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Cited by 179Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAntioxidant Activity and Oxidative Stress

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Open access
Buccellato, Francesca Romana, D’Anca, Marianna, Fenoglio, Chiara, Scarpini, Elio, Galimberti, Daniela·2021·Antioxidants
DOI 10.3390/antiox10091353PMC PMC8471953
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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that oxidative damage from reactive oxygen/nitrogen species, mitochondrial dysfunction, and microglial/astrocytic activation is an early and progressive contributor to Alzheimer’s disease pathogenesis. It evaluates oxidative-damage products in blood, CSF, urine, and saliva as candidate early biomarkers and discusses antioxidant/oxidative-stress-targeted therapies, concluding that no reliable peripheral marker has yet been established.

Key findings

  • AD accounts for over 50% of dementia patients and affects over 50 million people worldwide; about 2–3% of cases are due to autosomal dominant mutations, while the rest are sporadic and prevalent in aging populations.
  • Oxidative damage products—including 3-nitrotyrosine, protein carbonyls, 4-hydroxy-2-trans-nonenal (HNE), F2-/F3-/F4-isoprostanes, advanced glycation end products (AGEs), 8-OHdG, 8-oxoGua, and 8-oxoGuo—are described in AD and MCI brain and in body fluids such as blood, CSF, urine, and saliva.
  • Mitochondria are both sources and targets of oxidative damage in AD; mtDNA is preferentially affected, and mitochondrial abnormalities marked by 8-OHdG and nitrotyrosine are found in neurons lacking neurofibrillary tangles, suggesting early pathological change.
  • Microglia and astrocytes contribute to ROS production via mechanisms including NOX2, NOX4, NLRP3 inflammasome, and TREM2-related pathways; TREM2 mutation is associated with a three-fold higher risk of developing AD.
  • In the 2021 AD drug pipeline, of 18 phase 3 agents classified as disease-modifying treatments, three had oxidative stress as mechanism of action, two had metabolism/bioenergetic mechanisms, and two had antioxidant properties; Azeliragon was among three agents acting on synaptic plasticity/neuroprotection and also meant to ameliorate oxidative stress.

Methods

  • Design: narrative review of oxidative damage in AD and neurodegeneration, covering pathogenic mechanisms, biomarker discovery, experimental models, and therapeutic approaches.
  • Data/sample: no primary cohort or systematic dataset; the review draws on cited human studies, animal models, in vitro models, metabolomic/proteomic studies, and clinical trial reports, with attention to blood, CSF, urine, and saliva.
  • Main analysis: qualitative synthesis of literature on ROS/RNS, oxidative damage products, mitochondrial dysfunction, microglial/astrocytic responses, and antioxidant or oxidative-stress-targeted interventions; tables referenced include oxidative stress markers and phase 3 trials.

Limitations

  • The paper states that studies on oxidative damage products in AD have failed “till now” to reveal one or more reliable markers, and that it is unlikely to find a peripheral specific marker because oxidative-damage pathways occur in other neurodegenerative conditions as well.
  • The paper notes that antioxidant supplementation cannot be considered curative, though it may help limit pathogenic events in a multifactorial disease.
  • Evident from the text: as a narrative review, no systematic search strategy, inclusion criteria, or risk-of-bias assessment is described; evidence is heterogeneous across human fluids, animal models, and in vitro systems.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/antiox10091353

Cites

170 of 170 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 208 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Oxidative damage products are suggested as biomarkers in neurodegeneration and Alzheimer's disease.

    “Oxidative damage products, as the ones deriving from oxidation of lipid, DNA, RNA, or glycation ends products, are extensively studied, and are suggested as biomarkers in neurodegeneration and AD [22,23,24].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Peeters, 2017, Blood-based metabolic signatures in Alzheimer’s disease, Alzheimer’s Dementia: Diagn. Assess. Dis. Monit.

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  • Premisecitation

    Microglia can respond to Aβ or to other danger-associated molecules released by damaged cells by producing reactive oxygen species.

    “Microglia can respond to Aβ, or to other danger-associated molecules released by damaged cells, by producing reactive oxygen species (ROS) [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Schilling, 2011, Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia, J. Cell. Physiol. source

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    Higher levels of RAGE expression are found in neuronal, microglial, and endothelial cells in Alzheimer's disease patients compared with age-matched non-demented controls.

    “AGEs and the receptor for advanced glycation end-products (RAGE) can play an important role in AD pathogenesis as higher levels of RAGE expression in neuronal, microglial, and endothelial cells in patients with AD compared with age-matched, non- demented controls are found [43,44,45,46].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [43] Fang, 2018, RAGE mediates Aβ accumulation in a mouse model of Alzheimer’s disease via modulation of β- and γ-secretase activity, Hum. Mol. Genet. source

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    • cites [44] Origlia, 2010, Microglial Receptor for Advanced Glycation End Product-Dependent Signal Pathway Drives-Amyloid-Induced Synaptic Depression and Long-Term Depression Impairment in Entorhinal Cortex, J. Neurosci. source

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    • cites [45] Miller, 2008, Hippocampal RAGE immunoreactivity in early and advanced Alzheimer’s disease, Brain Res. source

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    • cites [46] Sasaki, 2001, Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease, Brain Res. source

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  • Premisecitation

    Oxidative damage products are detected in body fluids such as blood, plasma, serum, cerebrospinal fluid, urine, and saliva.

    “They are detected in body fluids such as blood, plasma, serum, cerebrospinal fluid (CSF), urine, and saliva [25,26,27].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Vigor, 2019, New screening approach for Alzheimer’s disease risk assessment from urine lipid peroxidation compounds, Sci. Rep. source

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    • cites [26] Choromańska, M., Klimiuk, A., Kostecka-Sochoń, P., Wilczyńska, K., Kwiatkowski, M., Okuniewska, N., Waszkiewicz, N., Zalewska, A., and Maciejczyk, M. (2017). Antioxidant Defence, Oxidative Stress and Oxidative Damage in Saliva, Plasma and Erythrocytes of Dementia Patients. Can Salivary AGE be a Marker of Dementia?. Int. J. Mol. Sci., 18. source

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    • cites [27] Johnson, 2020, Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation, Nat. Med. source

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  • Premisecitation

    The oxidative stress hypothesis can be applied to other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis, where accumulation of oxidative damage over time leads to late-life onset and progressive nature.

