FlavonoidsCatechin
Epicatechin
ProanthocyanidinsVitis vinifera (Grape seed polyphenol extract—GSPE)Male Sprague–Dawley rats.
 
Rates aged 12 weeks and weighing between 250–260 g. GSPE was administered at doses of 25 or 250 mg/kg BW. The mode of administration was oral gavage, carried out once daily over a period of 11 days.GSPE-derived phenolic acids, specifically 3-hydroxybenzoic acid (3-HBA) and 3-(3′-hydroxyphenyl) propionic acid (3-HPP):
Interfere with the assembly of Aβ peptides into neurotoxic aggregates. This suggests potential therapeutic effects in modulating AD pathogenesis by preventing the formation of Aβ oligomers and fibrils.[197]Baicalin
Icariin
Dihydromyricetin (DHM)
HesperidinBaicalin: C₂₁H₁₈O₁₁
Icariin: C₃₃H₄₀O₁₅
Dihydromyricetin (DHM): C₁₅H₁₂O₈
Hesperidin: C₂₈H₃₄O₁₅Baicalin: Scutellaria baicalensis
Icariin: Epimedium species
Dihydromyricetin (DHM): Hovenia dulcis
Hesperidin: Citrus sinensis and Citrus reticulataHeterozygous male transgenic APP/PS1-(21) mice, bred with female wild-type C57BL/6J mice.
 
Each polyphenol (baicalin, icariin, DHM, hesperidin) was administered at a dose of 100 mg/kg BW. The polyphenols were administered orally via gavage, dissolved in 1% carboxymethylcellulose (CMC). The treatment period was ten days, with daily administration of the polyphenols.Hesperidin and icariin:
Restore behavioral deficits.
Reduce Aβ deposits in both the cortex and hippocampus of the transgenic mice.
Baicalin and DHM:
No substantial effects on the above parameters.[198]Gallic acid
Catechin
Epicatechin
ProanthocyanidinsGallic acid: C₇H₆O₅
Catechin: C₁₅H₁₄O₆
Epicatechin: C₁₅H₁₄O₆
Proanthocyanidins:
C₃₁H₂₈OVitis vinifera L. (grape seed extract (GSE) is rich in polyphenols)APPSwe/PS1dE9 transgenic mice.
 
Mice were administered daily polyphenols with a total polyphenolic content of 592.5 mg/g DW, including gallic acid (49 mg/g DW), catechin (41 mg/g DW), epicatechin (66 mg/g DW), and proanthocyanidins (436.6 mg catechin Eq./g DW). The daily consumption of polyphenols was approximately 1.2–1.7 mg per gram of BW, which is equivalent to about 5.9 g per day for a 60 kg human.GSE:
Reduces the Aβ burden in the brain and blood.
Prevents Aβ deposition.
Attenuates microgliosis and inflammation.
Reduces brain Aβ levels by 33%, serum Aβ levels by 44%, amyloid plaques by 49%, and microgliosis by 70%.[199]StilbenesResveratrolC₁₄H₁₂O₃Grapes, red wine, and mulberry (Morus atropurpurea L.)Senescence-accelerated mouse prone 8 (SAMP8) and senescence-accelerated mouse resistant 1 (SAMR1).
 
The diet was supplemented with trans-resveratrol at a concentration of 1 g/kg and administered ad libitum to mice, starting at 2 months of age and maintained on this regimen until 9 months of age.Resveratrol:
Increases lifespan and reduces neurodegenerative markers in SAMP8 mice.
Reduces levels of Aβ peptides.
Decreases tau hyperphosphorylation.
Enhances cognitive function and memory in animal models.
Activates SIRT1 and AMPK pathways, promoting non-amyloidogenic processing of APP.
Reduces oxidative stress.[200]ResveratrolC₁₄H₁₂O₃Double-transgenic AβPP/PS1 mice, which express a chimeric mouse/human Aβ protein precursor (Mo/Hu AβPP695swe) and a mutant human presenilin 1 (PS1-dE9).
 
