Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease

In the paper

“Glucose enters the brain from the vasculature through highly efficient glucose transporters and requires insulin for optimal cellular utilization7.”

What the sources say

• Partly supported

  The “Effects of insulin in neurons” section describes glucose uptake through GLUT3 and says insulin-regulated GLUT4 may improve glucose flux during high metabolic demand. It also explicitly says neuronal glucose uptake and utilization are influenced by insulin, not dependent on it. The source therefore does not support the general claim that optimal cellular use requires insulin. (LLM, conf=0.87)

  cites [7] Arnold, S. E. et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14, 168–181 (2018). This paper is an excellent review of the links between AD, dysfunctional glucose metabolism and diabetes. sourceExperimental — accuracy not yet measured

In the paper

“Diabetes also leads to oxidative stress (ref8, also see later discussion), which may make a contribution to its propensity to favour AD development9.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 5th edn (Oxford Univ. Press, 2015). This book provides a thorough and detailed summary of the role of ROS and antioxidants in human health and disease, including neurodegenerative diseases. source
• Supported

  Section 3.1.1 reports increased oxidative-stress markers in people with type 2 diabetes and says oxidative stress may be a link between diabetes and Alzheimer disease. Section 3 also describes oxidative imbalance in a diabetes-related mouse model alongside Alzheimer-like pathological features. These passages support the citing sentence’s hedged claim. (LLM, conf=0.92)

  cites [9] Butterfield, D. A., Di Domenico, F. & Barone, E. Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochim. Biophys. Acta 1842, 1693–1706 (2014). source

In the paper

“In AD and aMCI, however, brain insulin resistance is present6,7.”

What the sources say

• ?Not checked — no full text of the sourcecites [6] Croteau, E. et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp. Gerontol. 107, 18–26 (2018). source
• Partly supported

  The section “Brain insulin resistance in ADRD, irrespective of T2DM” reports experimentally demonstrated brain insulin resistance in AD and insulin-signalling abnormalities in post-mortem brains from people with AD or MCI. It does not specify that the MCI cases were amnestic, so the aMCI-specific part of the claim is not established by our copy. (LLM, conf=0.84)

  cites [7] Arnold, S. E. et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14, 168–181 (2018). This paper is an excellent review of the links between AD, dysfunctional glucose metabolism and diabetes. sourceExperimental — accuracy not yet measured

In the paper

“AD is characterized by an accumulation of senile plaques (SP) [composed mostly of fibrillary amyloid beta-peptide (Aβ) and dystrophic neurites] and neurofibrillary tangles (NFT) [composed of hyperphosphorylated tau protein] in the brain”

What the sources say

• Partly supported

  Table 1 and the Figure 1 caption (both indexed under Summary and Conclusions; page unavailable) describe AD amyloid plaques as having a fibrillary amyloid-peptide core and neuritic plaques as surrounded by degenerating neurites. The caption says neurofibrillary tangles are composed of tau fibrils, but the available passages do not specify that the tau is hyperphosphorylated. (LLM, conf=0.83)

  cites [1] Nelson, P. T., Braak, H. & Markesbery, W. R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) identifies amyloid plaques and neurofibrillary tangles as characteristic AD pathology and says plaques are mainly made of fibrillized amyloid-β while tangles are mostly made of hyperphosphorylated tau. It does not state that dystrophic neurites are a component of the plaques. (LLM, conf=0.87)

  cites [2] Martins, R. N. et al. Alzheimer’s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies—gains from AIBL and DIAN cohort studies. J. Alzheimers Dis. 62, 965–992 (2018). This article provides a detailed review of how cohort studies have contributed to our understanding of AD. sourceExperimental — accuracy not yet measured

In the paper

“Clinically, AD is characterized by several features, notably a progressive cognitive decline involving loss of memory and higher executive functioning1.”

What the sources say

• Supported

  The section on AD lesions and clinical context describes early memory changes and identifies executive function among the cognitive domains impaired in AD. The Summary and Conclusions describes worsening cognitive impairment as pathology advances, supporting the claim of progressive decline. (LLM, conf=0.88)

  cites [1] Nelson, P. T., Braak, H. & Markesbery, W. R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009). source

In the paper

“One important process that becomes dysfunctional in AD and aMCI is metabolism of glucose5,6.”

What the sources say

• Partly supported

  The Introduction describes declining regional cerebral glucose metabolism in AD, and the Conclusion reports such declines in amyloid-β-positive people with MCI. The paper does not identify its MCI group specifically as amnestic MCI, so it does not fully establish that part of the claim. (LLM, conf=0.82)

  cites [5] Weise, C. M. et al. Left lateralized cerebral glucose metabolism declines in amyloid-β positive persons with mild cognitive impairment. Neuroimage. Clin. 20, 286–296 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [6] Croteau, E. et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp. Gerontol. 107, 18–26 (2018). source

In the paper

“there has been a suggestion that defects in sirtuin 3 (SIRT 3) contribute to oxidative damage in AD mitochondria37.”

What the sources say

• Supported

  The Results section (page not provided) describes a proposed AD mechanism in which reduced SIRT3 leads to increased mitochondrial ROS accumulation and neuronal damage. It also reports that functional SIRT3 reduced ROS in cells with induced mitochondrial p53, supporting the citing sentence’s hedged claim. (LLM, conf=0.93)

  cites [37] Lee, J. et al. SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer’s disease. Aging Cell 17, e12679 (2018). source

In the paper

“Aβ42 oligomers contribute to this synaptic dysfunction, impairing learning and memory31.”

