97.	Scutellaria baicalensis	Lamiaceae	Baicalin, baicalein, wogonin, and chrysin	Roots	Anti-inflammatory, inhibit BACE1, and AChE	Aqueous, n-hexane, ethanol, and methanol extract	BACE1, AChE, TACE, trypsin, chymotrypsin, elastase, MTT assay, mouse monocyte/macrophage cell line	^163,164
98.	Sorghum bicolor	Poaceae	Quercetin, quercetrin, rutin, caffeic and chlorogenic acid	Stem	Inhibit AChE, ecto-5′-nucleotidase activities, and increased Na⁺/K⁺-ATPase activity	Methanol: 1 N HCl (1:1, v/v) extract	Albino rats, modified colorimetric method	¹⁶⁵
99.	Stephania tetrandra	Menispermaceae	Tetrandrine (alkaloid)	Roots	Inhibit NF-κB activation, down-regulation of TNF-α and IL-1β	Pure form	Male Sprague–Dawley rats, Morris water maze test	^166,167
100.	Symphyocladia latiuscula	Rhodomelaceae	2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether, 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol, and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether bromophenols	Alga	Inhibit AChE and BChE, GSK-3β, and BACE1, antioxidant	Methanolic extract	Human recombinant β-secretase and a BACE1 fluorescence resonance energy transfer, GSK-3β enzyme inhibition, self-induced Aβ_25–35 aggregation inhibition assay	^168,169
101.	Tabernaemontana pandacaqui	Apocynaceae	Astragalin (flavonoid)	Flowers	Inhibit AChE	Methanolic extract	Ellman's method	¹⁷⁰
102.	Terminalia chebula	Combretaceae	Ethyl N-(N-benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide	Fruits	Inhibit AChE, antioxidant	Ethyl acetate extract	Ellman's method, DPPH radical scavenging assay	¹⁷¹
103.	Tinospora cordifolia	Menispermaceae	Tinosporide and 8-hydroxytinosporide	Stem	Inhibit AChE and BuChE	Methanolic extract	Ellman's method, AChE inhibition assay method	¹⁷²
104.	Uncaria rhynchophylla	Rubiaceae	Rhynchophylline and isorhynchophylline (alkaloid)	Stem	Inhibit Aβ-generated neurotoxicity, intracellular calcium overloading, and tau protein hyperphosphorylation.	Hydroalcoholic extract	Rat pheochromocytoma cells, MTT method	^173,174
105.	Uncaria tomentosa	Rubiaceae	Mitraphylline (alkaloid)	Root bark	Prevent Aβ protein aggregation, mitraphylline amyloid protein	Aqueous extract	Aβ protein fragment 1–40	¹⁷⁵
106.	Valeriana officinalis	Valerianaceae	Volvalerenal acid	Roots	Inhibit AChE	Ethanolic extract	Ellman's method, Seventy-five Class SPF APPswe/PS1E9 double-transgenic dementia mice, Morris water maze	^176,177
107.	Vitis vinifera	Vitaceae	Resveratrol (stilbenoid)	Grapes/berry	Decrease aggregation and toxicity of Aβ peptides, stimulation of regulation by AMPK-dependent signaling pathways, mTOR inhibition, inhibit cholinesterase, transcription factor (NF-κB), and cellular autophagy stimulation.	Pure form	Rodent model	¹⁷⁸
108.	Withania somnifera	Solanaceae	Withanolides (steroid)	Roots	Decreases Aβ_1–42-induced toxicity	Chloroform extract	Adult male Wistar rats	^179,180
109.	Xanthoceras sorbifolia	Sapindaceae	Xanthoceraside	Fruits, husk	Inhibits tau hyperphosphorylation, PI3K/Akt-dependent GSK-3β signaling pathway, and increases the activity of phosphatases.	Pure form	Adult male and female Wistar rats	¹⁸¹
110.	Zingiber officinale	Zingiberaceae	6-shogaol	Rhizomes	Inhibit Aβ_1–42 induced activation of astrocytes and microglial cells, TNF-α, iNOS, NO, and COX-2 inflammatory gene PGE2, prompt NGF and modulate NF-κB pathway (anti-inflammatory)	Methanolic extract	Adults Sprague–Dawley rats, DPPH, FRAP assay, Ellman's method	^182,183
111.	Zizyphus jujuba var. spinosa	Rhamnaceae	Jujuboside A, and jujuboside B	Seeds	Improve Aβ-induced synaptic dysfunction and increase the level of BDNF and TrkB.	Ethanolic extract	Male CD-1 mice	¹⁸⁴

