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Papers by Ashley Bush

Research paper thumbnail of Predicting Alzheimer disease from a blood-based biomarker profile: A 54-month follow-up

Neurology, Jan 17, 2016

We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying i... more We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying individuals with high or low neocortical β-amyloid burden (NAB), to determine whether it could also identify individuals at risk of progression to Alzheimer disease (AD) within 54 months. We generated the blood-based signature for 585 healthy controls (HCs) and 74 participants with mild cognitive impairment (MCI) from the Australian Imaging, Biomarkers and Lifestyle Study who underwent clinical reclassification (blinded to biomarker findings) at 54-month follow-up. The individuals were split into estimated high and low NAB groups based on a cutoff of 1.5 standardized uptake value ratio. We assessed the predictive accuracy of the high and low NAB groupings based on progression to mild cognitive impairment or AD according to clinical reclassification at 54-month follow-up. Twelve percent of HCs with estimated high NAB progressed in comparison to 5% of HCs with estimated low NAB (odds ratio ...

Research paper thumbnail of Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2016

Introduction: For early detection of Alzheimer's disease (AD), the field needs biomarkers that ca... more Introduction: For early detection of Alzheimer's disease (AD), the field needs biomarkers that can be used to detect disease status with high sensitivity and specificity. Apolipoprotein J (ApoJ, also known as clusterin) has long been associated with AD pathogenesis through various pathways. The aim of this study was to investigate the potential of plasma apoJ as a blood biomarker for AD. Methods: Using the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the present study assayed plasma apoJ levels over baseline and 18 months in 833 individuals. Plasma ApoJ levels were analyzed with respect to clinical classification, age, gender, apolipoprotein E (APOE) ε4 allele status, mini-mental state examination score, plasma amyloid beta (Ab), neocortical Ab burden (as measured by Pittsburgh compound B-positron emission tomography), and total adjusted hippocampus volume. Results: ApoJ was significantly higher in both mild cognitive impairment (MCI) and AD groups as compared with healthy controls (HC; P , .0001). ApoJ significantly correlated with both "standardized uptake value ratio" (SUVR) and hippocampus volume and weakly correlated with the plasma Ab1-42/Ab1-40 ratio. Plasma apoJ predicted both MCI and AD from HC with greater than 80% accuracy for AD and greater than 75% accuracy for MCI at both baseline and 18-month time points. Discussion: Mean apoJ levels were significantly higher in both MCI and AD groups. ApoJ was able to differentiate between HC with high SUVR and HC with low SUVR via APOE ε4 allele status, indicating that it may be included in a biomarker panel to identify AD before the onset of clinical symptoms.

Research paper thumbnail of Homo - cysteine potentiates copper - and amyloid peptide - mediated tox - icity in primary cultures: possible risk factors in the Alzheimer''''s - type neurodegenerative pathways

Research paper thumbnail of Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's-type neurodegenerative pathways

Journal of Neurochemistry, 2001

Oxidative stress may have an important role in the progression of neurodegenerative disorders suc... more Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. Oxidative damage could result from interactions between highly reactive transition metals such as copper (Cu) and endogenous reducing and/or oxidizing molecules in the brain. One such molecule, homocysteine, a thiol-containing amino acid, has previously been shown to modulate Cu toxicity in HeLa and endothelial cells in vitro. Due to a possible link between hyperhomocysteinemia and AD, we examined whether interaction between homocysteine and Cu could potentiate Cu neurotoxicity. Primary mouse neuronal cultures were treated with homocysteine and either Cu (II), Fe (II or III) or Zn (II). Homocysteine was shown to selectively potentiate toxicity from low micromolar concentrations of Cu. The toxicity of homocysteine/Cu coincubation was dependent on the ability of homocysteine to reduce Cu (II) as re¯ected by the inhibition of toxicity with the Cu (I)-speci®c chelator, bathocuproine disulphonate. This was supported by data showing that homocysteine reduced Cu (II) more effectively than cysteine or methionine but did not reduce Fe (III) to Fe (II). Homocysteine also generated high levels of hydrogen peroxide in the presence of Cu (II) and promoted Ab/Cu-mediated hydrogen peroxide production and neurotoxicity. The potentiation of metal toxicity did not involve excitotoxicity as ionotropic glutamate receptor antagonists had no effect on neurotoxicity. Homocysteine alone also had no effect on neuronal glutathione levels. These studies suggest that increased copper and/or homocysteine levels in the elderly could promote signi®cant oxidant damage to neurons and may represent additional risk factor pathways which conspire to produce AD or related neurodegenerative conditions.