What the sources say

• Partly supported

  The Results show that synthetic Aβ1-42 and other soluble Aβ preparations disrupt hippocampal synaptic plasticity, and the paper describes long-term potentiation as a correlate of learning and memory. It does not directly show that Aβ42 oligomers impair learning or memory; that part of the claim goes beyond the outcomes reported here. The indexed passages provide section labels but no page numbers. (LLM, conf=0.83)

  cites [31] Li, S. et al. Soluble oligomers of amyloid β-protein facilitate hippocampal long term depression by disrupting glutamate uptake. Neuron 62, 788–801 (2009). sourceExperimental — accuracy not yet measured

In the paper

“Elevated levels of 3-nitrotyrosine (3-NT), suggestive of damage by peroxynitrite (Table 1) are also observed in AD18,24 and aMCI25.”

What the sources say

• Supported

  The Abstract and Discussion report increased nitrotyrosine immunoreactivity in regions of Alzheimer’s disease pathology and identify it as evidence of likely peroxynitrite involvement (J. Neurosci., pp. 2653–2657). In the citing sentence, this source is cited for the Alzheimer’s disease finding; a separate citation is attached to the aMCI finding. (LLM, conf=0.92)

  cites [18] Smith, M. A., Richey Harris, P. L., Sayre, L. M., Beckman, J. S. & Perry, G. Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J. Neurosci. 15, 2653–2657 (1997). source
• Supported

  The Results report an 18% increase in nitrated proteins in the inferior parietal lobule of early-AD patients versus controls. The Introduction says increased 3-NT indexes nitrosative stress in MCI and late AD, and explains how peroxynitrite can lead to 3-NT formation. The paper reports the MCI finding from earlier research rather than measuring aMCI in this study. (LLM, conf=0.92)

  cites [24] Reed, T. T., Pierce, W. M., Turner, D. M., Markesbery, W. R. & Butterfield, D. A. Proteomic identification of nitrated brain proteins in early Alzheimer’s disease inferior parietal lobule. J. Cell. Mol. Med. 13, 2019–2029 (2009). source
• Supported

  Citation 25 is attached to the aMCI portion of the sentence, not the AD portion. The Introduction states that brain from subjects with MCI has elevated 3-NT and explains that peroxynitrite can lead to 3-NT formation. (LLM, conf=0.92)

  cites [25] Sultana, R. et al. Proteomic identification of nitrated brain proteins in amnestic mild cognitive impairment. J. Cell. Mol. Med. 11, 839–851 (2007). source

In the paper

“Activated mTORC1 is intimately involved in regulation of protein synthesis, autophagy, mitochondrial function, lipogenesis, ketogenesis, and insulin signaling, and is crucially linked to glucose metabolism, where it becomes activated by growth factors, amino acids, and high cellular energy status41,42 (Fig 2).”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [41] Di Domenico, F. et al. mTOR in Down syndrome: role in Aβ and Tau neuropathology and transition to redox Alzheimer disease-like dementia. Free Radic. Biol. Med. 114, 94–101 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source

In the paper

“The varied phenotypes of DS result from full or partial triplication of chromosome 21, the most common human chromosomal disorder59.”

What the sources say

• Partly supported

  The Dementia section links Down syndrome to trisomy 21 and overexpression of a chromosome 21 gene, while the Neuroanatomic abnormalities section discusses effects of an extra chromosome 21 on development. These passages support a chromosome 21 basis for Down syndrome phenotypes, but the copy does not establish that partial triplication of chromosome 21 produces the varied human phenotypes; its reference to partial trisomy concerns mice. (LLM, conf=0.82)

  cites [59] Lott, I. T. Neurological phenotypes for Down syndrome across the life span. Prog. Brain Res. 197, 101–121 (2012). sourceExperimental — accuracy not yet measured

In the paper

“Redox proteomics has identified several oxidatively damaged proteins (including ceruloplasmin, transferrin, retinol-binding protein 4, apolipoprotein Al, complement C9, and collagen α−1Vchain) in amniotic fluid that correlate with the various phenotypes presented in individuals with DS, suggesting that oxidative stress contributes to these phenotypes64.”

What the sources say

• Partly supported

  Section 4 reports increased HNE and an elevated GSSG/GSH ratio in amniotic fluid from Down syndrome pregnancies, supporting early oxidative stress. It does not identify the six named proteins as oxidatively damaged in amniotic fluid or report that they correlate with Down syndrome phenotypes. The section also says whether these peripheral changes are associated with intellectual disability has yet to be evaluated; no page number is available in our copy. (LLM, conf=0.85)

  cites [64] Barone, E., Head, E., Butterfield, D. A. & Perluigi, M. HNE-modified proteins in Down syndrome: involvement in development of Alzheimer disease neuropathology. Free Radic. Biol. Med. 111, 262–269 (2017). sourceExperimental — accuracy not yet measured

In the paper

“This significant mediator of neuronal death is present in the early stages of AD, and evidence of impaired autophagy is also found in aMCI brain and PCAD brains41–43.”

What the sources say

• Partly supported

  Section 2.1 (page unavailable) says autophagy is impaired in AD brains, supporting that part of the claim. It reports reduced autophagosome formation early in Down syndrome brains, not specifically in early AD, aMCI, or preclinical AD brains. The reference list names a study of mTOR signaling across preclinical AD, aMCI, and late-stage AD, but this paper does not state that impaired autophagy was found in those groups. (LLM, conf=0.85)

  cites [41] Di Domenico, F. et al. mTOR in Down syndrome: role in Aβ and Tau neuropathology and transition to redox Alzheimer disease-like dementia. Free Radic. Biol. Med. 114, 94–101 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source
• ?Could not verify

  The “Other diseases” section links dicarbonyl stress to Alzheimer’s disease through clinical biomarker studies, but does not discuss impaired autophagy or the early-AD, aMCI, and preclinical-AD brain groups in the claim. Searches for those terms and for autophagy found no passage addressing the attributed finding; page numbers were unavailable in our copy. (LLM, conf=0.74)

  cites [43] Rabbani, N., Xue, M. & Thornalley, P. Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Glycoconj. J. 33, 513–525 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Unfortunately, degradation of oxidatively modified proteins is still compromised in AD brain as the 20S proteasome enzymatic activities are dysfunctional51,52 (including inhibition by Aβ), resulting in accumulation of oxidatively modified, often misfolded and dysfunctional proteins.”

