THE NEUROPROTECTIVE POTENTIAL OF COFFEE COMPOUNDS IN THE PREVENTION AND PROGRESSION OF NEURODEGENERATIVE DISORDERS: A SYSTEMATIC REVIEW FOCUSING ON ALZHEIMER’S AND PARKINSON’S DISEASES

Agnieszka Jóźwicka; Wojciech Janikowski; Ewa  Bąkowska; Aleksandra Stępka; Lena Jaworowicz; Weronika Plichtowicz-Kordowska; Karina Lewandowska; Sara Awad; Paweł Szymonek; Adam Zysk

doi:10.31435/ijitss.2(50).2026.5914

Authors

Agnieszka Jóźwicka Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0008-1130-1518
Wojciech Janikowski Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0008-4078-9698
Ewa Bąkowska Medical University of Lublin, Aleje Racławickie 1, 20-059 Lublin, Poland https://orcid.org/0009-0007-4135-9748
Aleksandra Stępka Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0007-5034-0037
Lena Jaworowicz Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0008-4210-7216
Weronika Plichtowicz-Kordowska Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0009-7713-8597
Karina Lewandowska Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0004-5298-1426
Sara Awad Samodzielny Publiczny Szpital Kliniczny im. prof. W. Orłowskiego CMKP, Warsaw, Mazovia, Poland https://orcid.org/0009-0004-0942-6240
Paweł Szymonek SPZOZ w Lubartowie, ul. Cicha 10, 21-100 Lubartów, Poland https://orcid.org/0009-0002-6345-7721
Adam Zysk Warsaw Southern Hospital, Warsaw, Poland https://orcid.org/0009-0006-0425-2493

DOI:

https://doi.org/10.31435/ijitss.2(50).2026.5914

Keywords:

Coffee, Neuroprotection, Alzheimer’s Disease, Parkinson’s Disease, Caffeine, Chlorogenic Acid

Abstract

Background: Neurodegenerative disorders (NDDs), particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD), present a profound and growing global health burden with a notable lack of disease-modifying therapies. Emerging epidemiological and preclinical evidence suggests that habitual coffee consumption may confer significant neuroprotective benefits, driven by its complex matrix of bioactive phytochemicals.

Objective: This systematic review aims to critically evaluate the efficacy and underlying molecular mechanisms of coffee-derived compounds in the prevention and progression of Alzheimer’s and Parkinson’s diseases.

Methods: A comprehensive literature search was conducted across PubMed and Google Scholar databases using predefined Medical Subject Headings (MeSH) and keywords. The review synthesized data from epidemiological cohorts, clinical trials, and preclinical models focusing on caffeine and non-caffeine constituents, such as chlorogenic acids and phenylindanes.

Results: Coffee exerts neuroprotective effects through a synergistic, multi-target approach. Caffeine primarily acts via adenosine A2A receptor antagonism, enhancing dopaminergic signaling and reducing excitotoxicity, which strongly correlates with a reduced risk of PD (relative risk ranging from 0.65 to 0.80). Non-caffeine constituents provide robust antioxidant and anti-inflammatory activity, upregulating the Nrf2 pathway and directly inhibiting the aggregation of amyloid-beta, tau, and alpha-synuclein proteins. While epidemiological evidence for PD is highly consistent, data regarding AD is more variable; however, regular midlife coffee consumption is significantly associated with a reduced risk of late-life cognitive decline. Individual responses are notably modulated by genetic polymorphisms (e.g., CYP1A2).

Conclusion: Coffee represents a potent, biologically plausible dietary intervention with significant potential to mitigate NDD pathology. While its multifaceted mechanisms position it as a promising neuroprotective agent, particularly against PD, further rigorous randomized controlled trials are essential to establish causality and define optimal, personalized consumption guidelines.