Mice were fed a chow diet containing 1% resveratrol, which translated to a daily resveratrol consumption of approximately 4 mg/kg/day, over a period of 10 months starting from 2 months of age.Resveratrol:
Prevents memory loss as measured by the object recognition test.
Reduces the Aβ burden.
Increases mitochondrial complex IV protein levels.
These effects were mediated by increased activation of SIRT1 and AMPK pathways.
Promotes changes in inflammatory processes (increased IL1β and TNF gene expression).[201]ResveratrolC₁₄H₁₂O₃Male wild-type (WT) and AD transgenic 5xFAD mice.
Mice were subjected to a high-fat diet (HFD) and resveratrol supplementation for 16 weeks, starting from 2 months of age to 6 months. The HFD constituted 60% of calories from fat, while the resveratrol-supplemented diet included 1 g/kg of trans-resveratrol (0.1% w/w). This concentration was chosen based on previous studies demonstrating its neuroprotective effects. The mice received approximately 120 mg/kg BW of trans-resveratrol per day.Resveratrol:
Neuroprotective effects against HFD-induced amyloid pathology, reducing amyloid burden and tau pathology in the cerebral cortex.
Improves memory deficits and enhanced brain resilience against neurodegeneration through proteostasis enhancement and tau deacetylation mediated by SIRT1.[202]Mix of polyphenolsGrape seed polyphenol extract (GSPE)Vitis vinifera L. (Grape seeds)TMHT mouse model of AD.
 
Mice were treated with 200 mg/kg/day of GSPE, starting at 4 months of age and continued for 2 months.GSPE:
Interferes with the assembly of tau peptides into neurotoxic aggregates
Reduces the development of AD-type tau neuropathology.
Decreases tau phosphorylation at specific sites, thereby preventing the formation of NFTs and reducing ERK 1/2 activity.
Led to a significant reduction in the accumulation of insoluble tau and hyperphosphorylation of tau in the brains of TMHT mice.[203]Flavonoids
Phenolic acids
AnthocyaninsMuscadine wine was generated from Vitis rotundifolia (cv. Noble grapes).
Cabernet Sauvignon wine was generated from Vitis vinifera L. grapes.Tg2576 AD mouse model mice.
 
Mice consumed approximately 4 mL of wine-adulterated water per day over a period of 10 months, with the concentration of polyphenols in the muscadine wine measured as 1.731 mg/L (as gallic acid).Muscadine wine polyphenols:
Interfere with the aggregation of Aβ peptides into high-molecular-weight oligomeric species, which are implicated in cognitive dysfunction in AD.
 
Cabernet Sauvignon wine polyphenols:
Promote non-amyloidogenic α-secretase activity, reducing Aβ neuropathology.[204]Anthocyanins
Flavonoids
Organic acids (malic acid, oxalic acid, and tartaric acid)Vitis vinifera L. (red grape),Wistar rats (12–15 weeks old, weighing 250–300 g)
 
AD was induced by orally administering AlCl3 at a dose of 17 mg/kg BW daily for four consecutive weeks. After the induction period, the rats were divided into five groups: normal healthy controls, normal rats receiving Vitis vinifera leaf polyphenol (VLP) extract, AD-induced positive controls, AD-induced rats treated with VLP extract, and AD-induced rats treated with rivastigmine (RIVA). The VLP extract was administered orally at a dose of 100 mg/kg BW daily for 21 days, whereas RIVA was administered at a dose of 0.3 mg/kg BW daily for the same duration.VLP:
Neurorestorative activity.
Antiapoptotic activity.
Anti-inflammatory activity.
Anticholinesterase activity.
Antioxidative activity.
Anti-amnesic activity.
Improves behavioral outcomes in T-maze tests.
Reduces brain damage as evidenced by histopathological investigations.[205]Anthocyanins
Hydroxycinnamic acid derivatives (e.g., caffeic acid)
Hydrolyzable tannins (e.g., ellagic acid, quercetin-3-O-glucoside, punicalin)
Hydroxybenzoic acids (e.g., gallic acid, protocatechuic acid)
Hydroxycyclohexane carboxylic acids (e.g., quinic acid)
Hydroxyphenyls (e.g., kaempferol, catechin)Punica granatumAPPsw/Tg2576 transgenic mice were used alongside wild-type control mice.
 