What the sources say

• ?Not checked — no full text of the sourcecites [51] Tseng, B. P., Green, K. N., Chan, J. L., Blurton-Jones, M. & LaFerla, F. M. Abeta inhibits the proteasome and enhances amyloid and tau accumulation. Neurobiol. Aging 29, 1607–1618 (2008). source
• ?Could not verify

  Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

  cites [52] Mota, S. I. et al. Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer’s disease. Biochim. Biophys. Acta 1852, 1428–1441 (2015). sourceExperimental — accuracy not yet measured

In the paper

“These oxidatively modified, and likely dysfunctional, proteins include ones associated with altered glucose metabolism, mTOR signaling (including inhibited autophagy and increased insulin resistance), and the proteostasis network42,61,62,65,66.”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source
• Partly supported

  The Discussion (page unavailable) reports oxidative modification of proteins in the proteostasis network, including components of protein-degradation pathways. The Conclusion (page unavailable) links mTOR hyperactivation to reduced autophagy and decreased IRS1 activity, which can lead to insulin resistance. It does not identify oxidatively modified proteins associated with altered glucose metabolism or establish that the mTOR–insulin-resistance findings concern oxidatively modified proteins. (LLM, conf=0.86)

  cites [61] Perluigi, M. et al. Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome. Biochim. Biophys. Acta 1842, 1144–1153 (2014). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [62] Busciglio, J. & Yankner, B. A. Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 378, 776–779 (1995). source
• Partly supported

  The Discussion (page unavailable) identifies oxidatively modified energy-metabolism enzymes and a proteostasis protein, HSP60. It also reports mTOR hyperactivation with disturbed autophagosome formation in Down syndrome brain, but does not identify an oxidatively modified mTOR-signaling protein or substantiate the claim of increased insulin resistance. (LLM, conf=0.86)

  cites [65] Tramutola, A. et al. Polyubiquitinylation profile in Down syndrome brain before and after the development of Alzheimer neuropathology. Antioxid. Redox Signal. 26, 280–298 (2017). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Introduction discusses brain glucose metabolism, and the Discussion links lower aerobic glycolysis with greater tau deposition in people with preclinical or very mild Alzheimer disease; neither passage addresses oxidatively modified proteins in Down syndrome. Searches for Down syndrome, oxidatively modified proteins, mTOR, autophagy, insulin resistance, and proteostasis found no passage supporting the attributed claim. (LLM, conf=0.78)

  cites [66] Vlassenko, A. G. et al. Aerobic glycolysis and tau deposition in preclinical Alzheimer’s disease. Neurobiol. Aging 67, 95–98 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Other biomarkers of increased oxidative damage in the brains of persons with DS and persons with DS with AD neuropathology (DS with AD) include elevated levels of HNE and PC15,42; the increases are greater in people with DS with AD62,65,66.”

What the sources say

• ?Not checked — no full text of the sourcecites [15] Di Domenico, F., Tramutola, A. & Butterfield, D. A. Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of Alzheimer disease and other selected age-related neurodegenerative disorders. Free Radic. Biol. Med. 111, 253–261 (2017). source
• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source
• ?Not checked — no full text of the sourcecites [62] Busciglio, J. & Yankner, B. A. Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 378, 776–779 (1995). source
• Partly supported

  The Discussion (page unavailable) says that many polyubiquitinated proteins in DS brain are also carbonylated and/or HNE-modified. It does not establish that overall HNE and protein carbonyl levels are elevated in both DS and DS/AD brains, or that those levels rise more in DS/AD; the larger increases reported in the Results concern polyubiquitinylation. (LLM, conf=0.82)

  cites [65] Tramutola, A. et al. Polyubiquitinylation profile in Down syndrome brain before and after the development of Alzheimer neuropathology. Antioxid. Redox Signal. 26, 280–298 (2017). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Participants and Results sections describe PET measures of aerobic glycolysis, amyloid, and tau in adults with preclinical or mild Alzheimer disease. Our copy does not address Down syndrome or report HNE or protein carbonyl levels; searches for those markers and Down syndrome found no relevant passage. (LLM, conf=0.76)

  cites [66] Vlassenko, A. G. et al. Aerobic glycolysis and tau deposition in preclinical Alzheimer’s disease. Neurobiol. Aging 67, 95–98 (2018). sourceExperimental — accuracy not yet measured

In the paper

“In addition to mTOR activation, insulin resistance can also result in neuronal glucose deficiency, with consequent decreased glucose metabolism, impaired ATP production, and dysfunction and/or death7,42”

What the sources say

• Partly supported

  The “Effects of insulin in neurons” section says insulin can influence neuronal glucose uptake through GLUT4 and promotes neuronal survival. It also says most neuronal glucose uptake occurs through insulin-independent GLUT3. The paper does not establish the claimed sequence from insulin resistance to neuronal glucose deficiency, impaired ATP production, and dysfunction or death. (LLM, conf=0.84)

  cites [7] Arnold, S. E. et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14, 168–181 (2018). This paper is an excellent review of the links between AD, dysfunctional glucose metabolism and diabetes. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source

In the paper

“In AD brain, markers of ER stress are elevated and correlate with progression of this disorder53,54,58.”

