Clinical Neurology and Neuroscience

Submit a Manuscript

Publishing with us to make your research visible to the widest possible audience.

Propose a Special Issue

Building a community of authors and readers to discuss the latest research and develop new ideas.

Research Article |

The Therapeutic Role of Flavonoids for Alzheimer's Disease

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized with mainly cognitive impairments, and the number of elderly having AD is continuously increasing. Objective: To summarize the pathogenesis of AD and the therapeutic effects of flavonoids on related inflammatory processes. Main ideas: Flavonoids have been shown to alleviate effects of AD both in vitro and in vivo. Conclusion: The clinical significance of these research summaries lay a potential groundwork for the development of new drugs targeting AD treatment.

Flavonoids, Neurodegenerative Diseases, Alzheimer’s Disease, Mitochondrial Dysfunction, Neuroinflammation

APA Style

Wei, J., Liu, Z., Wei, C. (2023). The Therapeutic Role of Flavonoids for Alzheimer's Disease. Clinical Neurology and Neuroscience, 7(4), 86-96.

ACS Style

Wei, J.; Liu, Z.; Wei, C. The Therapeutic Role of Flavonoids for Alzheimer's Disease. Clin. Neurol. Neurosci. 2023, 7(4), 86-96. doi: 10.11648/j.cnn.20230704.13

AMA Style

Wei J, Liu Z, Wei C. The Therapeutic Role of Flavonoids for Alzheimer's Disease. Clin Neurol Neurosci. 2023;7(4):86-96. doi: 10.11648/j.cnn.20230704.13