Research paper thumbnail of Decreased Plasma Iron in Alzheimer’s Disease Is Due to Transferrin Desaturation

ACS Chemical Neuroscience, 2015

Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic an... more Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic anemia. We examined iron-binding plasma proteins from AD patients and healthy controls from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing using size exclusion chromatography-inductively coupled plasma-mass spectrometry. Peak area corresponding to transferrin (Tf) saturation was directly compared to routine pathological testing. We found a significant decrease in transferrin-associated iron in AD that was missed by routine pathological tests of transferrin saturation, and that was able to discriminate between AD and controls. The AD cases showed no significant difference in transferrin concentration, only a decrease in total transferrin-bound iron. These findings support that a previously identified decrease in plasma iron levels in AD patients within the AIBL study is attributable to decreased loading of iron into transferrin, and that this subtle but discriminatory change is not observed through routine pathological testing.

Research paper thumbnail of Plasma amyloid-beta as a biomarker in Alzheimer's disease: the AIBL study of aging

Journal of Alzheimer's disease : JAD, 2010

Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD) and... more Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Abeta as an AD biomarker and its relationship with Abeta load and to determine the effect of different assay methods on the interpretation of Abeta levels. Plasma Abeta1-40, Abeta1-42, and N-terminal cleaved fragments were measured using both a commercial multiplex assay and a well-documented ELISA in 1032 individuals drawn from the well-characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Further, Abeta levels were compared to Abeta load derived from positron-emission tomography (PET) with the Pittsburgh compound B (PiB). Lower Abeta1-42 and Abeta1-42/1-40 ratio were observed in patients with AD and inversely correlated with PiB-PET derived Abeta load. How...

Research paper thumbnail of A domain level interaction network of amyloid precursor protein and Aβ of Alzheimer's disease

PROTEOMICS, 2010

The primary constituent of the amyloid plaque, beta-amyloid (Abeta), is thought to be the causal ... more The primary constituent of the amyloid plaque, beta-amyloid (Abeta), is thought to be the causal "toxic moiety" of Alzheimer's disease. However, despite much work focused on both Abeta and its parent protein, amyloid precursor protein (APP), the functional roles of APP and its cleavage products remain to be fully elucidated. Protein-protein interaction networks can provide insight into protein function, however, high-throughput data often report false positives and are in frequent disagreement with low-throughput experiments. Moreover, the complexity of the CNS is likely to be under represented in such databases. Therefore, we…

Research paper thumbnail of Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice

Neuron, 2001

transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn ... more transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble A␤ (1.45% of total cerebral A␤); APP, synaptophysin, and GFAP levels were unaffected. General health and body

Research paper thumbnail of Competitive regulation of aβredox activity by copper and zinc: Parallels in the pathogenetic mechanisms of Alzheimer's disease and familial amyotrophic lateral sclerosis

Neurobiology of Aging, 2000

Research paper thumbnail of IN54-TH-01 Biomarkers for Alzheimer's disease from large cohort studies

Journal of the Neurological Sciences, 2009

Research paper thumbnail of Metalloenzyme-like Activity of Alzheimer's Disease β-Amyloid

Journal of Biological Chemistry, 2002

Research paper thumbnail of Evidence that the β-Amyloid Plaques of Alzheimer's Disease Represent the Redox-silencing and Entombment of Aβ by Zinc