    “The oxidative stress hypothesis can be applied to other neurodegenerative diseases, such as Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) where the accumulation of oxidative damage over time leads to the late life onset and to the progressive nature of these diseases [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Markesbery, 1997, Oxidative Stress Hypothesis in Alzheimer’s Disease, Free. Radic. Biol. Med. source

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    Premisecitation

    Alzheimer's disease is the most common cause of dementia, a progressive neurodegenerative disorder affecting over 50 million people worldwide.

    “The most common cause of dementia is Alzheimer’s disease (AD), a progressive neurodegenerative disorder, affecting over 50 million people worldwide [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Prince, 2016, Recent global trends in the prevalence and incidence of dementia, and survival with dementia, Alzheimer’s Res. Ther. source

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    Premisecitation

    The amyloid cascade hypothesis proposes that inappropriate processing of amyloid-β precursor leads to amyloid plaque build-up, tau tangle formation, and ultimately neuronal death.

    “the most studied pathogenic mechanism has been the “amyloid cascade hypothesis” proposed in 1991 by Hardy and Allsop, who suggested that inappropriate processing of amyloid-β (Aβ) precursor leads to the build-up of amyloid plaques, the formation of tau tangles, and ultimately to neuronal death [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Hardy, 1991, Amyloid deposition as the central event in the aetiology of Alzheimer’s disease, Trends Pharmacol. Sci. source

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    Alzheimer's disease is irreversible and presents with neurodegeneration caused by toxic aggregation of extracellular amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein.

    “The disease is irreversible and presents with neurodegeneration caused by toxic aggregation of extracellular amyloid plaques, and intracellular neurofibrillary tangles of hyperphosphorylated tau protein [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Stelzmann, 1995, An english translation of alzheimer’s 1907 paper, “über eine eigenartige erkankung der hirnrinde”, Clin. Anat. source

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    Premisecitation

    Oxidative damage is an early event in the pathogenesis of Alzheimer's disease, occurring before the onset of clinical symptoms, and is also a factor contributing to disease progression.

    “Past and recent studies have demonstrated that oxidative damage is not only an early event in the pathogenesis of AD, occurring before the onset of clinical symptoms but also a factor contributing to the disease progression [17,18,19,20,21].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [17] Butterfield, 1997, β-Amyloid-Associated Free Radical Oxidative Stress and Neurotoxicity: Implications for Alzheimer’s Disease, Chem. Res. Toxicol. source

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    • cites [18] Butterfield, 2019, Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease, Nat. Rev. Neurosci. source

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    • cites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source

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    • cites [20] Uryu, 2001, Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis, J. Neurosci. source

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    • cites [21] Ansari, 2011, NADPH-oxidase activation and cognition in Alzheimer disease progression, Free. Radic. Biol. Med. source

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    • Rests on an assumption: Alzheimer’s disease pathogenesis starts decades before symptoms appear.

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    Premisecitation

    The brain is very susceptible to oxidative stress because it is rich in polyunsaturated fatty acids, has high oxygen consumption, has a high content of metals, especially iron, that can catalyze oxidative reactions, and has fewer antioxidant enzymes than other organs.

    “The brain is very susceptible to OS because it is rich in polyunsaturated fatty acids, has a high oxygen consumption and a high content of metals in particular, iron, that can catalyze oxidative reactions, in contrast, it has less antioxidant enzymes in comparison with other organs [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jellinger, 1990, Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases, J. Neural Transm. source

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    Premisecitation

    Redox proteomic studies confirm that carbonylated proteins are present in cerebrospinal fluid of amnestic mild cognitive impairment patients compared with controls, and these proteins remain oxidized in the progression towards Alzheimer's disease.

    “Redox proteomic studies confirm previous results that carbonylated proteins are present in CSF of amnestic MCI patients compared with controls, and these proteins remain oxidized in the progression towards AD [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Pupo, 2016, Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients, Free. Radic. Biol. Med. source

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    Premisecitation

    In Alzheimer's disease, reactive microglia and astrocytes are associated with amyloid plaques and respond to Aβ with expression of pro-inflammatory cytokines.

    “In AD, reactive microglia and astrocytes are associated with the amyloid plaques and respond to Aβ with the expression of pro-inflammatory cytokines [12,13,14].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Mielke, 2011, Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer’s Disease, Am. J. Pathol. source

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    • cites [13] Hanisch, 2007, Microglia: Active sensor and versatile effector cells in the normal and pathologic brain, Nat. Neurosci. source

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    • cites [14] Galimberti, 1999, α-MSH Peptides Inhibit Production of Nitric Oxide and Tumor Necrosis Factor-α by Microglial Cells Activated with β-Amyloid and Interferon γ, Biochem. Biophys. Res. Commun. source

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    Premisecitation

    In 2021, recommendations proposed that Alzheimer's disease diagnosis should be restricted to people with positive biomarkers together with specific AD phenotypes, and cognitively unimpaired biomarker-positive individuals should be considered at-risk for progression to AD.

    “In 2021, new recommendations for the clinical diagnosis of AD were proposed by the International working group, highlighting that the diagnosis of AD should be restricted to people who have positive biomarkers together with specific AD phenotypes. Cognitively unimpaired individuals who are only positive to biomarkers should be considered at-risk for progression to AD [10].”
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    • cites [10] Dubois, 2021, Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group, Lancet Neurol. source

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    Premisecitation

    Decreased levels of phosphatidylcholine, phosphatidylethanolamine, and the phospholipid precursors choline and ethanolamine have been described in Alzheimer's disease and are considered specific for the pathogenic mechanism of AD; the depletion is referred to increased ROS-mediated lipid peroxidation.

    “Decreased levels of phosphatidylcholine, phosphatidylethanolamine and the phospholipid precursors, choline and ethanolamine, have been described in AD and are considered specific for the pathogenic mechanism of AD. The depletion of phospholipids in AD has been referred to an increase of ROS-mediated lipid peroxidation [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Markesbery, 1997, Oxidative Stress Hypothesis in Alzheimer’s Disease, Free. Radic. Biol. Med. source

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    Premisecitation

    Protein oxidation, nucleic acid oxidation, and lipid peroxidation are markers of oxidative stress described as early alterations in the Alzheimer's disease brain, supporting the oxidative stress hypothesis of AD pathogenesis.