Copyright © 2023 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Kirkwood T. B. L. Understanding the Odd Science of Aging. Cell. 2005; 120: 437–447. doi: 10.1016/j.cell.2005.01.027.
2. Dugger B. N., Dickson D. W. Pathology of Neurodegenerative Diseases. Cold Spring Harb. Perspect. Biol. 2017; 9: a028035. doi: 10.1101/cshperspect.a028035.
3. López-Valdés H. E., Martínez-Coria H. The Role of Neuroinflammation in Age-Related Dementias. Rev. Investig. Clín. Organo Hosp. Enferm. Nutr. 2016; 68: 40–48.
4. Wen K., Fang X., Yang J., Yao Y., Nandakumar K. S., Salem M. L., Cheng K. Recent Research on Flavonoids and Their Biomedical Applications. Curr. Med. Chem. 2021; 28: 1042–1066. doi: 10.2174/0929867327666200713184138.
5. Ramzan I., Li G. Q. Phytotherapies. John Wiley & Sons, Ltd.; Hoboken, NJ, USA: 2015. Phytotherapies—Past, Present, and Future; pp. 1–17.
6. Parnetti L, Chipi E, Salvadori N, D'Andrea K, Eusebi P. Prevalence and risk of progression of preclinical Alzheimer's disease stages: a systematic review and meta-analysis. Alzheimers Res Ther. 2019; 11 (1): 7. doi: 10.1186/s13195-018-0459-7. PMID: 30646955; PMCID: PMC6334406.
7. Elahi FM, Miller BL. A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol. 2017; 13 (8): 457-476. doi: 10.1038/nrneurol.2017.96. Epub 2017 Jul 14. PMID: 28708131; PMCID: PMC5771416.
8. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer's disease. Lancet. 2021; 397 (10284): 1577-1590. doi: 10.1016/S0140-6736(20)32205-4. Epub 2021 Mar 2. PMID: 33667416; PMCID: PMC8354300.
9. Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O'Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR Jr; Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016; 12 (3): 292-323. doi: 10.1016/j.jalz.2016.02.002. PMID: 27012484; PMCID: PMC6417794.
10. Serrano-Pozo A, Growdon JH. Is Alzheimer's Disease Risk Modifiable? J Alzheimers Dis. 2019; 67 (3): 795-819. doi: 10.3233/JAD181028. PMID: 30776012; PMCID: PMC6708279.
11. Wu C, Sun D. GABA receptors in brain development, function, and injury. Metab Brain Dis. 2015; 30 (2): 367-79. doi: 10.1007/s11011-014-9560-1. Epub 2014 May 13. PMID: 24820774; PMCID: PMC4231020.
12. Möhler H. The rise of a new GABA pharmacology. Neuropharmacology. 2011; 60 (7-8): 1042-9. doi: 10.1016/j.neuropharm.2010.10.020. Epub 2010 Oct 28. PMID: 21035473.
13. Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer's disease. Sleep Med Rev. 2015; 19: 29-38. doi: 10.1016/j.smrv.2014.03.007. Epub 2014 Apr 3. PMID: 24846773.
14. Urrestarazu E, Iriarte J. Clinical management of sleep disturbances in Alzheimer's disease: current and emerging strategies. Nat Sci Sleep. 2016; 8: 21-33. doi: 10.2147/NSS.S76706. PMID: 26834500; PMCID: PMC4716729.
15. Xu X, Lin L, Sun S, Wu S. A review of the application of three-dimensional convolutional neural networks for the diagnosis of Alzheimer's disease using neuroimaging. Rev Neurosci. 2023; 34 (6): 649-670. doi: 10.1515/revneuro-2022-0122. PMID: 36729918.
16. Zeng F, Li Y, Xu Y, Yang J, Liu Z, Li X, Ren L. Strategies Targeting Soluble β-Amyloid Oligomers and their Application to Early Diagnosis of Alzheimer's. Disease. Curr Alzheimer Res. 2019; 16 (12): 1132-1142. doi: 10.2174/1567205016666191031163504. PMID: 31670622.
17. Pinheiro L, Faustino C. Therapeutic Strategies Targeting Amyloid-β in Alzheimer's Disease. Curr Alzheimer Res. 2019; 16 (5): 418-452. doi: 10.2174/1567205016666190321163438. PMID: 30907320.
18. Lim D, Ronco V, Grolla AA, Verkhratsky A, Genazzani AA. Glial calcium signalling in Alzheimer's disease. Rev Physiol Biochem Pharmacol. 2014; 167: 45-65. doi: 10.1007/112_2014_19. PMID: 24935225.
