Oxidative stress in Alzheimer's disease: The shortcomings of antioxidant therapies

Author Identifier

Ralph N. Martins: https://orcid.org/0000-0002-4828-9363

Document Type

Journal Article

Publication Title

Journal of Alzheimer's Disease : JAD

Volume

101

Issue

s1

First Page

S155

Last Page

S178

PubMed ID

39422961

Publisher

IOS Press

School

Centre of Excellence for Alzheimer's Disease Research and Care / School of Medical and Health Sciences

Comments

Pappolla, M. A., Martins, R. N., Poeggeler, B., Omar, R. A., & Perry, G. (2024). Oxidative stress in Alzheimer’s disease: The shortcomings of antioxidant therapies. Journal of Alzheimer's Disease, 101(s1), S155-S178. https://doi.org/10.3233/JAD-240659

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.

DOI

10.3233/JAD-240659

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