The experimental groups consisted of wild-type controls on a regular diet, transgenic controls on a regular diet, and transgenic mice fed with a 4% pomegranate-enriched diet. The pomegranate supplementation was administered for 15 monthsPomegranate:
Attenuates oxidative damage, as evidenced by decreased lipid peroxidation and protein carbonyl levels.
Restores the activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione S transferase) in the brain.
This suggests that the therapeutic potential of pomegranate in the treatment of AD might be associated with its ability to counteract oxidative stress.[206]Cranberry extract (CBE)Vaccinium macrocarponCaenorhabditis elegans (C. elegans) transgenic strain CL4176.
The polyphenol concentration used was 2 mg/mL of CBE. The administration of CBE was performed through supplementation in the nematode growth medium (NGM) plates. For the preventive treatment, CBE supplementation began from egg hatching and continued until the L3 larval stage, before the induction of Aβ expression via heat-shock. For the therapeutic treatment, CBE was administered starting from the L3 stage after Aβ expression induction. The incubation/administration time varied accordingly: in the preventive treatment, CBE exposure was until the L3 stage prior to Aβ induction, whereas in the therapeutic treatment, it was from L3 stage until paralysis occurred. Both protocols aimed to assess the efficacy of CBE in alleviating Aβ toxicity and its potential preventive versus therapeutic effects in the C. elegans AD model.CBE:
Delays the body paralysis triggered by Aβ toxicity.
Reduces Aβ expression at both RNA and protein levels.
Improves memory health.[207]Dark chocolate (DC) containing 4% total polyphenol contentOne of the primary polyphenols in dark chocolate is epicatechin: C₁₅H₁₄O₆Theobroma cacaoSprague–Dawley rat pups.
 
Rats were divided into four groups: control rats (Ctrl), control rats treated with dark chocolate (Ctrl Choc), non-transgenic AD (NTAD) model rats induced by monosodium glutamate (MSG), and NTAD rats treated with dark chocolate (MSG Choc). The dark chocolate (DC) used contained 70% cocoa solids and 4% total polyphenol content, administered orally at a dosage of 500 mg/kg BW per day. The polyphenol content in the dark chocolate used in the study was determined to be 20 mg of total polyphenol content (TPC) in 500 mg of dark chocolateDark chocolate:
Reduces hyperglycemia in the treated rats.
Inhibits the cholinesterase activity in the hippocampal tissue homogenates.
Enhances cognitive performance in the spatial memory-related Barnes maze task.
Increases cell volume in the CA3 region of the hippocampus.
Improves cognitive function and cholinergic activity in the hippocampus while correcting metabolic disturbances in aged NTAD rats.[208]Harrisonia abyssinicaQuercetin (C₁₅H₁₀O)
Kaempferol (C₁₅H₁₀O₆)
Apigenin (C₁₅H₁₀O₅)Harrisonia abyssinicaMale Wistar albino rats.
 
The rats were divided into five groups: a control group, an AlCl_:treated group, a rivastigmine-treated group, and two groups treated with different doses of Harrisonia abyssinica extract.
AlCl₃ was administered at a dose of 100 mg/kg BW per day orally. Rivastigmine was administered at a dose of 0.3 mg/kg BW intraperitoneally. Harrisonia abyssinica extract was administered at two doses: 100 mg/kg BW and 200 mg/kg BW per day by oral gavage.
The treatments were administered for a period of 3 weeks.Harrisonia abyssinica:
 
Improves memory and learning performance as assessed by the passive avoidance test.
Reduces hippocampal levels of AChE and extracellular regulated kinase, both of which were elevated by AlCl₃.
Restores normal levels of neurotransmitters (noradrenaline, dopamine, serotonin) in the brain.
Decreases oxidative stress markers, pro-inflammatory cytokines, and apoptotic markers.
Prevents Aβ plaque deposition and restoration of normal histological appearance of the hippocampus.[209]AnthocyaninCcyanidin-3-glucosylrutinoside (C₂₇H₃₁O₁₅), Cyanidin-3-rutinoside (C₂₇H₃₁O₁₅), and Cyanidin-3-glucoside (C₂₁H₂₁O₁₁)Montmorency cherries5xFAD transgenic mouse.
 
