Oxidative Stress in Alzheimer’s Disease: The Shortcomings of Antioxidant Therapies
Open accessAbstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease’s neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability—epitomized by the dictum “no on-site protection, no protection”—and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Oxidative stress is substantially elevated in AD through a variety of mechanisms.
“SGK1 is induced by oxidative stress [43–45], which is substantially elevated in AD through a variety of mechanisms [46].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [46]
Cites
Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G., & Gluud, C. (2007) · JAMA · doi:10.1001/jama.297.8.842 · Cited by 2,275 · see citing works
Sharifi-Rad, M., Anil Kumar, N. V., Zucca, P., Varoni, E. M., Dini, L., Panzarini, E., Rajkovic, J., Tsouh Fokou, P. V., Azzini, E., Peluso, I., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00694 · Cited by 1,971 · see citing works
Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
Milne, J. C., Lambert, P. D., Schenk, S., Carney, D. P., Smith, J. J., Gagne, D. J., Jin, L., Boss, O., Perni, R. B., Vu, C. B., et al. (2007) · Nature · doi:10.1038/nature06261 · Cited by 1,707 · see citing works
Moi, P., Chan, K., Asunis, I., Cao, A., & Kan, Y. W. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.21.9926 · Cited by 1,607 · see citing works
Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130 · see citing works
Dysken, M. W., Sano, M., Asthana, S., Vertrees, J. E., Pallaki, M., Llorente, M., Love, S., Schellenberg, G. D., McCarten, J. R., Malphurs, J., et al. (2014) · JAMA · doi:10.1001/jama.2013.282834 · Cited by 628 · see citing works
Antioxidant Vitamin Intake and Risk of Alzheimer Disease
Luchsinger, J. A., Tang, M.-X., Shea, S., & Mayeux, R. (2003) · Archives of Neurology · doi:10.1001/archneur.60.2.203 · Cited by 414 · see citing works
Activation of the classical complement pathway in brain tissue of Alzheimer patients
McGeer, P. L., Akiyama, H., Itagaki, S., & McGeer, E. G. (1989) · Neuroscience Letters · doi:10.1016/0304-3940(89)90843-4 · Cited by 383 · see citing works
Galasko, D. R., Peskind, E., Clark, C. M., Quinn, J. F., Ringman, J. M., Jicha, G. A., Cotman, C., Cottrell, B., Montine, T. J., Thomas, R. G., et al. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.85 · Cited by 377 · see citing works
Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide
Pappolla, M. A., Sos, M., Omar, R. A., Bick, R. J., Hickson-Bick, D. L. M., Reiter, R. J., Efthimiopoulos, S., & Robakis, N. K. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-05-01683.1997 · Cited by 359 · cited 1× · see citing works
“Historically, Pappolla et al. published the first experimental evidence link-S164 ing the potential therapeutic use of melatonin (or related indoles) in AD [111, 112].”
Regulation of the aging process by autophagy.
Salminen, A., & Kaarniranta, K. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.03.004 · Cited by 270 · see citing works
Martins, R. N., Harper, C. G., Stokes, G. B., & Masters, C. L. (1986) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1986.tb00615.x · Cited by 234 · see citing works
Self-citationLymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease
Mecocci, P. (2002) · Archives of Neurology · doi:10.1001/archneur.59.5.794 · Cited by 229 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Saleem, K., Xiao, Z., Zhu, B., Ren, Y., Yan, Z., & Feng, J. (2026) · Molecular Psychiatry · doi:10.1038/s41380-025-03225-4 · Cited by 10 · see citing works
- Authors
- Pappolla, M. A., Martins, R. N., Poeggeler, B., Omar, R. A., & Perry, G.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Edith Cowan University (AU)
- Johann-Friedrich-Blumenbach-Institute for Zoology and Anthropology, Faculty of Biology and Psychology, Georg August University, Gottingen, Germany
- University of Louisville (US)
- The University of Texas at San Antonio (US)
- Corresponding author
- Pappolla, Miguel A.
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2024-10-18
- Volume
- 101
- Issue
- s1
- Pages
- S155-S178
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W4403538742
- Cited by
- 29
- References
- 13
- Citations by year
- 2026: 12 · 2025: 17
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- Alzheimer's disease, oxidative stress
- MeSH terms
- Alzheimer Disease, Animals, Antioxidants, Humans, Oxidative Stress
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