    “All of these markers of OS have been described as an early alteration in the AD brain, and this concept has been used in the past to support the ‘oxidative stress hypothesis’ in the pathogenesis of AD [20,28,29,30].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [20] Uryu, 2001, Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis, J. Neurosci. source

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    • cites [28] Jellinger, 1990, Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases, J. Neural Transm. source

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    • cites [29] Markesbery, 1997, Oxidative Stress Hypothesis in Alzheimer’s Disease, Free. Radic. Biol. Med. source

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    • cites [30] Smith, 2000, Oxidative stress in Alzheimer’s disease, Biochim. et Biophys. Acta (BBA) Mol. Basis Dis. source

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    Premisecitation

    In brains of individuals with Alzheimer's disease, preclinical AD, and mild cognitive impairment, many oxidative damage products are measured, and oxidative stress is a key and early player in the pathogenesis of neurodegeneration and AD.

    “In the brains of individuals with AD and preclinical AD (i.e., evidence of Aβ and tau deposition in the brain without any clinical manifestation of the disease), as well as patients with MCI (a mild clinical impairment with no proof of underlying pathology with biomarkers), many oxidative damage products are measured, and numerous investigations have pointed to OS as a key and early player in the”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Butterfield, 2019, Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease, Nat. Rev. Neurosci. source

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    • cites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source

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    Premisecitation

    Following the 2018-NIA-AA-RF, Alzheimer's disease is defined by underlying pathology measured by lifetime biomarkers, and both Aβ and phosphorylated tau pathology are required for classification as AD, whereas Aβ deposition alone is an early sign.

    “Following the new research framework (2018-NIA-AA-RF), AD is not defined by its clinical consequences but by its underlying pathology measured by lifetime biomarkers. Regardless of the presence of clinical symptoms, both Aβ and phosphorylated tau pathology are required for classification as AD, whereas Aβ deposition alone is an early sign, labelling the pathologic change towards AD [9].”
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    • cites [9] Carandini, 2019, Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: From biological biomarkers to clinical syndromes, Alzheimer’s Res. Ther. source

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    Premisecitation

    Activated microglia can respond to injured neurons in a neuroprotective manner and afterwards become toxic, contributing to neuroinflammation and neurodegeneration.

    “Further, activated microglia can respond to injured neurons in a neuroprotective manner and, afterwards, become toxic, contributing to neuroinflammation and neurodegeneration [15].”
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    • cites [15] Clark, 2015, Amyloid β: One of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate A lzheimer’s disease, Br. J. Pharmacol. source

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    Premisecitation

    About 2-3% of Alzheimer's disease cases are due to autosomal dominant mutations, while the rest are sporadic cases prevalent in the aging population.

    “About 2–3% of AD cases are due to autosomal dominant mutations. The rest are sporadic cases and are prevalent in the aging population [8].”
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    • cites [8] Galimberti, 2010, Treatment of Alzheimers Disease: Symptomatic and Disease-Modifying Approaches, Curr. Aging Sci. source

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    Premisecitation

    Aβ oligomers can target and activate NMDAR, leading to a rapid increase in neuronal calcium levels and reactive oxygen species production in mature hippocampal neurons in culture.

    “Aβ oligomers can target and activate NMDAR leading to a rapid increase in neuronal calcium levels and ROS production in mature hippocampal neurons in culture [75].”
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    • cites [75] Velasco, 2007, Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine, J. Biol. Chem. source

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    Memantine blocks excessive calcium entry through the NMDAR channel and Aβ-induced oxidative stress, providing a specific biological mechanism for its therapeutic action.

    “During pathological activation of the NMDAR, memantine blocks excessive calcium entry through the channel and Aβ-induced OS, providing a specific biological mechanism for the therapeutic action of memantine.”
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    • cites [74] Robinson, 2006, Memantine: A Review of Its Use in Alzheimer’s Disease, Drugs source

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    • cites [75] Velasco, 2007, Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine, J. Biol. Chem. source

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    Premisecitation

    Amyloid oligomers can access mitochondria, contributing to compromised mitochondrial function and triggering a vicious circle in which it is not defined whether Aβ accumulation precedes or follows mitochondrial decline.

    “Besides, amyloid oligomers can access mitochondria, contributing to compromise their function and triggering a vicious circle in which it is not defined if the accumulation of Aβ came before mitochondrial declined function or after [67].”
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    • cites [67] Oka, 2016, Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease, Sci. Rep. source

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    Mitochondrial function declines with age and leads to increased production of reactive oxygen species.

    “In this explanation, the mitochondrial function declines with age and leads to increased production of ROS [65,66].”
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    • cites [65] Swerdlow, 2004, A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease, Med. Hypotheses source

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    • cites [66] Swerdlow, 2010, The Alzheimer’s Disease Mitochondrial Cascade Hypothesis, J. Alzheimer’s Dis. source

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    In the Alzheimer's disease brain, mitochondria can be sources of reactive oxygen species and also targets of oxidative stress, and mitochondrial DNA is especially susceptible to oxidative damage.

    “In the AD brain, mitochondria can be sources of ROS and also the target of OS, especially mitochondrial DNA (mtDNA) is susceptible to oxidative damage [19,53,63].”
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    • cites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source

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    • cites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source

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    • cites [63] Lin, 2006, Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases, Nat. Cell Biol.

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    Premisecitation

    Aβ can be toxic to neuronal mitochondria and causes Ca2+ elevation and changes in mitochondrial size and shape in the APP/PS1 Alzheimer's disease mouse model.

    “Aβ can be toxic on neuronal mitochondria and causes Ca2+ elevation, changes in mitochondrial size and shape in APP/PS1 AD mouse model [70].”
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    • cites [70] Xie, 2013, Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model, J. Neurosci. source

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    Mitochondrial abnormalities are found in neurons lacking neurofibrillary tangles, suggesting that mitochondrial abnormalities are one of the earliest pathological changes in Alzheimer's disease.

    “These abnormalities are found in neurons lacking neurofibrillary tangles, suggesting that mitochondrial abnormalities are one of the earliest pathological changes in AD.”
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    • cites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source

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    Glucose metabolism is dysregulated in Alzheimer's disease and mild cognitive impairment, and the metabolic rate of glucose is decreased in the brain of patients with senile dementia.