Journal of Biological Chemistry, 2000

A␤ binds Zn 2؉ , Cu 2؉ , and Fe 3؉ in vitro, and these metals are markedly elevated in the neocor... more A␤ binds Zn 2؉ , Cu 2؉ , and Fe 3؉ in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn 2؉ precipitates A␤ in vitro, and Cu 2؉ interaction with A␤ promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H 2 O 2 (A␤1-42 > A␤1-40 > ratA␤1-40). Because Zn 2؉ is redox-inert, we studied the possibility that it may play an inhibitory role in H 2 O 2-mediated A␤ toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu 2؉ , Zn 2؉ rescued primary cortical and human embryonic kidney 293 cells that were exposed to A␤1-42, correlating with the effect of Zn 2؉ in suppressing Cu 2؉-dependent H 2 O 2 formation from A␤1-42. Since plaques contain exceptionally high concentrations of Zn 2؉ , we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn 2؉ in AD, where plaques form as the result of a more robust Zn 2؉ antioxidant response to the underlying oxidative attack.

Research paper thumbnail of Effects of Anticholinergic Drugs on Cognitive Function in Older Australians: Results from the AIBL Study

Dementia and Geriatric Cognitive Disorders, 2011

Background/Aims: The nature and extent of adverse cognitive effects due to the prescription of an... more Background/Aims: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. Methods: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer’s disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). Results: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. Conclusion: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in heal...

Research paper thumbnail of Copper and Zinc Binding Modulates the Aggregation and Neurotoxic Properties of the Prion Peptide PrP106−126

Biochemistry, 2001

The abnormal form of the prion protein (PrP) is believed to be responsible for the transmissible ... more The abnormal form of the prion protein (PrP) is believed to be responsible for the transmissible spongiform encephalopathies. A peptide encompassing residues 106-126 of human PrP (PrP106-126) is neurotoxic in vitro due its adoption of an amyloidogenic fibril structure. The Alzheimer's disease amyloid beta peptide (Abeta) also undergoes fibrillogenesis to become neurotoxic. Abeta aggregation and toxicity is highly sensitive to copper, zinc, or iron ions. We show that PrP106-126 aggregation, as assessed by turbidometry, is abolished in Chelex-100-treated buffer. ICP-MS analysis showed that the Chelex-100 treatment had reduced Cu(2+) and Zn(2+) levels approximately 3-fold. Restoring Cu(2+) and Zn(2+) to their original levels restored aggregation. Circular dichroism showed that the Chelex-100 treatment reduced the aggregated beta-sheet content of the peptide. Electron paramagnetic resonance spectroscopy identified a 2N1S1O coordination to the Cu(2+) atom, suggesting histidine 111 and methionine 109 or 112 are involved. Nuclear magnetic resonance confirmed Cu(2+) and Zn(2+) binding to His-111 and weaker binding to Met-112. An N-terminally acetylated PrP106-126 peptide did not bind Cu(2+), implicating the free amino group in metal binding. Mutagenesis of either His-111, Met-109, or Met-112 abolished PrP106-126 neurotoxicity and its ability to form fibrils. Therefore, Cu(2+) and/or Zn(2+) binding is critical for PrP106-126 aggregation and neurotoxicity.

Research paper thumbnail of Copper Mediates Dityrosine Cross-Linking of Alzheimer's Amyloid-β

Biochemistry, 2004

, a feature characteristic of neurotoxic soluble A extracted from the AD brain. Since residues co... more , a feature characteristic of neurotoxic soluble A extracted from the AD brain. Since residues coordinating Cu are most vulnerable to oxidation, we investigated whether modifications of these residues were responsible for A cross-linking. SDS-resistant oligomerization of A caused by incubation with Cu was found to induce a fluorescence signal characteristic of tyrosine cross-linking. Using ESI-MS and a dityrosine specific antibody, we confirmed that Cu(II) (at concentrations lower than that associated with amyloid plaques) induces the generation of dityrosine-cross-linked, SDS-resistant oligomers of human, but not rat, A peptides. The addition of H 2 O 2 strongly promoted Cu-induced dityrosine cross-linking of A 1-28, A 1-40, and A 1-42, suggesting that the oxidative coupling is initiated by interaction of H 2 O 2 with a Cu(II) tyrosinate. The dityrosine modification is significant since it is highly resistant to proteolysis and is known to play a role in increasing structural strength. Given the elevated concentration of Cu in senile plaques, our results suggest that Cu interactions with A could be responsible for causing the covalent cross-linking of A in these structures.