The study administered a proprietary product, Total Body Rhythm (TBR), composed of tart cherry extract rich in anthocyanins (426.7 μg/mg) and omega fatty acids, to both 6-month-old and 12-month-old mice. The TBR treatment, dosed at 60 mg/kg, was delivered via oral gavage every other day for two months, with a 0.5% methyl-cellulose PBS solution as the vehicleTBR:
Reduces memory deficits in the MWM and NOR tests.
Decreases anxiety levels in the OF task primarily in 6-month-old male mice.
Protects against neuron loss, reduces activation of astrocytes and microglia primarily in 6-month-old mice, and attenuates Aβ deposition.[210]Cyanidin 3,5-O-diglucoside
Cyanidin 3-O-glucoside
Cyanidin 3-O-rutinoside
(+)-Catechin
(−)-Epicatechin
Procyanidin dimer B1, B3, B4, and B5
Procyanidin trimer C1, C2, EEC, and T2
Kaempferol 3,7-O-diglucoside
Kaempferol 3-O-(6″-acetyl-galactoside) 7-O-rhamnoside
Kaempferol 3-O-galactoside
Kaempferol 3-O-galactoside 7-O-rhamnosideCyanidin 3,5-O-diglucoside: C₂₇H₃₁O₁₆
Cyanidin 3-O-glucoside: C₂₁H₂₁O₁₁
Cyanidin 3-O-rutinoside: C₂₇H₃₁O₁₅
(+)-Catechin: C₁₅H₁₄O₆
(−)-Epicatechin: C₁₅H₁₄O₆
Procyanidin dimer B1, B3, B4, and B5: C₃₀H₂₆O₁₂
Procyanidin trimer C1, C2, EEC, and T2: C₄₅H₃₈O₁₈
Kaempferol 3,7-O-diglucoside: C₂₇H₃₀O₁₆
Kaempferol 3-O-(6″-acetyl-galactoside) 7-O-rhamnoside: C₂₉H₃₂O₁₆
Kaempferol 3-O-galactoside: C₂₁H₂₀O₁₁
Kaempferol 3-O-galactoside 7-O-rhamnoside: C₂₇H₃₀O₁₅Rosa x hybridaC. elegans that express human Aβ peptide, a key protein involved in AD.
 
Concentration used: 100 μg/mL. Worms were exposed to the extract in their growth medium.Rosa x hybrida:
Reduces paralysis rate significantly.
Significant improvements in mobility were observed at 36, 38, 40, and 42 h post-induction.
Increases the chemotactic index, which measures the worms’ ability to move towards a chemical stimulus.
No toxicity was observed, as indicated by normal metabolism, reproduction, and lifespan parameters even after exposure to the Rosa x hybrida extract at a concentration of 100 μg/mL.[211]Cocoa polyphenolsCatechin: C₁₅H₁₄O₆
Epicatechin: C₁₅H₁₄O₆
Procyanidin B2: C₃₀H₂₆O₁₂
Theobromine: C₇H₈N₄O₂Theobroma cacaoCaenorhabditis elegans, the specific transgenic strain employed expressed Aβ in neurons, demonstrating middle-age onset behavioral dysfunction similar to human AD.
 
For the polyphenol treatment, a concentration of 5 mg/mL cocoa powder, which contains 27.01 mg GAE/g of total phenolics and 10.13 mg CE/g of total flavonoids, was used. The administration method involved suspending the cocoa powder in M9 buffer with concentrated Escherichia coli OP50, which was then added to NGM plates. The worms were exposed to the cocoa treatment starting from the L1 larval stage and continued daily transfers onto fresh plates to avoid progeny production until they stopped laying eggs around day 9. Samples were collected at three different time points: days 4, 8, and 12, to represent young, middle, and old age, respectively.Cocoa:
Reduces Aβ-induced cognitive deficits.
Reduces elevated levels of proline and asparagine in young transgenic worms, which are associated with cognitive deficits.
Normalizes hypoxanthine levels in middle-aged transgenic worms, which is linked to memory deficits.
Alters urea cycle metabolites, reducing ornithine levels in transgenic worms expressing Aβ, indicating potential modulation of AD pathology.[212]Ellagic acid
Pelargonidin-3-glucoside
Chrysanthemin
Kaempferol-3-O-D-glucoside
Pelargonidin-3-rutinosideEllagic acid: C₁₄H₆O₈
Pelargonidin-3-glucoside: C₂₁H₂₁ClO₁₀
Chrysanthemin: C₂₁H₂₁O₁₁
Kaempferol-3-O-D-glucoside:C₂₁H₂₀O₁₁
Pelargonidin-3-rutinoside: C₂₇H₃₁O₁₄Strawberry variety Fragaria × ananassa cv. RominaCaenorhabditis elegans. The specific strains utilized included N2 Bristol (wild-type), CL4176 (expressing human amyloid β1–42 peptide), and others.
 