AChE: acetylcholinesterase; AβPP: amyloid-β protein precursor; Aβ: amyloid-β; BACE1, β secretase; BChE, butyrylcholinesterase; BDNF: brain-derived neurotrophic factor; ChAT: choline acetyltransferase; ChE: cholinesterase; COX-2: cyclooxygenase-2; DMPD: dimethyl-4-phenylenediamine; DPPH: 2,2-diphenyl-1-picrylhydrazyl; ERK: extracellular regulated kinases; FRAP: ferric reducing antioxidant power; FRET: fluorescence resonance energy transfer; GSK-3β: glycogen synthase kinase-3β; ICAM: intercellular adhesion molecule; IL: Interleukin; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NGF: nerve growth factor; NO: nitric oxide; PGE2: prostaglandin E2; PI3K: phosphatidylinositide 3-kinase; pTau: phospho-Tau; PTP1B: protein tyrosine phosphatase 1B; RAGE: receptor of advanced glycation end products; ROS: reactive oxygen species; TACE: TNF-α-converting enzyme; TLC: thin layer chromatography; TNF: tumor necrosis factor; TrkB: tropomyosin-related kinase B.

According to this review, there are 64 families of herbal plants, and around 23 parts demonstrated anti-AD activity. The families, including Leguminosae, Lamiaceae, Apiaceae, Rubiaceae, and Moraceae, devote a large number of anti-AD agents (Figure 3). More than 15 different anti-AD mechanisms have been discovered in phytoconstituents from these plants. The plants from the Leguminosae family inhibit the Aβ aggregation, AChE, BChE, AβPP, and BACE1, anti-amyloidogenic, blockage of NF-kB pathway, NO, PGE2 (anti-inflammatory and antioxidant), pro-inflammatory mediators, TNF-α, IL-8, MCP-1, IL-1β (cytokines), and ICAM-1, along with others. The most common mechanism behind the anti-AD activity is inhibiting the cholinesterase enzyme (BChE/AChE); the second most common mechanism is the antioxidant-mediated effect. Only a few researchers, however, have focused on the particular molecular mechanism responsible for anti-AD action. As a result, the expanding threat of AD to world health has prompted experts and researchers to devote more time and exercise to identifying an effective molecular mode of action.

Figure 3.

Plants associated with several families having anti-AD action.

It is observed from Figure 4 that Korea is first, China is second, India is third in phytochemical research against AD, followed by Iran, Brazil, and Japan. It has been noted that research efforts are gradually growing day by day for the evaluation of potent anti-AD phytochemicals in the management of AD. Research done in the year 2021 is more than in other years, indicating a growing interest of researchers in investigating the therapeutic application of plant-derived compounds in treating AD (Figure 5).

Figure 4.

Country-wise research trends.

Figure 5.

Year-wise research was done to estimate trends of natural anti-AD agents.

Figure 6 illustrates phytochemicals derived from various plant parts exhibiting anti-AD activity, and analysis reveals that phytochemicals obtained from leaves exhibit the highest and most significant therapeutic potential against AD, followed by roots, fruits, bark, and seeds. This information holds valuable implications for selecting specific plant parts for further investigation in herbal plant research related to AD. However, there is another aspect that we should not miss: the common observation that not all plant parts have been explored for all the medicinal plants. So, in the present case, it would be more appropriate to indicate leaves as the most explored plant part for anti-AD potential.

Figure 6.

Different parts of the plants have anti-AD activity.

Figure 7 summarizes the different modes of action by which various plants demonstrated their anti-AD activity. Most plants showed anti-AD activity by inhibiting the cholinesterase enzyme (BChE/AChE), followed by antioxidant activity.

Figure 7.

Graphical representation of different modes of action shown by various natural anti-AD phytochemicals.

As data is given in Figure 8, alkaloids play a vital role in treating AD, followed by flavonoids, terpenoids, glycosides, and many more. We could also mention alkaloids are the most explored phytochemical class in evaluating anti-AD potential.