Research paper thumbnail of An update on an AIBL blood-based biomarker panel for the prediction of Aβ burden

Alzheimer's & Dementia, 2012

Background: Evidence for the role of inflammation in Alzheimer's disease (AD) pathogenesis is inc... more Background: Evidence for the role of inflammation in Alzheimer's disease (AD) pathogenesis is increasing, with particular attention given to complement proteins that are involved in the clearance of amyloid plaque in addition to a causal role through chronic activation of the inflammatory response. Multiple studies suggest a role for both early and acute phase proteins within the complement network including Factor I, Factor H, C3 and C1 inhibitor all of which are altered in AD patient plasma. It is now necessary to study plasma complement proteome in depth to determine whether variation in complement proteins have sufficiently discriminatory power as an AD biomarker. Methods: Subjects were recruited from 2 large multi-centre cohorts with 399 cognitively normal subjects, 165 with mild cognitive impairment, and 411 Alzheimer's disease subjects that were gender-and age matched with an average age of 76.9 6 7.5 years. Plasma collected in EDTA tubes were anonymised and randomized. The concentration of 19 analytes was quantified using antibody-based multiplex assays on the Luminex and MSD platforms in 975 longitudinal samples using a case versus control design. Using the multiplex assays, we have at least 70% coverage of the complement cascade. Results: The intra-assay precision of the Luminex and MSD assays was calculated using coefficient of variation (%CV) showing <15% variation in duplicate samples. Univariate analyses to correlate protein expression levels with clinical parameters (MMSE, ADAS-cog, CDR) will be followed by multivariate analyses to identify the set of complement proteins that have discriminatory power. Conclusions: Peripheral inflammatory markers predictive of disease progression or with diagnostic power are of critical relevance for AD. This work aims to identify such markers within the complement cascade.

Research paper thumbnail of The effect of vascular risk factors on the rate of cognitive change in older adults: Data from the Australian Imaging Biomarkers and Lifestyle (AIBL) flagship study

Alzheimer's & Dementia, 2013

Research paper thumbnail of Change in cognition over 36 months in relation to blood biomarkers

Alzheimer's & Dementia, 2013

P1-149 CANADA-CHINA COHORT STUDY OF EARLY-ONSET FAMILIAL ALZHEIMER’S DISEASE Serge Gauthier, Jian... more P1-149 CANADA-CHINA COHORT STUDY OF EARLY-ONSET FAMILIAL ALZHEIMER’S DISEASE Serge Gauthier, Jianping Jia, Sylvie Belleville, Doris Doudet, Ging-Yuek Hsiung, A. Labbe, Dan Li, Wei Qin, Pedro Rosa-Neto, Dessa Sadovnick, Jean-Paul Soucy, Liyong Wu, McGill Centre for Studies in Aging, Montreal, Quebec, Canada; Xuan Wu Hospital of Capital Medical University, Beijing, China; Research Center, Institut Universitaire de G eriatrie de Montr eal, Montreal, Quebec, Canada; University of British Columbia, Vancouver, British Columbia, Canada; McGill Department of Biostatistics, Montreal, Quebec, Canada; Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China; Xuan Wu Hospital, Beijing, China; MCSA, Montreal, Quebec, Canada; University of British Columbia Hospital, Vancouver, British Columbia, Canada; McGill University, Montreal, Quebec, Canada; McGill Center for Studies in Aging, Verdun, Quebec, China. Contact e-mail: serge.gauthier@mcgill.ca

Research paper thumbnail of Alzheimer's disease is associated with lower hemoglobin levels and anemia: The Australian Imaging Biomarker Lifestyle (AIBL) study of aging

Alzheimer's & Dementia, 2010

Research paper thumbnail of Associations between gonadotropins, testosterone, plasma Aβ and PiB retention in men with subjective memory complaints or mild cognitive impairment