References

Scheltens, P., De Strooper, B., Kivipelto, M., et al. (2021). Alzheimer’s disease. Lancet, 397(10284), 1577–1590. https://doi.org/10.1016/S0140-6736(20)32205-4

Knopman, D. S., Amieva, H., Petersen, R. C., et al. (2021). Alzheimer disease. Nature Reviews Disease Primers, 7(1), 33. https://doi.org/10.1038/s41572-021-00269-y

Long, J. M., & Holtzman, D. M. (2019). Alzheimer disease: An update on pathobiology and treatment strategies. Cell, 179(2), 312–339. https://doi.org/10.1016/j.cell.2019.09.001

Bloem, B. R., Okun, M. S., & Klein, C. (2021). Parkinson’s disease. Lancet, 397(10291), 2284–2303. https://doi.org/10.1016/S0140-6736(21)00218-X

Poewe, W., Seppi, K., Tanner, C. M., et al. (2017). Parkinson disease. Nature Reviews Disease Primers, 3, 17013. https://doi.org/10.1038/nrdp.2017.13

Kalia, L. V., & Lang, A. E. (2015). Parkinson’s disease. Lancet, 386(9996), 896–912. https://doi.org/10.1016/S0140-6736(14)61393-3

Yiannopoulou, K. G., & Papageorgiou, S. G. (2013). Current and future treatments for Alzheimer’s disease. Therapeutic Advances in Neurological Disorders, 6(1), 19–33. https://doi.org/10.1177/1756285612461679

Ascherio, A., & Schwarzschild, M. A. (2016). The epidemiology of Parkinson’s disease: Risk factors and prevention. Lancet Neurology, 15(12), 1257–1272. https://doi.org/10.1016/S1474-4422(16)30230-7

Eskelinen, M. H., Ngandu, T., Tuomilehto, J., Soininen, H., & Kivipelto, M. (2009). Midlife coffee and tea drinking and the risk of late-life dementia: A population-based CAIDE study. Journal of Alzheimer’s Disease, 16(1), 85–91. https://doi.org/10.3233/JAD-2009-0920

Ross, G. W., Abbott, R. D., Petrovitch, H., et al. (2000). Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA, 283(20), 2674–2679. https://doi.org/10.1001/jama.283.20.2674

Liu, Q. P., Wu, Y. F., Cheng, H. Y., et al. (2016). Habitual coffee consumption and risk of cognitive decline/dementia: A systematic review and meta-analysis of prospective cohort studies. Nutrition, 32(6), 628–636. https://doi.org/10.1016/j.nut.2015.11.015

Xu, K., Bastia, E., & Schwarzschild, M. A. (2005). Therapeutic potential of adenosine A2A receptor antagonists in Parkinson’s disease. Pharmacology & Therapeutics, 105(3), 267–310. https://doi.org/10.1016/j.pharmthera.2004.10.007

Wierzejska, R. (2017). Can coffee consumption lower the risk of Alzheimer’s disease and Parkinson’s disease? A literature review. Archives of Medical Science, 13(3), 507–514. https://doi.org/10.5114/aoms.2016.63599

Arendash, G. W., Schleif, W., Rezai-Zadeh, K., et al. (2006). Caffeine protects Alzheimer’s mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience, 142(4), 941–952. https://doi.org/10.1016/j.neuroscience.2006.07.021

Ludwig, I. A., Clifford, M. N., Lean, M. E., Ashihara, H., & Crozier, A. (2014). Coffee: Biochemistry and potential health benefits. Food & Function, 5(8), 1695–1717. https://doi.org/10.1039/c4fo00042k

Kolb, H., Kempf, K., & Martin, S. (2020). Health effects of coffee: Mechanism unraveled? Nutrients, 12(6), 1842. https://doi.org/10.3390/nu12061842

Mancini, R. S., Wang, Y., & Weaver, D. F. (2018). Phenylindanes in brewed coffee inhibit amyloid-beta and tau aggregation. Frontiers in Neuroscience, 12, 735. https://doi.org/10.3389/fnins.2018.00735

Heitman, E., & Ingram, D. K. (2017). Cognitive and neuroprotective effects of chlorogenic acid. Nutritional Neuroscience, 20(1), 32–39. https://doi.org/10.1179/1476830514Y.0000000146

Kim, J. W., Byun, M. S., Yi, D., et al. (2019). Coffee consumption and reduced amyloid-beta deposition in the human brain. Translational Psychiatry, 9(1), 270. https://doi.org/10.1038/s41398-019-0604-5

Ren, X., & Chen, J. F. (2020). Caffeine and Parkinson’s disease: Multiple benefits and emerging mechanisms. Frontiers in Neuroscience, 14, 602697. https://doi.org/10.3389/fnins.2020.602697

Grosso, G., Godos, J., Galvano, F., & Giovannucci, E. L. (2017). Coffee, caffeine, and health outcomes: An umbrella review. Annual Review of Nutrition, 37, 131–156. https://doi.org/10.1146/annurev-nutr-071816-064941