    “Glucose metabolism is dysregulated in AD and MCI and the metabolic rate of glucose is decreased in the brain of patients with senile dementia [18].”
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    • cites [18] Butterfield, 2019, Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease, Nat. Rev. Neurosci. source

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    Premisecitation

    There is a progressive age-related accumulation of oxidative damage to DNA in the human brain, and mitochondrial DNA is preferentially affected; increased 8-OHdG in mtDNA and nuclear DNA is demonstrated in the aging human brain and in Alzheimer's disease.

    “It is demonstrated that there is a progressive age-related accumulation of oxidative damage to DNA in the human brain and that mtDNA is preferentially affected. The increased amount of 8-OHdG in mtDNA and nuclear DNA is demonstrated in the aging human brain and in AD [50,51,64].”
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    • cites [50] Mecocci, 1993, Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain, Ann. Neurol. source

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    • cites [51] Mecocci, 1994, Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease, Ann. Neurol. source

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    • cites [64] Mecocci, 1997, Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain, Mol. Chem. Neuropathol. source

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    Premisecitation

    Hirai et al. demonstrated that oxidative damage marked by 8-OHdG and nitrotyrosine occurs in neurons of Alzheimer's disease patients, with reduction of mitochondria and accumulation of mtDNA and mitochondrial proteins in these same neurons.

    “Hirai et al. have demonstrated that oxidative damage marked by 8-OHdG and nitrotyrosine occurs in the neurons of AD patients. Morphometric analysis showed a reduction of mitochondria in these same neurons and an accumulation of mtDNA and mitochondrial proteins [53].”
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    • cites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source

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    Excessive Ca2+ accumulation into mitochondria leads to decreased mitochondrial membrane potential and increased reactive oxygen species production in the APP/PS1 Alzheimer's disease mouse model.

    “Excessive Ca2+ accumulation into mitochondria leads to decreased mitochondrial membrane potential and increased ROS production in the same AD mouse model [67,68,70].”
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    • cites [67] Oka, 2016, Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease, Sci. Rep. source

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    • cites [68] Mattson, 2007, Calcium and neurodegeneration, Aging Cell source

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    • cites [70] Xie, 2013, Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model, J. Neurosci. source

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    Mitochondrial DNA is a target of oxidative damage, and increased damage to DNA contributes to Alzheimer's disease and the neurodegenerative process.

    “These results confirmed that mtDNA is a target of oxidative damage and that the increased damage to DNA contributes to AD and the neurodegenerative process [51,53].”
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    • cites [51] Mecocci, 1994, Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease, Ann. Neurol. source

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    • cites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source

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    SIRT3 defects contribute to oxidative stress in Alzheimer's disease mitochondria, and SIRT3 is linked to dysregulation of mitochondrial DNA expression, ROS accumulation, and neuronal damage in AD.

    “Recently, sirtuin 3 (SIRT3) defects have been considered to contribute to OS in AD mitochondria. Indeed, SIRT3 has been linked to dysregulation of mitochondrial DNA expression, ROS accumulation and neuronal damage in AD [76,77].”
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    • cites [76] Lee, 2017, SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer’s disease, Aging Cell source

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    • cites [77] Zhang, 2020, Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target, Theranostics source

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    Premisenone given

    Antioxidant treatments are studied in experimental models and in human trials to counterbalance the increase of oxidative stress that is characteristic in age-related neurodegenerative diseases.

    “To counterbalance the increase of OS that is characteristic in age-related neurodegenerative diseases antioxidant treatment are studied in experimental models and in human trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In Alzheimer's disease, Aβ can act as a danger-associated molecular pattern, and its interaction with microglia creates an oxidative and neuroinflammatory environment through increased production of reactive oxygen species and release of proinflammatory cytokines.

    “In AD, Aβ can act as DAMP and its interaction with microglia creates an oxidative and neuroinflammatory environment through an increased production of ROS and release of proinflammatory cytokines [107].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Venegas, 2016, Danger-associated molecular patterns in Alzheimer’s disease, J. Leukoc. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOX4 levels are significantly elevated in astrocytes of patients with Alzheimer's disease and in the APP/PS1 double-transgenic mouse model of AD.

    “NO X4 is the astrocytes isoform, and its levels are reported significantly elevated in astrocytes of patients with AD and APP/PS1 double-transgenic mouse model of AD [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Park, 2021, NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases, Redox Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Colocalization of reactive microglia with Aβ deposits is a hallmark of Alzheimer's disease pathology and has been reported in brains from AD mouse models.

    “Colocalization of reactive microglia with Aβ deposits is a hallmark of AD pathology and has been reported also in brains from AD mouse models [102,103].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Sarlus, 2017, Microglia in Alzheimer’s disease, J. Clin. Investig. source

      Not checked in the free run.

    • cites [103] Schwabe, 2020, Shifting paradigms: The central role of microglia in Alzheimer’s disease, Neurobiol. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevation of NOX4 promotes impairment of mitochondrial metabolism, mitochondrial ROS production, and fragmentation in human astrocytes.

    “The levels of two products of oxidative damage, 4-HNE and MDA, were also significantly elevated, suggesting that the elevation of NOX4 promotes the impairment of mitochondrial metabolism, mitochondrial ROS production and fragmentation in human astrocytes [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Park, 2021, NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases, Redox Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of Nrf2 by Centella asiatica extracts improved mitochondrial and cognitive function and enhanced synaptic density in Alzheimer's disease and aging mouse models.

    “Another Nrf2 activating compound is Centella asiatica extracts, which can activate Nrf2 in neuroblastoma cells, isolated primary neurons and in the brains of AD and aging mouse models. This activation improved mitochondrial and cognitive function, and enhanced synaptic density [113,114,115].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [113] Brandes, M.S., and Gray, N.E. (2020). NRF2 as a Therapeutic Target in Neurodegenerative Diseases. ASN Neuro, 12. source

      Not checked in the free run.

    • cites [114] Gray, 2018, Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in β-amyloid overexpressing mice, Mol. Cell. Neurosci. source

      Not checked in the free run.

    • cites [115] Matthews, D.G., Caruso, M., Murchison, C.F., Zhu, J.Y., Wright, K.M., Harris, C.J., Gray, N.E., Quinn, J.F., and Soumyanath, A. (2019). Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice. Antioxidants, 8. source

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  • May combine two claims.

    Premisecitation

    NOX activation is evident in the Alzheimer's disease brain, and NOX2 is highly expressed in microglia.