Alzheimer's & Dementia, 2010

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulat... more Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of b amyloid (Ab) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Ab levels have focused primarily on plasma Ab 1-40 and not on the more pathogenic Ab 1-42. Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Ab levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Ab 1-40 and Ab 1-42 levels (beta ¼ 0.163, Po0.001; beta ¼ 0.446, Po0.001). This held in subjective memory complainers (SMC) (Ab 1-40 ; beta ¼ 0.208, P ¼ 0.017; Ab 1-42 ; beta ¼ 0.215, P ¼ 0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-e4 allele (beta ¼ 0.536, Po0.001) and increasing serum LH levels (beta ¼ 0.421, P ¼ 0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-e4 allele copy number (beta ¼ 0.674, Po0.001) and decreasing calculated free testosterone (beta ¼ À 0.303, P ¼ 0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

Research paper thumbnail of Predicting Alzheimer disease from a blood-based biomarker profile: A 54-month follow-up

Neurology, Jan 17, 2016

We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying i... more We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying individuals with high or low neocortical β-amyloid burden (NAB), to determine whether it could also identify individuals at risk of progression to Alzheimer disease (AD) within 54 months. We generated the blood-based signature for 585 healthy controls (HCs) and 74 participants with mild cognitive impairment (MCI) from the Australian Imaging, Biomarkers and Lifestyle Study who underwent clinical reclassification (blinded to biomarker findings) at 54-month follow-up. The individuals were split into estimated high and low NAB groups based on a cutoff of 1.5 standardized uptake value ratio. We assessed the predictive accuracy of the high and low NAB groupings based on progression to mild cognitive impairment or AD according to clinical reclassification at 54-month follow-up. Twelve percent of HCs with estimated high NAB progressed in comparison to 5% of HCs with estimated low NAB (odds ratio ...

Research paper thumbnail of Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2016

Introduction: For early detection of Alzheimer's disease (AD), the field needs biomarkers that ca... more Introduction: For early detection of Alzheimer's disease (AD), the field needs biomarkers that can be used to detect disease status with high sensitivity and specificity. Apolipoprotein J (ApoJ, also known as clusterin) has long been associated with AD pathogenesis through various pathways. The aim of this study was to investigate the potential of plasma apoJ as a blood biomarker for AD. Methods: Using the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the present study assayed plasma apoJ levels over baseline and 18 months in 833 individuals. Plasma ApoJ levels were analyzed with respect to clinical classification, age, gender, apolipoprotein E (APOE) ε4 allele status, mini-mental state examination score, plasma amyloid beta (Ab), neocortical Ab burden (as measured by Pittsburgh compound B-positron emission tomography), and total adjusted hippocampus volume. Results: ApoJ was significantly higher in both mild cognitive impairment (MCI) and AD groups as compared with healthy controls (HC; P , .0001). ApoJ significantly correlated with both "standardized uptake value ratio" (SUVR) and hippocampus volume and weakly correlated with the plasma Ab1-42/Ab1-40 ratio. Plasma apoJ predicted both MCI and AD from HC with greater than 80% accuracy for AD and greater than 75% accuracy for MCI at both baseline and 18-month time points. Discussion: Mean apoJ levels were significantly higher in both MCI and AD groups. ApoJ was able to differentiate between HC with high SUVR and HC with low SUVR via APOE ε4 allele status, indicating that it may be included in a biomarker panel to identify AD before the onset of clinical symptoms.

Research paper thumbnail of Homo - cysteine potentiates copper - and amyloid peptide - mediated tox - icity in primary cultures: possible risk factors in the Alzheimer''''s - type neurodegenerative pathways

Research paper thumbnail of Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's-type neurodegenerative pathways