What the sources say

• Partly supported

  In “ER stress in AD mouse models and human AD samples,” the review reports elevated ER-stress markers in post-mortem AD brains and an increase in p-PERK-positive neurons with Braak stage. But the same section reports decreases in other markers, calls the human findings inconsistent and poorly reproduced, and says the authors are not convinced that ER stress is generally upregulated in AD brain. The unqualified claim therefore overstates the review's conclusion. (LLM, conf=0.88)

  cites [53] Hashimoto, S. & Saido, T. C. Critical review: involvement of endoplasmic reticulum stress in aetiology of Alzheimer’s disease. Open Biol. 8, 180024 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  Section 4 reports increased ER stress in postmortem AD brain, including elevated GRP78/BiP and UPR activation in the temporal cortex and hippocampus. It says these findings occur alongside neurofibrillary tangles and amyloid plaques, but does not report that ER-stress markers correlate with disease progression. Page information is unavailable in our copy. (LLM, conf=0.86)

  cites [54] Di Domenico, F., Head, E., Butterfield, D. A. & Perluigi, M. Oxidative stress and proteostasis network: culprit and casualty of Alzheimer’s-like neurodegeneration. Adv. Geriatr. 2014, 1–14 (2014). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results section discusses amyloid-β deposition and cognitive deficits, while Materials and methods > Tissue preparation and western blotting lists APP-related proteins rather than ER-stress markers (pages unavailable). Searches for “ER stress,” “endoplasmic reticulum,” and unfolded-protein-response markers found no passage addressing elevated ER-stress markers in Alzheimer disease brain or their correlation with disease progression. (LLM, conf=0.73)

  cites [58] Wiseman, F. K. et al. Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP. Brain 141, 2457–2474 (2018). sourceExperimental — accuracy not yet measured

In the paper

“In summary, oxidative and/or nitrosative damage to multiple proteins, including synaptic proteins is very likely to contribute to the memory problems and other cognitive deficits, reduced ATP availability in neurons, and decreased clearance of abnormal proteins34, creating a “perfect storm” (or sTORm perhaps!) of detrimental cognitive effects in AD9,34,35,41,42.”

What the sources say

• Partly supported

  Section 3.1.1, Protein oxidation (page unavailable), links oxidation of metabolic proteins to reduced ATP production, synaptic dysfunction, and cognitive decline. Section 3 also describes oxidative and nitrosative protein damage. The copy does not establish that the damaged proteins include synaptic proteins or that this damage decreases clearance of abnormal proteins. (LLM, conf=0.85)

  cites [9] Butterfield, D. A., Di Domenico, F. & Barone, E. Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochim. Biophys. Acta 1842, 1693–1706 (2014). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [34] Di Domenico, F., Barone, E., Perluigi, M. & Butterfield, D. A. The triangle of death in Alzheimer’s disease brain: the aberrant cross-talk among energy metabolism, mammalian target of rapamycin signaling, and protein homeostasis revealed by redox proteomics. Antioxid. Redox Signal. 26, 364–387 (2017). This paper demonstrates the utility of redox proteomics to increase our understanding of molecular processes involved in neurodegeneration in the pathogenesis and progression of AD. source
• ?Not checked — no full text of the sourcecites [35] Reed, T. et al. Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer’s disease. Neurobiol. Dis. 30, 107–120 (2008). source
• Partly supported

  Section 2.1 reports oxidative damage to several protein-clearance components in Down syndrome brain, associated with reduced proteasome activity and autophagosome formation; section 3.1 links oxidative modification of lysosomal proteins to potentially reduced autophagy. The paper does not establish that damage to synaptic proteins causes memory or other cognitive deficits, or that protein oxidation reduces neuronal ATP availability in Alzheimer disease. Its reduced-ATP discussion in section 2.2 concerns neuronal progenitor cells from a Down syndrome mouse model, not that proposed causal link. (LLM, conf=0.86)

  cites [41] Di Domenico, F. et al. mTOR in Down syndrome: role in Aβ and Tau neuropathology and transition to redox Alzheimer disease-like dementia. Free Radic. Biol. Med. 114, 94–101 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source

In the paper

“It is likely that both a dose effect of triplication of APP and gene-environment interactions play a role59,60.”

What the sources say

• Partly supported

  The Dementia section links increased APP gene dosage in Down syndrome to early β-amyloid deposition, supporting the APP-dose part of the claim. The introductory section says the neurological phenotype reflects genetic expression and environmental influences, but our copy does not specifically link gene–environment interactions to Alzheimer-like dementia. (LLM, conf=0.84)

  cites [59] Lott, I. T. Neurological phenotypes for Down syndrome across the life span. Prog. Brain Res. 197, 101–121 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) identifies APP as a chromosome 21 gene and reports that amyloid accumulation in Down syndrome increases with age, leading generally to Alzheimer pathology. It also says Down syndrome phenotypes need not arise exclusively from specific chromosome 21 genes. The paper does not specifically attribute Alzheimer-like dementia to an APP triplication dose effect or to gene–environment interactions. (LLM, conf=0.76)

  cites [60] Di Domenico, F. et al. Bach1 overexpression in Down syndrome correlates with the alteration of the HO-1/BVR-A system: Insights for transition to Alzheimer disease. J. Alzheimers Dis. 44, 1107–1120 (2015). sourceExperimental — accuracy not yet measured

In the paper

“Following a report of success of high-dose vitamin E in keeping late-stage AD patients out of long-term care facilities longer than patients on a placebo81, other studies with vitamin E have been less impressive70,78,80.”

What the sources say

• Partly supported

  The Discussion reports a significant delay in institutionalization with alpha-tocopherol (vitamin E), and the Methods specify a high dose of 2,000 IU daily in a placebo-controlled trial. The participants had moderately severe Alzheimer’s disease (Clinical Dementia Rating 2), not late-stage disease; severe dementia was a possible study outcome. The statement about later studies is cited to other sources, not this paper. (LLM, conf=0.88)

  cites [81] Sano, M. et al. A controlled trial of selegiline, α-tocopherol, or both as treatment for Alzheimer disease. N. Engl. J. Med. 336, 1216–1222 (1996). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [70] Winblad, B. et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol. 15, 455–532 (2016). This article provides a comprehensive review of the current state of AD research and prospects for treatment. source
• ?Not checked — no full text of the sourcecites [78] Polidori, M. C. & Nelles, G. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease-challenges and perspectives. Curr. Pharm. Des. 20, 3083–3092 (2014). source
• Supported

  This source supports the sentence’s later-studies-were-less-impressive clause, not the earlier nursing-home-placement report, which the citing sentence attributes to reference 81. In the primary outcome measures section, vitamin E did not significantly reduce progression from mild cognitive impairment to Alzheimer’s disease compared with placebo at any point in the trial. (LLM, conf=0.93)

  cites [80] Petersen, R. C. et al. Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–2388 (2005). source

In the paper

“Indeed, impairment of Nrf2 function worsened cognitive defects in a mouse model of AD90, suggesting the importance of the Nrf2 system in AD.”