Concentrations of 100, 500, and 1000 µg/mL of strawberry methanolic extract were used. Worms were exposed to these concentrations for various durations, depending on the specific assay, ranging from 15 min to several days.Strawberry:
 
Reduces Aβ-protein induced paralysis.
Decreases Aβ aggregation.
Prevents oxidative stress.
The effects were mediated through the DAF-16/FOXO and SKN-1/NRF2 signaling pathways.[213]Desmodium elegans:
Gallic acid
Coumaric acid
Chlorogenic acid
Caffeic acid
p-Coumaroylhexose
3-O-Caffeoylquinic acid
4-O-Caffeoylquinic acid
(+)-Catechin
Quercetin-3-rutinoside
Quercetin-3-O-glucuronide
Kaempferol-7-O-glucuronide
Isorhamnetin-7-O-glucuronide
Isorhamnetin-3-O-rutinosideGallic acid: C₇H₆O₅
Coumaric acid: C₉H₈O₃
Chlorogenic acid: C₁₆H₁₈O₉
Caffeic acid: C₉H₈O₄
p-Coumaroylhexose: C₁₅H₁₈O₈
3-O-Caffeoylquinic acid: C₁₆H₁₈O₉
4-O-Caffeoylquinic acid: C₁₆H₁₈O₉
(+)-Catechin: C₁₅H₁₄O₆
Quercetin-3-rutinoside: C₂₇H₃₀O₁₆
Quercetin-3-O-glucuronide: C₂₁H₂₀O₁₃
Kaempferol-7-O-glucuronide: C₂₁H₁₈O₁₃
Isorhamnetin-7-O-glucuronide: C₂₂H₂₀O₁₃
Isorhamnetin-3-O-rutinoside: C₂₈H₃₂O₁₆Desmodium elegans, which was collected from Ganajeer, Malamjaba Swat, Khyber Pakhtunkhwa, PakistanMice.
 
The mice were administered the test sample at a dose of 1 mg/kg per day (i.p.).Desmodium elegans extracts:
Improves cognitive performance, showing anxiolytic effects and enhancement in spatial memory.
Improves the escape latency in the shallow water maze test, indicating enhanced memory and learning abilities in the treated mice compared to the disease control group.[214]Gallic acid
Ferulic acid
p-Coumaric acidGallic acid: C₇H₆O₅
Ferulic acid: C₁₀H₁₀O₄
p-Coumaric acid: C₉H₈O₃Solanum lycopersicum (tomato), Cenostigma pluviosum, and Peltophorum dubium represented 76.66% of the pollen types sampledDrosophila melanogaster AD model (AD-like)
Drosophila were treated with different concentrations of the methanolic pollen extract (0.1 mg/mL, 0.04 mg/mL, 0.02 mg/mL, and 0.004 mg/mL) over a period of up to 21 days. The administration was carried out using an enriched puree medium refreshed every two days.Pollen:
 
Enhances climbing ability of Drosophila melanogaster AD-like model flies.
Reduces neurodegeneration index in histopathological analysis.
Improves survival rate.
Exhibits significant antioxidant response.
Reduces damage in brain tissue.[215]Phenolic acidsChlorogenic acid (CGA)C₁₆H₁₈O₉Tea, coffee, roasted green beans, berries, cocoa, citrus fruits, apples, and many vegetablesMale albino Swiss mice weighing 25–35 g.
 