Journal of Neurochemistry, 2001

Oxidative stress may have an important role in the progression of neurodegenerative disorders suc... more Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. Oxidative damage could result from interactions between highly reactive transition metals such as copper (Cu) and endogenous reducing and/or oxidizing molecules in the brain. One such molecule, homocysteine, a thiol-containing amino acid, has previously been shown to modulate Cu toxicity in HeLa and endothelial cells in vitro. Due to a possible link between hyperhomocysteinemia and AD, we examined whether interaction between homocysteine and Cu could potentiate Cu neurotoxicity. Primary mouse neuronal cultures were treated with homocysteine and either Cu (II), Fe (II or III) or Zn (II). Homocysteine was shown to selectively potentiate toxicity from low micromolar concentrations of Cu. The toxicity of homocysteine/Cu coincubation was dependent on the ability of homocysteine to reduce Cu (II) as re¯ected by the inhibition of toxicity with the Cu (I)-speci®c chelator, bathocuproine disulphonate. This was supported by data showing that homocysteine reduced Cu (II) more effectively than cysteine or methionine but did not reduce Fe (III) to Fe (II). Homocysteine also generated high levels of hydrogen peroxide in the presence of Cu (II) and promoted Ab/Cu-mediated hydrogen peroxide production and neurotoxicity. The potentiation of metal toxicity did not involve excitotoxicity as ionotropic glutamate receptor antagonists had no effect on neurotoxicity. Homocysteine alone also had no effect on neuronal glutathione levels. These studies suggest that increased copper and/or homocysteine levels in the elderly could promote signi®cant oxidant damage to neurons and may represent additional risk factor pathways which conspire to produce AD or related neurodegenerative conditions.

Research paper thumbnail of Decreased Plasma Iron in Alzheimer’s Disease Is Due to Transferrin Desaturation

ACS Chemical Neuroscience, 2015

Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic an... more Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic anemia. We examined iron-binding plasma proteins from AD patients and healthy controls from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing using size exclusion chromatography-inductively coupled plasma-mass spectrometry. Peak area corresponding to transferrin (Tf) saturation was directly compared to routine pathological testing. We found a significant decrease in transferrin-associated iron in AD that was missed by routine pathological tests of transferrin saturation, and that was able to discriminate between AD and controls. The AD cases showed no significant difference in transferrin concentration, only a decrease in total transferrin-bound iron. These findings support that a previously identified decrease in plasma iron levels in AD patients within the AIBL study is attributable to decreased loading of iron into transferrin, and that this subtle but discriminatory change is not observed through routine pathological testing.

Research paper thumbnail of Plasma amyloid-beta as a biomarker in Alzheimer's disease: the AIBL study of aging

Journal of Alzheimer's disease : JAD, 2010

Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD) and... more Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Abeta as an AD biomarker and its relationship with Abeta load and to determine the effect of different assay methods on the interpretation of Abeta levels. Plasma Abeta1-40, Abeta1-42, and N-terminal cleaved fragments were measured using both a commercial multiplex assay and a well-documented ELISA in 1032 individuals drawn from the well-characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Further, Abeta levels were compared to Abeta load derived from positron-emission tomography (PET) with the Pittsburgh compound B (PiB). Lower Abeta1-42 and Abeta1-42/1-40 ratio were observed in patients with AD and inversely correlated with PiB-PET derived Abeta load. How...

Research paper thumbnail of A domain level interaction network of amyloid precursor protein and Aβ of Alzheimer's disease

PROTEOMICS, 2010

The primary constituent of the amyloid plaque, beta-amyloid (Abeta), is thought to be the causal ... more The primary constituent of the amyloid plaque, beta-amyloid (Abeta), is thought to be the causal &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;toxic moiety&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. However, despite much work focused on both Abeta and its parent protein, amyloid precursor protein (APP), the functional roles of APP and its cleavage products remain to be fully elucidated. Protein-protein interaction networks can provide insight into protein function, however, high-throughput data often report false positives and are in frequent disagreement with low-throughput experiments. Moreover, the complexity of the CNS is likely to be under represented in such databases. Therefore, we…

Research paper thumbnail of Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice

Neuron, 2001

transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn ... more transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble A␤ (1.45% of total cerebral A␤); APP, synaptophysin, and GFAP levels were unaffected. General health and body

Research paper thumbnail of Competitive regulation of aβredox activity by copper and zinc: Parallels in the pathogenetic mechanisms of Alzheimer's disease and familial amyotrophic lateral sclerosis

Neurobiology of Aging, 2000

Research paper thumbnail of IN54-TH-01 Biomarkers for Alzheimer's disease from large cohort studies