19. Ehrenstein G, Galdzicki Z, Lange GD. The choline-leakage hypothesis for the loss of acetylcholine in Alzheimer's disease. Biophys J. 1997; 73 (3): 1276-80. doi: 10.1016/S0006-3495(97)78160-8. PMID: 9284295; PMCID: PMC1181027.
20. Hachisu M, Konishi K, Hosoi M, Tani M, Tomioka H, Inamoto A, Minami S, Izuno T, Umezawa K, Horiuchi K, Hori K. Beyond the Hypothesis of Serum Anticholinergic Activity in Alzheimer's Disease: Acetylcholine Neuronal Activity Modulates Brain-Derived Neurotrophic Factor Production and Inflammation in the Brain. Neurodegener Dis. 2015; 15 (3): 182-7. doi: 10.1159/000381531. Epub 2015 Jun 30. PMID: 26138497.
21. Kurup P, Zhang Y, Venkitaramani DV, Xu J, Lombroso PJ. The role of STEP in Alzheimer's disease. Channels (Austin). 2010; 4 (5): 347-50. doi: 10.1523/JNEUROSCI.0157-10.2010. Epub 2010 Sep 6. PMID: 20699650; PMCID: PMC3230511.
22. Chang CH, Lin CH, Lane HY. d-glutamate and Gut Microbiota in Alzheimer's Disease. Int J Mol Sci. 2020; 21 (8): 2676. doi: 10.3390/ijms21082676. PMID: 32290475; PMCID: PMC7215955.
23. Abd-Elrahman KS, Ferguson SSG. Noncanonical Metabotropic Glutamate Receptor 5 Signaling in Alzheimer's Disease. Annu Rev Pharmacol Toxicol. 2022; 62: 235-254. doi: 10.1146/annurev-pharmtox-021821-091747. Epub 2021 Sep 13. PMID: 34516293.
24. Liang J, López-Valdés HE, Martínez-Coria H, Lindemeyer AK, Shen Y, Shao XM, Olsen RW. Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer's disease. Neurochem Res. 2014; 39 (6): 1171-81. doi: 10.1007/s11064-014-1304-4. Epub 2014 Apr 13. Erratum in: Neurochem Res. 2014 Jul; 39 (7): 1403. PMID: 24728903.
25. Dias M. C., Pinto D. C. G. A., Silva A. M. S. Plant Flavonoids: Chemical Characteristics and Biological Activity. Molecules. 2021; 26: 5377. doi: 10.3390/molecules26175377.
26. Panche A. N., Diwan A. D., Chandra S. R. Flavonoids: An Overview. J. Nutr. Sci. 2016; 5: e47. doi: 10.1017/jns.2016.41.
27. Chen L., Cao H., Huang Q., Xiao J., Teng H. Absorption, Metabolism and Bioavailability of Flavonoids: A Review. Crit. Rev. Food Sci. Nutr. 2022; 62: 7730–7742. doi: 10.1080/10408398.2021.1917508.
28. Akhlaghi M., Foshati S. Bioavailability and Metabolism of Flavonoids: A Review. Int. J. Nutr. Sci. 2017; 2: 180–184.
29. Rezai-Zadeh K., Shytle R. D., Bai Y., Tian J., Hou H., Mori T., Zeng J., Obregon D., Town T., Tan J. Flavonoid-Mediated Presenilin-1 Phosphorylation Reduces Alzheimer’s Disease β-Amyloid Production. J. Cell. Mol. Med. 2009; 13: 574–588. doi: 10.1111/j.1582-4934.2008.00344.x.
30. Ansari M. A., Abdul H. M., Joshi G., Opii W. O., Butterfield D. A. Protective Effect of Quercetin in Primary Neurons against Aβ (1–42): Relevance to Alzheimer’s Disease. J. Nutr. Biochem. 2009; 20: 269–275. doi: 10.1016/j.jnutbio.2008.03.002.
31. Hirohata M., Hasegawa K., Tsutsumi-Yasuhara S., Ohhashi Y., Ookoshi T., Ono K., Yamada M., Naiki H. The Anti-Amyloidogenic Effect Is Exerted against Alzheimer’s Beta-Amyloid Fibrils in Vitro by Preferential and Reversible Binding of Flavonoids to the Amyloid Fibril Structure. Biochemistry. 2007; 46: 1888–1899. doi: 10.1021/bi061540x.
32. Ehrnhoefer D. E., Bieschke J., Boeddrich A., Herbst M., Masino L., Lurz R., Engemann S., Pastore A., Wanker E. E. EGCG Redirects Amyloidogenic Polypeptides into Unstructured, off-Pathway Oligomers. Nat. Struct. Mol. Biol. 2008; 15: 558–566. doi: 10.1038/nsmb.1437.
33. Bieschke J., Russ J., Friedrich R. P., Ehrnhoefer D. E., Wobst H., Neugebauer K., Wanker E. E. EGCG Remodels Mature α-Synuclein and Amyloid-β Fibrils and Reduces Cellular Toxicity. Proc. Natl. Acad. Sci. USA. 2010; 107: 7710–7715. doi: 10.1073/pnas.0910723107.