    “NOX activation is evident in the AD brain, in addition NOX2 is highly expressed in microglia [108,109].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [108] Shimohamaa, 2000, Activation of NADPH Oxidase in Alzheimer’s Disease Brains, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

    • cites [109] Geng, 2020, Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Down-regulation of microglial TREM2 expression and signaling might be one of the major pathogenetic mechanisms in sporadic cases of Alzheimer's disease, in which advanced age, oxidative stress, and neuroinflammation contribute to suppression of wild-type TREM2.

    “Regarding the relation of TREM2 with OS, it has been supposed that a down-regulation of microglial TREM2 expression and signaling might be one of the major pathogenetic mechanisms in sporadic cases of AD in which advanced age, OS, neuroinflammation contribute to the suppression of wild-type TREM2, considering that TREM2 mutation is rare in humans [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Liu, 2020, Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions, Hum. Mol. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxidative damage to RNA in entorhinal cortex, hippocampus, subiculum, and temporal neocortex of subjects with Alzheimer's disease has been described; levels of 8-OHdG increase early before pathological changes occur, which may explain that selective vulnerability of entorhinal cortex neurons in AD may be related to vulnerability to oxidative damage.

    “Oxidative damage to RNA in EC, hippocampus, subiculum, and temporal neocortex of subjects with AD has been described. The levels of 8-OHdG increase early before pathological changes occur, and this can explain that the selective vulnerability of neurons in the EC during AD may be related to the vulnerability of these particular neurons to oxidative damage [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pioneering studies conducted to validate early changes of products of oxidative damage found in specimens of Alzheimer's disease patients in the Tg2576 transgenic mouse model of AD amyloidosis date back more than 20 years.

    “The pioneering studies, conducted to validate the early changes of products of oxidative damage, found in specimens of AD patients, in a transgenic mouse model (Tg2576) of AD amyloidosis, dated back more than 20 years [20,124].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Uryu, 2001, Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis, J. Neurosci. source

      Not checked in the free run.

    • cites [124] Pratico, 1998, Increased F 2 -isoprostanes in Alzheimer’s disease: Evidence for enhanced lipid peroxidation in vivo, FASEB J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Abnormalities in iron homeostasis in brain tissue can increase reactive oxygen species production, causing oxidative damage to sensitive cellular structures and triggering ferroptosis.

    “Abnormalities in iron homeostasis in brain tissue can increase ROS production, causing noxious oxidative damage to sensitive cellular structures, and trigger a new cell death process called ferroptosis [98,99].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98] Li, 2020, Ferroptosis: Past, present and future, Cell Death Dis. source

      Not checked in the free run.

    • cites [99] Yan, 2021, Ferroptosis: Mechanisms and links with diseases, Signal Transduct. Target. Ther. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    HDAC1 has important roles in 8-oxoG repair and HDAC1 activation has therapeutic potential to counteract functional decline in brain aging and neurodegeneration.

    “uncovering important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counteract the functional decline in brain aging and neurodegeneration [126].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Pao, 2020, HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    γ-GC may lower inflammation and enhance Aβ plaque clearance in vivo.

    “γ-GC may also lower inflammation and enhance Aβ plaque clearance in vivo as suggested by cytokines and matrix metalloproteinase levels in the brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Liu, 2020, Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD, Neurochem. Int. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    MITOL is an integral mitochondrial outer membrane protein that regulates mitochondrial functions and morphology.

    “MITOL is an integral mitochondrial outer membrane protein which regulates mitochondrial functions and morphology [131].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Takeda, 2021, Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation, Commun. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GSH is a cellular antioxidant, and its depletion has been observed in AD.

    “Glutathione (GSH) is a cellular antioxidant, and its depletion has been observed in AD [133].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Haddad, M., Hervé, V., Ben Khedher, M.R., Rabanel, J.-M., and Ramassamy, C. (2021). Glutathione: An Old and Small Molecule with Great Functions and New Applications in the Brain and in Alzheimer’s Disease. Antioxid. Redox Signal., 35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In APP/PS1 mice on γ-GC diet, Aβ pathology was reduced and AChE activity was improved compared to standard chow.

    “Aβ pathology was reduced, and AChE activity was improved in APP/S1 mice on the γ-GC diet compared to APP/PS1 mice fed a standard chow diet.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Liu, 2020, Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD, Neurochem. Int. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    Dietary supplementation with γ-GC lowered brain lipid peroxidation, protein carbonyls and apoptosis, and maintained antioxidant status in APP/PS1 mice.

    “The authors report that the diet with γ-GC lowered the levels of brain lipid peroxidation, protein carbonyls and apoptosis, and maintain antioxidant status in APP/PS1 mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Liu, 2020, Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD, Neurochem. Int. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    SIRT1 can bind HDAC1, deacetylate HDAC1 and stimulate its enzymatic activity.

    “sirtuin (SIRT) 1 can also bind the class I histone deacetylase HDAC1, deacetylate HDAC1 and stimulate its enzymatic activity [128].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Dobbin, 2013, SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons, Nat. Neurosci. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Mitochondrial respiratory chain complex I might be a therapeutic target in AD.

    “Stojakovic et al. observed that mitochondrial respiratory chain complex I might be a therapeutic target in AD [129].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Stojakovic, 2021, Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice, Commun. Biol. source

      Not checked in the free run.

    • Rests on an assumption: Mitochondrial health is essential for maintaining energy homeostasis and preventing neuronal dysfunction in AD.

  • May combine two claims.

    Premisecitation

    HDAC1-deficient mice show DNA damage accumulation and cognitive impairment during aging.

    “HDAC1-deficient mice show DNA damage accumulation and cognitive impairment during aging [126].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Pao, 2020, HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease, Nat. Commun. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    Blood-based biomarkers are not available for AD and the potential ones are derived from Aβ and Tau.

    “Blood-based biomarkers are not available for AD and the potential ones are derived from Aβ and Tau [137].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Nakamura, 2018, High performance plasma amyloid-β biomarkers for Alzheimer’s disease, Nat. Cell Biol.

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Premisecitation

    In the 5XFAD mouse model of AD, elevated 8-oxoG is accompanied by reduced HDAC1 activity and downregulation of a gene set critical for brain function.

    “this work showed elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a gene set critical for brain function in the 5XFAD mouse model of AD”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Pao, 2020, HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease, Nat. Commun. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Interpretationcitation

    CP2 treatment induces multiple protective mechanisms including autophagy, anti-inflammatory, and antioxidant responses, which contribute to reduce Aβ pathology.