What the sources say

• Supported

  The Discussion reports that decreasing Nrf2 levels exacerbates cognitive deficits in a mouse model of AD and suggests a link between Nrf2 and AD. The Results describe the genetic removal of Nrf2 in APP/PS1 mice, matching the cited claim. (LLM, conf=0.94)

  cites [90] Branca, C. et al. Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. Hum. Mol. Genet. 26, 4823–4835 (2017). source

In the paper

“In vivo use of polyphenols (especially curcumin) in some mouse models of AD has been successful77,87, but this has not (yet) been translated to usefulness in human AD2,70,87,88.”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Perluigi, M. et al. In vivo protective effects of ferulic acid ethyl ester against amyloid β-peptide (1–42)-induced oxidative stress. J. Neurosci. Res. 84, 418–426 (2006). source
• Partly supported

  The Results report reduced plaque pathology in curcumin-fed Tg2576 mice. The Discussion says low plasma levels after oral dosing in humans predict limited clinical translation, but it does not establish that curcumin has not proved useful in human Alzheimer’s disease. (LLM, conf=0.82)

  cites [87] Begum, A. N. et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J. Pharmacol. Exp. Ther. 326, 196–208 (2008). sourceExperimental — accuracy not yet measured
• Partly supported

  The Diet section (page unavailable) reports that animal studies suggest curcumin may influence brain function and dementia development, and that clinical studies in humans with AD have failed to find significant improvement with curcumin supplementation. It does not specify successful treatment in AD mouse models, and its description of the animal evidence is more cautious than the claim. (LLM, conf=0.84)

  cites [2] Martins, R. N. et al. Alzheimer’s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies—gains from AIBL and DIAN cohort studies. J. Alzheimers Dis. 62, 965–992 (2018). This article provides a detailed review of how cohort studies have contributed to our understanding of AD. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [70] Winblad, B. et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol. 15, 455–532 (2016). This article provides a comprehensive review of the current state of AD research and prospects for treatment. source
• Supported

  The Alzheimer’s Disease section reports that curcumin reduced markers of central nervous system oxidative stress in Tg2576 APPsw mice. It also reports no difference in cognitive status between curcumin-treated and placebo groups after 24 weeks and says evidence is insufficient to recommend curcumin for dementia patients. The source supports the claim as it applies to curcumin, rather than polyphenols generally. (LLM, conf=0.90)

  cites [88] Nelson, K. M. et al. The essential medicinal chemistry of curcumin. J. Med. Chem. 60, 1620–1637 (2017). source

In the paper

“Although α-tocopherol is efficient in trapping lipid peroxyl radicals, gamma-tocopherol appears more efficient at scavenging RNS species84.”

What the sources say

• Partly supported

  The Introduction (page unavailable) says that, unlike α-tocopherol, γ-tocopherol traps reactive nitrogen species including nitrogen dioxide and peroxynitrite. That supports the comparative RNS claim. Our copy does not address α-tocopherol's efficiency at trapping lipid peroxyl radicals, so that part of the sentence is unsupported. (LLM, conf=0.86)

  cites [84] Pei, R., Mah, E., Leonard, S. W., Traber, M. G. & Bruno, R. S. α-Tocopherol supplementation reduces 5-nitro-γ-tocopherol accumulation by decreasing γ-tocopherol in young adult smokers. Free Radic. Res. 49, 1114–1121 (2015). sourceExperimental — accuracy not yet measured

In the paper

“Nrf2 is widely expressed in animal tissues but most of it is kept in an inactive form, largely in the cytosol, by binding to the Keap1 (Kelch-like erythroid cell-derived protein with CNC-homology associated protein 1) protein, which also promotes its rapid degradation by the proteasome8,89.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 5th edn (Oxford Univ. Press, 2015). This book provides a thorough and detailed summary of the role of ROS and antioxidants in human health and disease, including neurodegenerative diseases. source
• Supported

  The Protein Components section says Nrf2 is expressed in a broad range of tissues and describes Keap1 as a cytoplasmic repressor that binds and suppresses Nrf2. The Two-Site Binding Model section says Keap1 recruits Nrf2 for ubiquitination under basal conditions, after which Nrf2 is rapidly degraded by 26S proteasomes. (LLM, conf=0.92)

  cites [89] Ma, Q. & He, X. Molecular basis of electrophilic and oxidative defence: promises and perils of Nrf2. Pharmacol. Rev. 62, 1055–1081 (2012). source

In the paper

“BVR-A is nitrosatively modified and dysfunctional in AD and MCI brain100, and its impairment promotes insulin resistance101.”

What the sources say

• Supported

  Citation 100 is attached to the AD/MCI brain finding, not the separate insulin-resistance claim attributed to citation 101. The section on oxidative/nitrosative modifications reports increased BVR-A nitration and reduced BVR-A activity in the hippocampi of subjects with AD and MCI. (LLM, conf=0.93)

  cites [100] Barone, E., Di Domenico, F., Mancuso, C. & Butterfield, D. A. The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it’s time for reconciliation. Neurobiol. Dis. 62, 144–159 (2014). source
• ?Not checked — no full text of the sourcecites [101] Barone, E. et al. Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: a new paradigm. Free Radic. Biol. Med. 91, 127–142 (2016). source

In the paper

“The authors demonstrated that the first detectable pathological change in asymptomatic persons in the DIAN network is deposition of Aβ aggregates (which would imply membrane-resident oligomers that would lead to oxidative damage), followed by decreased glucose metabolism, and finally thinning of key brain areas116.”