Figure 8.

The different phytochemical classes responsible for anti-AD activity.

Clinical studies

Clinical trials have been conducted recently to assess their therapeutic efficacy and potential side effects. Nicotine was the first natural product studied in a clinical trial study in 1992. Several other compounds, such as vitamins, were studied in clinical trials for AD therapy during the 1990s.¹⁸⁵ The use of natural products in clinical trials has recently gained popularity. Through a webinar in 2017, the National Centre for Complementary and Integrative Health (NCCIH) announced new funding opportunities for natural product clinical trials.¹⁸⁶

A detailed report of clinical trial studies on natural products used to treat AD is described in Table 2.

Table 2.

Natural products that were used in the clinical trial studies for AD.

S. no.	Natural Products	Condition of Participants	Dose	Route of administration	Number of subjects	Duration	Outcomes	References
1.	Curcumin	AD	1–4 gm/day	Oral	34	Six months	Safer and well-tolerated	¹⁸⁷
2.	Nicotine	AD	5–10 mg/day	Transdermal	8	Ten weeks	Enhancement of attentional performance	¹⁸⁸
2.	Nicotine	AD	0.4–0.8 mg/day	Subcutaneous	70	Two weeks	Enhancement of visual and perceptual attentional deficits	¹⁸⁹
3.	Resveratrol	Mild to moderate AD	500–1000 mg/twice a day	Oral	119	52 weeks	Side effects, no effectiveness in the reduction of biomarker levels	¹⁹⁰
4.	Saffron	Mild to moderate AD	30 mg/day	Oral	46	16 weeks	Safe, improvement of memory and cognitive functions	¹⁹¹
5.	Blueberry	Early memory failures	Not mentioned	Oral	9	12 weeks	Reduction of depressive symptoms and enhancement of learning	¹⁹²
6.	Huperzine A	Mild to moderate AD	200–400 μg BID/day	Not mentioned	177	16 weeks	Safer and well-tolerated, improvement of cognitive functions	¹⁹³
6.	Huperzine A	AD	50–100 mg/day	Oral	60	60 days	Safer and well-tolerated, reduction of oxidative stress	¹⁹⁴
7.	Ginkgo biloba	Mild cognitive impairment	240 mg/day	Oral	160	24 weeks	Safer and well-tolerated, improvement of cognitive functions	¹⁹⁵
		Mild to moderate dementia	240 mg/day	Oral	410	24 weeks	Safe, improvement of neuropsychiatric symptoms	¹⁹⁶
		AD or vascular dementia	240 mg/day	Oral	404	24 weeks	Improvement of cognitive functions and functional abilities, improvement of neuropsychiatric symptoms	¹⁹⁷

Conclusion

AD is expanding at a frightening rate worldwide in old age people. AD and its comorbidities are generally lethal if not treated. Thus, to effectively manage and treat AD, numerous countries focus on research and development activities. Natural anti-Alzheimer's agents derived from plants might be promising alternatives to synthetic drugs in managing and treating AD. These plant-derived compounds have shown potential for improving cognitive function and slowing down the progression of the disease. However, it is essential to ensure the safety and efficacy of these phytoconstituents through rigorous toxicological studies and clinical trials. Additionally, further research is needed to elucidate the molecular mechanisms underlying the anti-Alzheimer's activity of these natural compounds, allowing for the development of more targeted and effective therapies. The exploration of plant-derived compounds in AD treatment will continue to be an area of significant interest and focus of future research, with the ultimate goal of providing improved care and management options for individuals affected by AD.

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

ORCID iDs

Sanjay Sharma

Rajeev K Singla

Author contributions

Kalpesh Mahajan (Data curation; Formal analysis; Investigation; Visualization; Writing – original draft); Sanjay Sharma (Conceptualization; Formal analysis; Project administration; Supervision; Validation; Writing – review & editing); Rupesh K Gautam (Conceptualization; Formal analysis; Project administration; Supervision; Writing – review & editing); Rajat Goyal (Data curation; Formal analysis; Investigation; Visualization; Writing – original draft); Dinesh Kumar Mishra (Formal analysis; Validation; Writing – review & editing); Rajeev K Singla (Conceptualization; Formal analysis; Project administration; Supervision; Writing – review & editing).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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