    “Taken together, the data suggest that CP2 treatment induces multiple protective mechanisms including autophagy, anti-inflammatory, and antioxidant responses, which contribute to reduce Aβ pathology [129].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Stojakovic, 2021, Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice, Commun. Biol. source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    Intranasal administration of a nano-formulation of graphene oxide loaded with dauricine has potential as a non-invasive drug delivery system that can pass the BBB and reach the brain.

    “This report highlights also the potential of non-invasive drug delivery system based on nanoparticles that can pass the BBB and reach the brain [135].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Wang, 2021, Intranasal administration of dauricine loaded on graphene oxide: Multi-target therapy for Alzheimer’s disease, Drug Deliv. source

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Interpretationcitation

    MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in the APP/PS1 mouse model of AD.

    “It is possible to affirm that MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in APP/PS1 mouse model with AD [131].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Takeda, 2021, Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation, Commun. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MITOL-deleted APP/PS1 mice show severe cognitive impairment, synapse alteration, and neuroinflammation mediated by excessive generation of toxic and dispersible Aβ oligomers.

    “MITOL-deleted APP/PS1 mice show severe cognitive impairment, synapse alteration, and neuroinflammation mediated by excessive generation of toxic and dispersible Aβ oligomers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Takeda, 2021, Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation, Commun. Biol. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    CP2 treatment reduces total Aβ levels triggering autophagy.

    “Further, this treatment can reduce total Aβ levels triggering autophagy, one of the neuroprotective pathways essential for Aβ clearance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Stojakovic, 2021, Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice, Commun. Biol. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Interpretationcitation

    TUFM is involved in AD pathology by regulating BACE1 translation, apoptosis, and Tau phosphorylation, in which ROS plays an important role.

    “Taken together these results pointed at TUFM involvement in AD pathology by regulating BACE1 translation, apoptosis, and Tau phosphorylation, in which ROS plays an important role [130].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Zhong, 2021, TUFM is involved in Alzheimer’s disease-like pathologies that are associated with ROS, FASEB J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular ROS levels are affected by TUFM expression, and TUFM-mediated regulation of apoptosis and Tau phosphorylation is counteracted by TEMPO.

    “Further, cellular ROS levels were affected by TUFM expression, and TUFM-mediated regulation of apoptosis and Tau phosphorylation is counteracted by the treatment with TEMPO, a potent antioxidant drug.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Zhong, 2021, TUFM is involved in Alzheimer’s disease-like pathologies that are associated with ROS, FASEB J. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    TUFM can maintain mitochondrial respiratory chain activity and protect cells against oxidative stress.

    “Mitochondrial Tu translation elongation factor (TUFM or EF-Tu) can maintain mitochondrial respiratory chain activity and protect cell against OS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Zhong, 2021, TUFM is involved in Alzheimer’s disease-like pathologies that are associated with ROS, FASEB J. source

      Not checked in the free run.

    • Rests on an assumption: Mitochondrial health is essential for maintaining energy homeostasis and preventing neuronal dysfunction in AD.

  • May combine two claims.

    Premisecitation

    In the same 3xTg-AD model, minocycline decreased nuclear accumulation of 8-oxoG in microglial cells and inhibited microgliosis and neuronal loss.

    “The use of minocycline, an inhibitor of microglial activation and neuroinflammation, in this model decreased the nuclear accumulation of 8-oxoG in microglial cells, and inhibited microgliosis and neuronal loss.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Oka, 2021, MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer’s brain, and prevent the progression of Alzheimer’s pathogenesis, Sci. Rep. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    In a 3xTg-AD mouse model, MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4-5 months of age.

    “They demonstrated that MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4–5 months of age.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Oka, 2021, MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer’s brain, and prevent the progression of Alzheimer’s pathogenesis, Sci. Rep. source

      Not checked in the free run.

    • Rests on an assumption: Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

  • May combine two claims.

    Premisecitation

    OS and inflammation can perturb the HDL proteome, possibly playing a role in AD pathogenesis.

    “OS and inflammation can perturbate the high-density lipoprotein (HDL) proteome, possibly playing a role in AD pathogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Zimetti, 2021, Connection between the Altered HDL Antioxidant and Anti-Inflammatory Properties and the Risk to Develop Alzheimer’s Disease: A Narrative Review, Oxidative Med. Cell. Longev. source

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Premisecitation

    NDAN patients display amyloid and tau pathology but resist dementia.

    “NDAN patients display amyloid and tau pathology, but they resist to dementia [154].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Fracassi, 2020, Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer’s Neuropathology, J. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Salivary levels of AGE correlate with deterioration in MMSE score and have been suggested as potentially useful in diagnosis of dementia.

    “Salivary levels of AGE have been described to correlate with the deterioration in mini mental state examination (MMSE) score and have been suggested as potentially useful in the diagnosis of dementia [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Choromańska, M., Klimiuk, A., Kostecka-Sochoń, P., Wilczyńska, K., Kwiatkowski, M., Okuniewska, N., Waszkiewicz, N., Zalewska, A., and Maciejczyk, M. (2017). Antioxidant Defence, Oxidative Stress and Oxidative Damage in Saliva, Plasma and Erythrocytes of Dementia Patients. Can Salivary AGE be a Marker of Dementia?. Int. J. Mol. Sci., 18. source

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Premisecitation

    Urine contains metabolites that reflect a response to injury, including OS, or carry information originated from the gut microbiome.

    “Urine contains metabolites that reflect a response to injury, including OS, occurring at high distance or carry information originated from the gut microbiome, a novel area of research in neurodegeneration and AD [138].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Kurbatova, 2020, Urinary metabolic phenotyping for Alzheimer’s disease, Sci. Rep. source

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Premisecitation

    Several redox markers (GR, GSH, GSSG, and GSSG/GSH) are altered in whole blood cells from AD patients, some already altered in MCI patients, suggesting potential use as markers of prodromal AD.

    “Several redox markers were found altered in whole blood cells from AD patients, some of them (GR, GSH, GSSG, and GSSG/GSH) are already altered in MCI patients, suggesting their potential use as markers of prodromal AD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Vida, 2019, Altered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer’s Disease, J. Alzheimer’s Dis. source

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Premisecitation

    Blood metabolic signature revealed decreased levels of specific amino acids and lipids in AD, and three markers of oxidative potentially predictive in demarcating AD patients from control subjects: 8,12-iPF-2a IV, PGD2, and NO2-aLA (C18:3).