34. Choi Y. T., Jung C. H., Lee S. R., Bae J. H., Baek W. K., Suh M. H., Park J., Park C. W., Suh S. I. The Green Tea Polyphenol (−)-Epigallocatechin Gallate Attenuates Beta-Amyloid-Induced Neurotoxicity in Cultured Hippocampal Neurons. Life Sci. 2001; 70: 603–614. doi: 10.1016/S0024-3205(01)01438-2.
35. Sonawane S. K., Uversky V. N., Chinnathambi S. Baicalein Inhibits Heparin-Induced Tau Aggregation by Initializing Non-Toxic Tau Oligomer Formation. Cell Commun. Signal. 2021; 19: 16. doi: 10.1186/s12964-021-00704-3.
36. Sonawane S. K., Balmik A. A., Boral D., Ramasamy S., Chinnathambi S. Baicalein Suppresses Repeat Tau Fibrillization by Sequestering Oligomers. Arch. Biochem. Biophys. 2019; 675: 108119. doi: 10.1016/
37. Jiménez-Aliaga K., Bermejo-Bescós P., Benedí J., Martín-Aragón S. Quercetin and Rutin Exhibit Antiamyloidogenic and Fibril-Disaggregating Effects in Vitro and Potent Antioxidant Activity in APPswe Cells. Life Sci. 2011; 89: 939–945. doi: 10.1016/j.lfs.2011.09.023.
38. Ishola I. O., Osele M. O., Chijioke M. C., Adeyemi O. O. Isorhamnetin Enhanced Cortico-Hippocampal Learning and Memory Capability in Mice with Scopolamine-Induced Amnesia: Role of Antioxidant Defense, Cholinergic and BDNF Signaling. Brain Res. 2019; 1712: 188–196. doi: 10.1016/j.brainres.2019.02.017.
39. Ramalingayya G. V., Nampoothiri M., Nayak P. G., Kishore A., Shenoy R. R., Rao C. M., Nandakumar K. Naringin and Rutin Alleviates Episodic Memory Deficits in Two Differentially Challenged Object Recognition Tasks. Pharmacogn. Mag. 2016; 12: S63–S70. doi: 10.4103/0973-1296.176104.
40. Darbandi N., Ramezani M., Khodagholi F., Noori M. Kaempferol Promotes Memory Retention and Density of Hippocampal CA1 Neurons in Intra-Cerebroventricular STZ-Induced Experimental AD Model in Wistar Rats. Biologija. 2016; 62: 157–168. doi: 10.6001/biologija.v62i3.3368.
41. Wang H., Wang H., Cheng H., Che Z. Ameliorating Effect of Luteolin on Memory Impairment in an Alzheimer’s Disease Model. Mol. Med. Rep. 2016; 13: 4215–4220. doi: 10.3892/mmr.2016.5052.
42. Javed H., Vaibhav K., Ahmed M. E., Khan A., Tabassum R., Islam F., Safhi M. M., Islam F. Effect of Hesperidin on Neurobehavioral, Neuroinflammation, Oxidative Stress and Lipid Alteration in Intracerebroventricular Streptozotocin Induced Cognitive Impairment in Mice. J. Neurol. Sci. 2015; 348: 51–59. doi: 10.1016/j.jns.2014.10.044.
43. Onozuka H., Nakajima A., Matsuzaki K., Shin R.-W., Ogino K., Saigusa D., Tetsu N., Yokosuka A., Sashida Y., Mimaki Y., et al. Nobiletin, a Citrus Flavonoid, Improves Memory Impairment and Aβ Pathology in a Transgenic Mouse Model of Alzheimer’s Disease. J. Pharmacol. Exp. Ther. 2008; 326: 739–744. doi: 10.1124/jpet.108.140293.
44. Sawmiller D., Habib A., Li S., Darlington D., Hou H., Tian J., Shytle R. D., Smith A., Giunta B., Mori T., et al. Diosmin Reduces Cerebral Aβ Levels, Tau Hyperphosphorylation, Neuroinflammation, and Cognitive Impairment in the 3xTg-AD Mice. J. Neuroimmunol. 2016; 299: 98–106. doi: 10.1016/j.jneuroim.2016.08.018.
45. Li C., Zug C., Qu H., Schluesener H., Zhang Z. Hesperidin Ameliorates Behavioral Impairments and Neuropathology of Transgenic APP/PS1 Mice. Behav. Brain Res. 2015; 281: 32–42. doi: 10.1016/j.bbr.2014.12.012.
46. Rezai-Zadeh K., Shytle D., Sun N., Mori T., Hou H., Jeanniton D., Ehrhart J., Townsend K., Zeng J., Morgan D., et al. Green Tea Epigallocatechin-3-Gallate (EGCG) Modulates Amyloid Precursor Protein Cleavage and Reduces Cerebral Amyloidosis in Alzheimer Transgenic Mice. J. Neurosci. 2005; 25: 8807–8814. doi: 10.1523/JNEUROSCI.1521-05.2005.