What the sources say

• Supported

  The Findings report that Aβ deposition diverged first in DIAN mutation carriers, followed by hypometabolism and then structural decline before expected symptom onset. The Discussion describes the same general ordering, while noting that it does not hold in every brain region. The parenthetical about oligomers and oxidative damage is the citing authors’ inference, not part of the finding attributed to this source. (LLM, conf=0.92)

  cites [116] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). This paper reports longitudinal PET and MRI results on brains in persons with autosomal dominantly inherited AD obtained regularly 22 years before up to 3 years after the onset of AD symptoms and demonstrates the temporal order of brain pathology observed prior to symptoms. source

In the paper

“Recently, intranasal treatment of a 3 X Tg mice model of AD with insulin showed a significant reduction of brain nitrosative stress, tau phosphorylation, and Aβ oligomers coupled to improved cognition, and these effects were dependent on the activity of biliverdin reductase-A (BVR-A)99,100.”

What the sources say

• ?Not checked — no full text of the sourcecites [99] Barone, E. et al. Biliverdin reductase-A mediates the beneficial effects of intranasal insulin in Alzheimer disease. Mol. Neurobiol. https://doi.org/10.1007/s12035-018-1231-5 (2018). This paper improves our mechanistic understanding of the beneficial effects of intranasal insulin in the cognitive improvement of patients with AD and MCI by demonstrating in the 3xTg mouse model of AD that BVRA was prevented from early impairment in adult mice, or rescued from damage in aged mice, following intranasal insulin that was correlated with improved insulin signalling, decreased nitrosative stress and i source
• ?Could not verify

  The ‘Reconciliation of the two hypotheses’ section reports reduced nitrosative-stress markers and improved cognition after atorvastatin treatment in aged beagles, not intranasal insulin in 3xTg AD mice. Searches for intranasal insulin and the claimed mouse outcomes found no passage in our copy addressing that experiment or showing that its effects required BVR-A activity; the passages have no page numbers. (LLM, conf=0.77)

  cites [100] Barone, E., Di Domenico, F., Mancuso, C. & Butterfield, D. A. The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it’s time for reconciliation. Neurobiol. Dis. 62, 144–159 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Studies on human ApoE gene-targeted female replacement mice show that apoE status appears to influence brain glucose and ketone metabolism, with the apoE4 allele being the most deleterious for the former103.”

What the sources say

• Supported

  The Abstract reports that the study examined glucose and ketone-body metabolism in human ApoE gene-targeted replacement female mice. It describes ApoE4 brains as having the most deficient profile for glucose uptake and metabolism, while the isoforms also differed in ketone-body metabolism. (LLM, conf=0.94)

  cites [103] Wu, L., Zhang, X. & Zhao, L. Human ApoE isoforms differentially modulate brain glucose and ketone body metabolism: implications for Alzheimer’s disease risk reduction and early intervention. J. Neurosci. 38, 6665–6681 (2018). source

In the paper

“BVR-A, in addition to being a reductase, is a kinase that can phosphorylate insulin receptor substrate-1100.”

What the sources say

• Partly supported

  The overview’s “HO by-products” section states that BVR-A reduces biliverdin to bilirubin and is also a serine/threonine/tyrosine kinase. It does not say that BVR-A phosphorylates insulin receptor substrate-1; instead, it describes phosphorylation of BVR-A by the insulin receptor kinase. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [100] Barone, E., Di Domenico, F., Mancuso, C. & Butterfield, D. A. The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it’s time for reconciliation. Neurobiol. Dis. 62, 144–159 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Many statins, including atorvastatin, do not penetrate the blood-brain barrier (BBB) significantly, yet atorvastatin use is associated with lowered risk of developing AD113,114.”

What the sources say

• Partly supported

  Section 3, “Statins and dementia” (page unavailable), reports that early observational studies linked statin use with reduced risk of developing dementia, including AD, but does not identify atorvastatin specifically for that association. Its “Ability to cross membranes” subsection describes atorvastatin as having intermediate lipophilicity and discusses how that may affect the fraction reaching the brain; it does not say that atorvastatin or many other statins cross the BBB poorly. (LLM, conf=0.83)

  cites [113] Butterfield, D. A., Barone, E. & Mancuso, C. Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders. Pharmacol. Res. 64, 180–186 (2011). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [114] Barone, E. et al. Biliverdin reductase-A: a novel drug target for atorvastatin in a dog preclinical model of Alzheimer disease. J. Neurochem. 120, 135–146 (2012). source

In the paper

“Both HO-1 and BVR-A are oxidatively damaged in aMCI and AD brain100.”

What the sources say

• Supported

  The section on oxidative/nitrosative modifications reports HO-1 oxidative modifications in AD hippocampus and HNE adducts on HO-1 in MCI hippocampus. It also reports increased oxidative/nitrosative modifications of BVR-A in AD and amnestic MCI brain, including BVR-A nitration in MCI hippocampus. (LLM, conf=0.93)

  cites [100] Barone, E., Di Domenico, F., Mancuso, C. & Butterfield, D. A. The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it’s time for reconciliation. Neurobiol. Dis. 62, 144–159 (2014). source

In the paper

“Positive effects on cognition were reported108,110 even in subjects with the apoE4 allele110.”