    “Blood metabolic signature revealed decreased levels of specific amino acids and lipids levels in AD, and three markers of oxidative potentially predictive in demarcating AD patients from control subjects: the isoprostane-pathway derivatives 8,12-iPF-2a IV, and PGD2, and the nitro-fatty acid NO2-aLA (C18:3) [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Peeters, 2017, Blood-based metabolic signatures in Alzheimer’s disease, Alzheimer’s Dementia: Diagn. Assess. Dis. Monit.

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Premisecitation

    Synaptic dysfunction and synapse loss are key hallmarks of AD, present in the early stages of the disease before clinical symptoms appear.

    “Synaptic dysfunction and synapse loss are key hallmarks of AD, present in the early stages of the disease before clinical symptoms appear [79,86,156].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [79] Selkoe, 2016, The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years, EMBO Mol. Med. source

      Not checked in the free run.

    • cites [86] Terry, 1991, Physical basis of cognitive alterations in alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment, Ann. Neurol. source

      Not checked in the free run.

    • cites [156] Scheff, 2014, Is synaptic loss a unique hallmark of Alzheimer’s disease?, Biochem. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC1α expression was lower in AD and similar to control levels in NDAN individuals, while expression of miRNA-485 was significantly increased in AD cortex compared to control and NDAN subjects.

    “PGC1α expression, as a key regulator of antioxidant response, was lower in AD and similar to control levels in NDAN individuals, while expression of miRNA-485, a PGC1α upstream regulator, was significantly increased in AD cortex as compared to the control and NDAN subjects [154].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Fracassi, 2020, Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer’s Neuropathology, J. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These redox markers are associated with MMSE scores and seem useful to monitor cognitive decline in AD progression.

    “Further, they are associated with MMSE scores and seem to be useful to monitor cognitive decline in AD progression [153].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Vida, 2019, Altered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer’s Disease, J. Alzheimer’s Dis. source

      Not checked in the free run.

    • Rests on an assumption: Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

  • May combine two claims.

    Premisecitation

    Nonenzymatic antioxidants such as vitamin C, vitamin A, vitamin E, and carotenoids are lower in the plasma of patients with AD compared with controls and are associated with increased levels of oxidative damage markers.

    “In addition, several nonenzymatic antioxidants such as vitamin C, vitamin A, vitamin E, and carotenoids were lower in the plasma of patients with AD compared with controls and are associated to increased levels of oxidative damage markers [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Mecocci, 2002, Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease, Arch. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHA exerts its indirect antioxidant action modulating thioredoxin and glutathione pathways, and DHA supplementation is beneficial in improving cognitive function in mild AD.

    “DHA exerts its indirect antioxidant action modulating thioredoxin and glutathione pathways, and DHA supplementation is beneficial in improving cognitive function in mild AD [165].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Díaz, M., Mesa-Herrera, F., and Marín, R. (2021). DHA and Its Elaborated Modulation of Antioxidant Defenses of the Brain: Implications in Aging and AD Neurodegeneration. Antioxidants, 10. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ginkgo Biloba extracts are supposed to improve mitochondrial function and brain blood flow, acting as a cognitive enhancer.

    “Ginkgo Biloba (NCT03090516) extracts are supposed to improve mitochondrial function and brain blood flow, acting as a cognitive enhancer [163].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Of the 18 agents in phase 3 classified as disease-modifying treatments, three have OS as mechanism of action, two have metabolism/bioenergetic, two have antioxidant properties, and among the three agents acting on synaptic plasticity/neuroprotection, Azeliragon is also meant to ameliorate OS.

    “Of the 18 agents in phase 3 classified as disease-modifying treatments, three have OS as mechanism of action, two have metabolism/bioenergetic, two have antioxidant properties, and among the three agents acting on synaptic plasticity/neuroprotection, Azeliragon is also meant to ameliorate OS (Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RAGE can also bind amyloid and is upregulated in astrocytes and microglia of AD patients.

    “RAGE can also bind amyloid and is upregulated in astrocytes and microglia of AD patients [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Lue, 2001, Involvement of Microglial Receptor for Advanced Glycation Endproducts (RAGE) in Alzheimer’s Disease: Identification of a Cellular Activation Mechanism, Exp. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The therapeutic purpose of Blarcamesine is its potential to correct metabolic and synaptic abnormalities, as the sigma 1 receptor restores cellular homeostasis and synaptic plasticity when activated by targeting mitochondrial dysfunction and associated OS, protein misfolding, proteostasis, autophagy, and neuroinflammation.

    “The therapeutic purpose of the treatment with this compound is its potential to correct a number of metabolic and synaptic abnormalities, as this receptor has been shown to restore cellular homeostasis and synaptic plasticity when activated by targeting mitochondrial dysfunction and associated OS, protein misfolding, proteostasis, and associated autophagy, and neuroinflammation [164].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Kaufmann, 2019, ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome, Pharmacol. Biochem. Behav. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxidative damage may be linked to the genetic risk of AD, and in this view more relevant in patients carrying the APOE ε4 allele.

    “Besides, oxidative damage may be linked to the genetic risk of AD, and in this view more relevant in patients carrying the APOE ε4 allele [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Zabel, 2017, Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer’s disease brain: A meta-analysis in human pathological specimens, Free. Radic. Biol. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    In the context of a multifactorial disease, antioxidative supplementation may help to reduce or limit pathogenic events eventually leading to neurodegeneration.

    “Concerning the treatment of patients with antioxidative compounds, clearly any supplementation can be considered curative, but, in the context of a multifactorial disease, it may help to reduce or limit pathogenic events eventually leading to neurodegeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The study of accumulation of products of oxidative damage in the brain and specimens has shed light on early events of AD pathology and contributed to knowledge of AD pathogenesis.

    “The study of accumulation of the products of oxidative damage in the brain and specimens has surely shed light on the early events of AD pathology and has contributed to the knowledge of AD pathogenesis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glucose metabolism amelioration in CNS is supposed to improve the cognitive decline of aMCI patients or prevent the cognitive decline in obese people.

    “Glucose metabolism amelioration in CNS is supposed to improve the cognitive decline of aMCI patients or prevent the cognitive decline in obese people [163,167].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source

      Not checked in the free run.