Chen, J. F., Xu, K., Petzer, J. P., et al. (2001). Neuroprotection by caffeine and A(2A) receptor inactivation in a model of Parkinson’s disease. Journal of Neuroscience, 21(10), RC143. https://doi.org/10.1523/JNEUROSCI.21-10-j0001.2001

Liu, R., Guo, X., Park, Y., et al. (2012). Caffeine intake, smoking, and risk of Parkinson disease in men and women. American Journal of Epidemiology, 175(11), 1200–1207. https://doi.org/10.1093/aje/kwr451

Qi, H., & Li, S. (2014). Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson’s disease. Geriatrics & Gerontology International, 14(2), 430–439. https://doi.org/10.1111/ggi.12123

Zhao, Y., Lai, Y., Konijnenberg, H., et al. (2024). Association of coffee consumption and prediagnostic caffeine metabolites with incident Parkinson disease in a population-based cohort. Neurology, 102(8), e209201. https://doi.org/10.1212/WNL.0000000000209201

Chen, X., Lan, X., Roche, I., et al. (2008). Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum. Journal of Neurochemistry, 107(4), 1147–1157. https://doi.org/10.1111/j.1471-4159.2008.05697.x

Chen, J. F., & Cunha, R. A. (2020). The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease. NPJ Parkinson’s Disease, 6, 13. https://doi.org/10.1007/s11302-020-09694-2

Panza, F., Solfrizzi, V., Barulli, M. R., et al. (2015). Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: A systematic review. Journal of Nutrition, Health & Aging, 19(3), 313–328. https://doi.org/10.1007/s12603-014-0563-8

Ashfaq, Z., Younas, Z., Nathaniel, E., et al. (2025). Association between caffeine intake and Alzheimer’s disease progression: A systematic review. Cureus, 17(3), e80923. https://doi.org/10.7759/cureus.80923

Gardener, S. L., Rainey-Smith, S. R., Villemagne, V. L., et al. (2021). Higher coffee consumption is associated with slower cognitive decline and less cerebral Aβ-amyloid accumulation over 126 months: Data from the Australian Imaging, Biomarkers, and Lifestyle Study. Frontiers in Aging Neuroscience, 13, 744872. https://doi.org/10.3389/fnagi.2021.744872

Gill, H., Phan, L., Chen-Li, D., et al. (2024). An umbrella review of meta-analysis to understand the effect of coffee consumption and the relationship between stroke, cardiovascular heart disease, and dementia among its global users. Journal of Family Medicine and Primary Care, 13(11), 4785–4795. https://doi.org/10.4103/jfmpc.jfmpc_654_24

Pham, K., Mulugeta, A., Zhou, A., O’Brien, J. T., Llewellyn, D. J., & Hyppönen, E. (2022). High coffee consumption, brain volume and risk of dementia and stroke. Nutritional Neuroscience, 25(10), 2111–2122. https://doi.org/10.1080/1028415X.2021.1945858

Loftfield, E., Freedman, N. D., Graubard, B. I., et al. (2018). Association of coffee drinking with mortality by genetic variation in caffeine metabolism: Findings from the UK Biobank. JAMA Internal Medicine, 178(8), 1086–1097. https://doi.org/10.1001/jamainternmed.2018.2425

Xie, L., Kang, H., Xu, Q., et al. (2013). Sleep drives metabolite clearance from the adult brain. Science, 342(6156), 373–377. https://doi.org/10.1126/science.1241224

Cornelis, M. C., & El-Sohemy, A. (2007). Coffee, caffeine, and coronary heart disease. Current Opinion in Clinical Nutrition and Metabolic Care, 10(6), 745–751. https://doi.org/10.1097/MOL.0b013e3280127b04

Jaquet, M., Rochat, I., Moulin, J., et al. (2009). Impact of coffee consumption on gut microbiota. International Journal of Food Microbiology, 130(2), 117–121. https://doi.org/10.1016/j.ijfoodmicro.2009.01.011

Higdon, J. V., & Frei, B. (2006). Coffee and health: A review of recent human research. Critical Reviews in Food Science and Nutrition, 46(2), 101–123. https://doi.org/10.1080/10408390500400009

Scarmeas, N., Anastasiou, C. A., & Yannakoulia, M. (2018). Nutrition and prevention of cognitive impairment. Lancet Neurology, 17(11), 1006–1015. https://doi.org/10.1016/S1474-4422(18)30338-7