Oxidative Stress in Alzheimer’s Disease: The Shortcomings of Antioxidant Therapies

Issue title: Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?

Guest editors: Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, Germán Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu and George Perry

Article type: Review Article

Authors: Pappolla, Miguel A.^{a; *} | Martins, Ralph N.^b | Poeggeler, Burkhard^c | Omar, Rawhi A.^d | Perry, George^e

Affiliations: [a] Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA | [b] Aging and Alzheimer’s Disease Centre, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia | [c] Johann-Friedrich-Blumenbach-Institute for Zoology and Anthropology, Faculty of Biology and Psychology, Georg August University, Gottingen, Germany | [d] Department of Pathology, University of Louisville, Louisville, KY, USA | [e] Department of Neuroscience, Developmental and Regenerative Biology, University of Texas at San Antonio, San Antonio, TX, USA

Correspondence: [*] Correspondence to: Miguel A. Pappolla, Professor of Neurology, Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA. E-mail: pappolla@aol.com.

Abstract: 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.

Keywords: Alzheimer’s disease, clinical trials, DASH diet, Mediterranean diet, melatonin, MIND diet, oxidative stress, resveratrol, vitamin E, vitamin C

DOI: 10.3233/JAD-240659

Journal: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S155-S178, 2024