What the sources say

• Supported

  The Intervention section describes diet, exercise, cognitive training, and management of metabolic and vascular risks. The Discussion reports beneficial cognitive intervention effects within the APOE ε4 carrier group in the 2-year FINGER trial. It cautions that the intervention was not shown to be more effective in carriers than in noncarriers, but the claim does not assert that comparison. (LLM, conf=0.92)

  cites [108] Solomon, A. et al. Effect of the Apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 75, 462–470 (2018). source
• ?Not checked — no full text of the sourcecites [110] Fyfe, I. APOE ε4 affects cognitive decline but does not block benefits of healthy lifestyle. Nat. Rev. Neurol. 14, 25 (2018). source

In the paper

“Craft and co-workers investigated insulin resistance in AD7,38 and reported improved cognition in early AD patients and decreased levels of neurotoxic Aβ42 following a short-term treatment with intranasal insulin98.”

What the sources say

• Partly supported

  The Introduction (page unavailable) reports improved memory and cognitive scores after intranasal insulin in people with early AD or MCI. It says amyloid-β levels may be modulated, but neither the Introduction nor the retrieved passages report a decrease in Aβ42; that part of the claim is unsupported. (LLM, conf=0.88)

  cites [98] Claxton, A. et al. Sex and ApoE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer’s disease. J. Alzheimers Dis. 35, 789–797 (2013). sourceExperimental — accuracy not yet measured

In the paper

“A recent paper is highly consistent with sequence of events116.”

What the sources say

• Supported

  The Discussion reports a general sequence in autosomal dominant Alzheimer’s disease: β-amyloid accumulation precedes metabolic decline, which precedes atrophy. It also cautions that this ordering varies across brain regions and that its timing is relative rather than absolute. The citing sentence does not specify which sequence it means, so the match is to this general ordering. (LLM, conf=0.84)

  cites [116] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). This paper reports longitudinal PET and MRI results on brains in persons with autosomal dominantly inherited AD obtained regularly 22 years before up to 3 years after the onset of AD symptoms and demonstrates the temporal order of brain pathology observed prior to symptoms. source

In the paper

“It also suggests that atorvastatin, although not a direct antioxidant and not able to cross the BBB, leads to antioxidant-like effects in brain100.”

What the sources say

• Partly supported

  In “Reconciliation of the two hypotheses” (page unavailable), the paper reports reduced brain oxidative-stress markers after atorvastatin treatment in aged beagles, supporting antioxidant-like effects in that preclinical model. It says atorvastatin can cross the BBB “only to a minute extent,” not that it cannot cross at all; the passage also does not explicitly establish that atorvastatin is not a direct antioxidant. (LLM, conf=0.87)

  cites [100] Barone, E., Di Domenico, F., Mancuso, C. & Butterfield, D. A. The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it’s time for reconciliation. Neurobiol. Dis. 62, 144–159 (2014). sourceExperimental — accuracy not yet measured

In the paper

“But, curcumin is actually a poor antioxidant in vitro8 and readily breaks down, for example in cell culture91, to a range of biologically active products.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 5th edn (Oxford Univ. Press, 2015). This book provides a thorough and detailed summary of the role of ROS and antioxidants in human health and disease, including neurodegenerative diseases. source
• ?Not checked — no full text of the sourcecites [91] Long, L. H., Hoi, A. & Halliwell, B. Instability of, and generation of hydrogen peroxide by, phenolic compounds in cell culture media. Arch. Biochem. Biophys. 501, 162–169 (2010). source

In the paper

“Elevated oxidative stress and mTOR activation with consequent inhibited autophagy that results in elevated levels of neuronal detritus are observed, and AD-like senile plaques form.”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source

In the paper

“Atorvastatin given to aged beagle dogs protected against oxidation of BVR-A and this statin increased HO-1 levels, whereas oxidative damage levels in brain were lowered114.”

What the sources say

• ?Not checked — no full text of the sourcecites [114] Barone, E. et al. Biliverdin reductase-A: a novel drug target for atorvastatin in a dog preclinical model of Alzheimer disease. J. Neurochem. 120, 135–146 (2012). source

In the paper

“levels of protein carbonyls (PC) are elevated in AD in brain regions that are rich in amyloid beta-peptide (Aβ)-containing senile plaques (Table 1), but at normal levels from brain regions devoid of Aβ-rich plaques19.”

What the sources say

• ?Not checked — no full text of the sourcecites [19] Hensley, K. et al. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J. Neurochem. 65, 2146–2156 (1995). source

In the paper

“Consequently, ATP-requiring processes for cognitive function are impaired, and synaptic dysfunction and neuronal death result, with ensuing thinning of key brain areas.”

In the paper

“It has been estimated that approximately 15 percent of people with aMCI progress to AD annually3.”

What the sources say

• ?Not checked — no full text of the sourcecites [3] Markesbery, W. R. Neuropathologic alterations in mild cognitive impairment: a review. J. Alzheimers Dis. 19, 221–228 (2010). source

In the paper

“Consequences of this increased oxidative and nitrosative damage are likely to include glucose dysmetabolism (see section on oxidative damage below) and loss of ion gradients with resulting impaired action potentials and Ca2+ dyshomeostasis”

In the paper

“Interestingly, large oligomers of Aβ42, which would have difficulty solubilizing in the neuronal lipid bilayer, seem relatively non-toxic, whereas small oligomers of Aβ42 (for example, dimers or trimers that easily enter lipid bilayers) appear highly toxic to synapses33.”

What the sources say

• ?Not checked — no full text of the sourcecites [33] Yang, T., Li, S., Xu, H., Walsh, D. M. & Selkoe, D. J. Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J. Neurosci. 37, 152–163 (2017). source

In the paper

“Excess intra-neuronal free Ca2+ can also cause loss of fidelity of microtubule assembly40, with consequent decreased anterograde and retrograde transport of mitochondria and neurotransmitter vesicles, starving presynaptic terminals of energy and decreasing neurotransmission.”