The mice received ICV-STZ injections at a concentration of 3 mg/kg on days 1 and 3 to induce SAD. Following the second STZ injection, CGA was administered at a concentration of 5 mg/kg orally, starting 2 h after the second STZ administration and continued daily for 26 days. The administration mode for CGA was oral gavage.CGA:
Alleviates memory deficits induced by ICV-STZ.
Protects against an increase in nitrite/nitrate and TBARS levels in the brain.
Preserves the number of viable cells in the prefrontal cortex and hippocampus.
Prevents the depletion of BDNF in the prefrontal cortex and hippocampus.
Mitigates astrogliosis and microgliosis in the prefrontal cortex and hippocampus.
Exhibits neuroprotective effects, suggesting its potential as a therapeutic agent in the treatment of SAD.[216]CurcuminoidCurcumin (Cur) and Nanocurcumin (NC)C₂₁H₂₀O₆Curcuma longaB6SJL-Tg (5xFAD) mice.
 
Cur and NC were dissolved in methanol and diluted with PBS to a final concentration of 50 mg/kg BW. These solutions were injected intraperitoneally once daily for either 2 or 5 days to one-year-old B6SJL-Tg (5xFAD) mice. The concentrations tested ranged from 1 mM to 1 nM to determine the minimum effective dose for labeling Aβ plaques.Curc:
Binds to Aβ plaques.
Inhibits misfolded Aβ aggregation
Reduces oxidative damage.
Decreases Aβ plaques in the brain.
NC:
Shows enhanced permeability into brain tissue and binds to Aβ plaques more effectively than dietary Cu.
Both Cu and NC can label Aβ plaques in postmortem and in vivo brain tissue, suggesting potential for monitoring Aβ plaque load after anti-amyloid therapy.[217]Polyprenol or isoprenoid alcoholRopren^®,H-(C5H8)n-OHPicea abies (L.) KarstMale Wistar rats, aged 3–4 months and weighing between 180–200 g.
 
The polyphenol being focusing on was Ropren^®, a substance containing polyprenols extracted from the green verdure of Picea abies. Ropren^® was administered orally at a dosage of 8.6 mg/kg BW daily for 28 days. Additionally, testosterone propionate (TP) was administered subcutaneously at a dose of 0.5 mg/kg BW daily for the same period. The experimental procedure began with the induction of an AD model through the intracerebroventricular injection of A peptide (25–35) at a concentration of 3 μg/μL, followed by a 14-day recovery period. Subsequently, the rats underwent gonadectomy and another 14-day recovery period before starting the daily administration of Ropren^®, TP, or oil solvent.Ropren^®:
Ameliorates cognitive impairment induced by Aβ (25–35) peptide injection.
Shows memory-enhancing effects
Increases locomotor activity, rearing and grooming events, and completely restores impaired cognitive performance.
Restores testosterone levels in the GDX/Aβ rats.[218]LignanMagnolol (MN)C₂₂H₁₈O₁₁Magnolia officinalisTgCRND8 transgenic mice.
 
Mice were fed with MN at concentrations of 20 mg/kg and 40 mg/kg via oral gavage. Donepezil, a commonly used AD medication, was administered at 5 mg/kg as a positive control. The treatments were carried out daily for a period of four consecutive months. The polyphenol and donepezil were dissolved in 0.5% sodium carboxymethyl cellulose (CMC-Na) for MN and in normal saline for donepezil.MN:
Ameliorates cognitive deficits.
Suppresses neuroinflammation and synaptic dysfunction.
Inhibits Aβ deposition.
Modulates PI3K/Akt/GSK-3β and NF-κB pathways.
Improves cognitive function through increased expression of synaptic proteins and anti-inflammatory cytokines.[219]EllagitanninsEllagic acid (EA)C₁₄H₆O₈Berries, nuts, and other fruitsSwiss albino male mice aged 8–12 weeks and weighing 26–30 g.
 
Mice were housed under standard conditions and provided with food and water ad libitum. The mice were randomly divided into three groups: Control (vehicle), STZ-sAD (AD model), and STZ-sAD treated with EA. The sporadic AD model was induced through ICV injection of STZ at a dose of 3 mg/kg BW. EA was administered orally at a dose of 75 mg/kg BW for 28 days.EA:
Reverses the upregulation of AD biomarkers caused by STZ.
Improves recognition memory as evidenced by the NORT test.
Modulates genes involved in synaptic plasticity, such as AMPAR, and its scaffolding proteins.
Reduces oxidative stress and neuronal loss.
Enhances antioxidant enzyme activity and reduce lipid peroxidation.
Downregulates apoptotic markers.[220]