47. Lee J. W., Lee Y. K., Ban J. O., Ha T. Y., Yun Y. P., Han S. B., Oh K. W., Hong J. T. Green Tea (−)-Epigallocatechin-3-Gallate Inhibits Beta-Amyloid-Induced Cognitive Dysfunction through Modification of Secretase Activity via Inhibition of ERK and NF-KappaB Pathways in Mice. J. Nutr. 2009; 139: 1987–1993. doi: 10.3945/jn.109.109785.
48. Rezai-Zadeh K., Arendash G. W., Hou H., Fernandez F., Jensen M., Runfeldt M., Shytle R. D., Tan J. Green Tea Epigallocatechin-3-Gallate (EGCG) Reduces Beta-Amyloid Mediated Cognitive Impairment and Modulates Tau Pathology in Alzheimer Transgenic Mice. Brain Res. 2008; 1214: 177–187. doi: 10.1016/j.brainres.2008.02.107.
49. Nakajima A., Aoyama Y., Shin E.-J., Nam Y., Kim H.-C., Nagai T., Yokosuka A., Mimaki Y., Yokoi T., Ohizumi Y., et al. Nobiletin, a Citrus Flavonoid, Improves Cognitive Impairment and Reduces Soluble Aβ Levels in a Triple Transgenic Mouse Model of Alzheimer’s Disease (3XTg-AD) Behav. Brain Res. 2015; 289: 69–77. doi: 10.1016/j.bbr.2015.04.028.
50. Nakajima A., Aoyama Y., Nguyen T.-T.L., Shin E.-J., Kim H.-C., Yamada S., Nakai T., Nagai T., Yokosuka A., Mimaki Y., et al. Nobiletin, a Citrus Flavonoid, Ameliorates Cognitive Impairment, Oxidative Burden, and Hyperphosphorylation of Tau in Senescence-Accelerated Mouse. Behav. Brain Res. 2013; 250: 351–360. doi: 10.1016/j.bbr.2013.05.025.
51. Paula P.-C., Maria S.-G. A., Luis C.-H., Patricia C.-G. G. Preventive Effect of Quercetin in a Triple Transgenic Alzheimer’s Disease Mice Model. Molecules. 2019; 24: 2287. doi: 10.3390/molecules24122287.
52. Qin L., Zhang J., Qin M. Protective Effect of Cyanidin 3-O-Glucoside on Beta-Amyloid Peptide-Induced Cognitive Impairment in Rats. Neurosci. Lett. 2013; 534: 285–288. doi: 10.1016/j.neulet.2012.12.023.
53. Currais A., Prior M., Dargusch R., Armando A., Ehren J., Schubert D., Quehenberger O., Maher P. Modulation of P25 and Inflammatory Pathways by Fisetin Maintains Cognitive Function in Alzheimer’s Disease Transgenic Mice. Aging Cell. 2014; 13: 379–390. doi: 10.1111/acel.12185.
54. Liang J., López-Valdés H. E., Martínez-Coria H., Lindemeyer A. K., Shen Y., Shao X. M., Olsen R. W. Erratum to: Dihydromyricetin Ameliorates Behavioral Deficits and Reverses Neuropathology of Transgenic Mouse Models of Alzheimer’s Disease. Neurochem. Res. 2014; 39: 1403. doi: 10.1007/s11064-014-1358-3.
55. Desideri G., Kwik-Uribe C., Grassi D., Necozione S., Ghiadoni L., Mastroiacovo D., Raffaele A., Ferri L., Bocale R., Lechiara M. C., et al. Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance through Cocoa Flavanol Consumption in Elderly Subjects with Mild Cognitive Impairment: The Cocoa, Cognition, and Aging (CoCoA) Study. Hypertension. 2012; 60: 794–801. doi: 10.1161/HYPERTENSIONAHA.112.193060.
56. Mastroiacovo D., Kwik-Uribe C., Grassi D., Necozione S., Raffaele A., Pistacchio L., Righetti R., Bocale R., Lechiara M. C., Marini C., et al. Cocoa Flavanol Consumption Improves Cognitive Function, Blood Pressure Control, and Metabolic Profile in Elderly Subjects: The Cocoa, Cognition, and Aging (CoCoA) Study—A Randomized Controlled Trial. Am. J. Clin. Nutr. 2015; 101: 538–548. doi: 10.3945/ajcn.114.092189.
57. Brickman A. M., Khan U. A., Provenzano F. A., Yeung L.-K., Suzuki W., Schroeter H., Wall M., Sloan R. P., Small S. A. Enhancing Dentate Gyrus Function with Dietary Flavanols Improves Cognition in Older Adults. Nat. Neurosci. 2014; 17: 1798–1803. doi: 10.1038/nn.3850.
58. Liu M, Guo H, Li Z, Zhang C, Zhang X, Cui Q, Tian J. Molecular Level Insight Into the Benefit of Myricetin and Dihydromyricetin Uptake in Patients With Alzheimer's Diseases. Front Aging Neurosci. 2020; 12: 601603. doi: 10.3389/fnagi.2020.601603. PMID: 33192493; PMCID: PMC7645199.