What the sources say

• ?Not checked — no full text of the sourcecites [40] Tramutola, A. et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment, and late-stage AD. J. Neurochem. 133, 739–749 (2015). This paper contains the first report of mTORC1 activation and consequent markers of insulin resistance and inhibition of autophagy in brains of subjects with aMCI, consistent with the notion that mTORC1 activation occurs well before dementia in the progression of AD and reflects glucose dysmetabolism early in the disease. source

In the paper

“decreased ATP will diminish the neuron’s ability to maintain ionic gradients, hindering production and propagation of action potentials and therefore neurotransmission.”

In the paper

“Moreover, loss of ion gradients can allow extracellular Ca2+ to enter, which can further raise intracellular free Ca2+ levels, stimulating Ca2+-dependent endonuclease, phospholipase, and proteinase activities8, contributing to synaptic dysfunction and eventual neuronal death.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 5th edn (Oxford Univ. Press, 2015). This book provides a thorough and detailed summary of the role of ROS and antioxidants in human health and disease, including neurodegenerative diseases. source

In the paper

“because oxidative stress is well known to raise intracellular free Ca2+ levels, from which several deleterious consequences can follow8.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 5th edn (Oxford Univ. Press, 2015). This book provides a thorough and detailed summary of the role of ROS and antioxidants in human health and disease, including neurodegenerative diseases. source

In the paper

“Excess Ca2+ can saturate the ability of endoplasmic reticulum (ER) and mitochondria to buffer and cycle Ca2+, causing swelling of the latter with consequent opening of the mitochondrial permeability transition pore, leading to release of cytochrome c and apoptosis inducing factor-1, provoking neuronal apoptotic death39.”

What the sources say

• ?Not checked — no full text of the sourcecites [39] Pirollet, F., Margolis, R. L. & Job, D. Ca2+-calmodulin regulated effectors of microtubule stability in neuronal tissues. Biochim. Biophys. Acta 1160, 113–119 (1992). source

In the paper

“A major contributor to inefficient glucose utilization may well be oxidative modification, which almost always leads to decreased activity of enzymes involved in glucose metabolism (Figure 1).”

In the paper

“the failure of oxidatively damaged UCH L1 to perform its function in aMCI and AD brains leads to accumulation of ubiquitinylated proteins, decreased proteasome function, and subsequent accumulation of damaged, aggregated proteins55.”

What the sources say

• ?Not checked — no full text of the sourcecites [55] Choi, J. et al. Oxidative modifications and down-regulation of ubiquitin caryl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J. Biol. Chem. 279, 13256–13264 (2004). source

In the paper

“This in turn leads to synaptic dysfunction, neuronal death, and ultimately to cognitive dysfunction.”

In the paper

“To summarize, the genetic abnormalities underlying DS drive mechanisms similar to those in AD, providing insights not only into DS but also into aMCI and AD and also suggesting novel therapeutic targets and approaches67.”

What the sources say

• ?Not checked — no full text of the sourcecites [67] Caraci, F. et al. Searching for new pharmacological targets for the treatment of Alzheimer’s disease in Down syndrome. Eur. J. Pharmacol. 817, 7–19 (2017). source

In the paper

“If administered vitamin E does not decrease oxidative damage in the brain significantly, then it will not be effective against MCI or AD.”

In the paper

“Among the non-degraded moieties is Aβ itself, whose accumulation leads to more oxidative damage, RAGE activation, and activation of mTOR, continuing the vicious cycle.”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source

In the paper

“The key role of oxidative damage in the pathology of aMCI, PCAD and AD suggests that inhibiting it should have therapeutic benefit8,11.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 5th edn (Oxford Univ. Press, 2015). This book provides a thorough and detailed summary of the role of ROS and antioxidants in human health and disease, including neurodegenerative diseases. source
• ?Not checked — no full text of the sourcecites [11] Halliwell, B. Oxidative stress and neurodegeneration: where are we now? J. Neurochem. 97, 1634–1658 (2006). source

In the paper

“Hyperphosphorylated tau leads to destabilization of microtubules, affecting mitochondrial trafficking thus leading to presynaptic energy deficits.”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017). source

In the paper

“Chains in which labile hydrogen atoms are replaced by deuterium atoms are more resistant to peroxidation. This is because abstraction of deuterium by ROS is harder, since the C-D bond is much stronger than the C-H bond.”

In the paper

“This produces reactive aldehydes (Table 1) that bind to critical brain proteins to change their conformation and to lower their activity in aMCI and AD brain.”

In the paper

“Presynaptic membranes are particularly vulnerable to such oxidative damage, leading to diminished learning and memory and ultimately dementia.”

In the paper

“An additional consideration when considering the effectiveness (or lack of it) of antioxidants is that, though aMCI and AD are strongly associated with oxidative damage, they are highly complex disorders, and processes other than oxidative damage are likely to contribute to their pathogenesis and progression.”

In the paper

“Decreased ATP results in numerous changes in brain function, such as impaired maintenance of membrane potentials, and increased intracellular Ca2+ levels leading to detrimental downstream effects on cell function and survival.”

In the paper

“The enzyme heme oxygenase 1 (HO-1) oxidizes heme (a pro-oxidant)8 to produce biliverdin, which is reduced by a biliverdin reductase-A (BVR-A) enzyme to bilirubin (a scavenger of ROS/RNS8,101).”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 5th edn (Oxford Univ. Press, 2015). This book provides a thorough and detailed summary of the role of ROS and antioxidants in human health and disease, including neurodegenerative diseases. source
• ?Not checked — no full text of the sourcecites [101] Barone, E. et al. Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: a new paradigm. Free Radic. Biol. Med. 91, 127–142 (2016). source

In the paper

“The overall hypothesis presented in this review for the pathogenesis and progression of AD is that Aβ42 oligomer-induced oxidative stress impairs glucose metabolism, leading to synaptic dysfunction and eventual neuronal death (demonstrated by thinning of key brain areas), ultimately causing aMCI, PCAD, and AD.”