    • cites [167] Correia, 2011, Insulin-resistant brain state: The culprit in sporadic Alzheimer’s disease?, Ageing Res. Rev. source

      Not checked in the free run.

    • Rests on an assumption: Energy metabolism dysregulation is linked to OS in AD.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    OS is a state which can be determined by aging and other comorbidities, representing a risk factor for AD in healthy people or a progression factor for MCI patients.

    “On the other hand, OS is a state which can be determined by aging and other comorbidities, representing a risk factor for AD in health people or a progression factor for the MCI patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Azeliragon is an inhibitor of RAGE that can be administered orally.

    “Another molecule in Phase 3 is Azeliragon (NTC03980730), an inhibitor of RAGE that can be administered orally [163].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AGEs through binding to RAGE can produce ROS and be involved in neurodegeneration.

    “As previously discussed in this review, AGEs through the binding to the receptor, can produce ROS and be involved in neurodegeneration [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Rungratanawanich, 2021, Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury, Exp. Mol. Med. source

      Not checked in the free run.

    • Rests on an assumption: RAGE binds AGEs, products of the glycosylation of proteins.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Blarcamesine (ANAVEX2-73) is an agonist of the sigma 1 receptor.

    “Blarcamesine or ANAVEX2-73 (NTC03790709) is a chemical compound known as an agonist of the sigma 1 receptor [164].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Kaufmann, 2019, ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome, Pharmacol. Biochem. Behav. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite failure of studies on oxidative damage products in AD to reveal reliable marker, oxidative damage can be localized to mitochondria in AD brain and ROS may act as second messenger, initiating a downstream signaling pathway to face up the alteration in the redox balance.

    “Despite the failure of studies on oxidative damage products in AD to reveal, till now, one or more reliable marker, oxidative damage can be localized to mitochondria in AD brain and ROS may act as second messenger, initiating a downstream signaling pathway to face up the alteration in the redox balance [169].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Zabel, 2017, Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer’s disease brain: A meta-analysis in human pathological specimens, Free. Radic. Biol. Med. source

      Not checked in the free run.

83 of 83

  • The paper relies on this without support.

    Effective treatments for overt Alzheimer’s disease are lacking.

    “The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD.”

  • The paper relies on this without support.

    Alzheimer’s disease pathogenesis starts decades before symptoms appear.

    “Independently of genetic aspects, it is well known that AD pathogenesis starts decades before the symptoms appear.”

  • The paper relies on this without support.

    Mitochondrial health is essential for maintaining energy homeostasis and preventing neuronal dysfunction in AD.

    “AD pathogenesis has been linked to mitochondria as their health is essential in maintaining energy homeostasis and in preventing neuronal dysfunction.”

  • The paper relies on this without support.

    Circulating levels of phospholipid synthesis-promoting nutrients are lower in AD compared with healthy controls.

    “This background plus the notion that circulating levels of these nutrients are lower in AD compared with healthy controls led to one of the first multicenter clinical trial to test the hypothesis that a diet supplement containing antioxidants and a combination of phospholipid synthesis-promoting nutrients could improve the synaptic function and the cognitive symptoms [160].”

  • The paper relies on this without support.

    Energy metabolism dysregulation is linked to OS in AD.

    “Energy metabolism is also implicated in AD pathogenesis, and its dysregulation can be linked to OS, as discussed previously.”

  • The paper relies on this without support.

    Animal models used in cited studies (3xTg-AD, APP/PS1, 5XFAD) adequately model human AD pathology.

    “utilizing a knockout of Mth1 and Ogg1 genes in a 3xTg-AD background”

  • The paper relies on this without support.

    Oxidative damage markers measured in peripheral fluids reflect oxidative damage in the brain.

    “Although the brain is the most affected in AD the search for markers of OS on peripheral fluids has been always active (Table 1).”

  • The paper relies on this without support.

    RAGE binds AGEs, products of the glycosylation of proteins.

    “RAGE binds AGEs, products of the glycosylation of proteins.”

  • The paper relies on this without support.

    Hyperglycemic conditions as in diabetes can cause nonenzymatic glycation of proteins and formation of AGEs.

    “Hyperglicemic conditions as the ones observed in diabetes can also cause the nonenzymatic glycation of proteins and the formation of AGEs.”
9 of 9

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?

  • Mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis.

    “Mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis [82].”

    From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [82]

  • Numerous findings support the involvement in AD pathogenesis of other mechanisms such as inflammation, imbalance among production and removal of ROS, mitochondrial dysfunction, in addition to the β-amyloid cascade and the deficiency of central cholinergic neurotransmitters.

    “Although the genetic susceptibility, numerous findings support the involvement in AD pathogenesis of other mechanisms such as inflammation [95], imbalance among production and removal of ROS [96], mitochondrial dysfunction [82], in addition to the β-amyloid cascade [97] and the deficiency of central cholinergic neurotransmitters [98] on which are based most of anti-AD drugs so far approved.”

    From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [82]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Pao study is dated 2021 in the text but 2020 in the reference

    Minor

    The text calls the cited report a 2021 study, while reference 126 lists its publication year as 2020.

1 of 1

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Related

Authors
Buccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D.
Affiliations
  • University of Milan (IT)
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
Corresponding author
Buccellato, Francesca Romana
ORCID
Venue
Antioxidants
Publisher
MDPI AG
Published
2021-08-26
Volume
10
Issue
9
Pages
1353
ISSN
2076-3921 (ISSN-L)
DOI
10.3390/antiox10091353
PMC
PMC8471953
OpenAlex
W3195006074
Semantic Scholar
279428f00de222807821a6060bb53ef0ce6d39a5
Cited by
179
References
175
Citations by year
2026: 37 · 2025: 51 · 2024: 30 · 2023: 26 · 2022: 30 · 2021: 4
FWCI
3.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Antioxidants (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Ministero della Salute (2018-, RF-2018-12365333, RF-2018, 12365333)
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, reactive oxygen species, oxidative damage, biomarkers, early diagnosis, mild cognitive impairment, prodromal Alzheimer's disease, amyloid-beta, tau hyperphosphorylation, neurofibrillary tangles, microglia, neurodegeneration, peripheral biomarkers, blood biomarkers, cerebrospinal fluid, saliva, urine, disease surveillance

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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