Journal of the Neurological Sciences, 2009

Research paper thumbnail of Metalloenzyme-like Activity of Alzheimer's Disease β-Amyloid

Journal of Biological Chemistry, 2002

Research paper thumbnail of Evidence that the β-Amyloid Plaques of Alzheimer's Disease Represent the Redox-silencing and Entombment of Aβ by Zinc

Journal of Biological Chemistry, 2000

A␤ binds Zn 2؉ , Cu 2؉ , and Fe 3؉ in vitro, and these metals are markedly elevated in the neocor... more A␤ binds Zn 2؉ , Cu 2؉ , and Fe 3؉ in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn 2؉ precipitates A␤ in vitro, and Cu 2؉ interaction with A␤ promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H 2 O 2 (A␤1-42 > A␤1-40 > ratA␤1-40). Because Zn 2؉ is redox-inert, we studied the possibility that it may play an inhibitory role in H 2 O 2-mediated A␤ toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu 2؉ , Zn 2؉ rescued primary cortical and human embryonic kidney 293 cells that were exposed to A␤1-42, correlating with the effect of Zn 2؉ in suppressing Cu 2؉-dependent H 2 O 2 formation from A␤1-42. Since plaques contain exceptionally high concentrations of Zn 2؉ , we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn 2؉ in AD, where plaques form as the result of a more robust Zn 2؉ antioxidant response to the underlying oxidative attack.

Research paper thumbnail of Effects of Anticholinergic Drugs on Cognitive Function in Older Australians: Results from the AIBL Study

Dementia and Geriatric Cognitive Disorders, 2011

Background/Aims: The nature and extent of adverse cognitive effects due to the prescription of an... more Background/Aims: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. Methods: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer’s disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). Results: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. Conclusion: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in heal...

Research paper thumbnail of Copper and Zinc Binding Modulates the Aggregation and Neurotoxic Properties of the Prion Peptide PrP106−126

Biochemistry, 2001

The abnormal form of the prion protein (PrP) is believed to be responsible for the transmissible ... more The abnormal form of the prion protein (PrP) is believed to be responsible for the transmissible spongiform encephalopathies. A peptide encompassing residues 106-126 of human PrP (PrP106-126) is neurotoxic in vitro due its adoption of an amyloidogenic fibril structure. The Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease amyloid beta peptide (Abeta) also undergoes fibrillogenesis to become neurotoxic. Abeta aggregation and toxicity is highly sensitive to copper, zinc, or iron ions. We show that PrP106-126 aggregation, as assessed by turbidometry, is abolished in Chelex-100-treated buffer. ICP-MS analysis showed that the Chelex-100 treatment had reduced Cu(2+) and Zn(2+) levels approximately 3-fold. Restoring Cu(2+) and Zn(2+) to their original levels restored aggregation. Circular dichroism showed that the Chelex-100 treatment reduced the aggregated beta-sheet content of the peptide. Electron paramagnetic resonance spectroscopy identified a 2N1S1O coordination to the Cu(2+) atom, suggesting histidine 111 and methionine 109 or 112 are involved. Nuclear magnetic resonance confirmed Cu(2+) and Zn(2+) binding to His-111 and weaker binding to Met-112. An N-terminally acetylated PrP106-126 peptide did not bind Cu(2+), implicating the free amino group in metal binding. Mutagenesis of either His-111, Met-109, or Met-112 abolished PrP106-126 neurotoxicity and its ability to form fibrils. Therefore, Cu(2+) and/or Zn(2+) binding is critical for PrP106-126 aggregation and neurotoxicity.

Research paper thumbnail of Copper Mediates Dityrosine Cross-Linking of Alzheimer's Amyloid-β

Biochemistry, 2004

, a feature characteristic of neurotoxic soluble A extracted from the AD brain. Since residues co... more , a feature characteristic of neurotoxic soluble A extracted from the AD brain. Since residues coordinating Cu are most vulnerable to oxidation, we investigated whether modifications of these residues were responsible for A cross-linking. SDS-resistant oligomerization of A caused by incubation with Cu was found to induce a fluorescence signal characteristic of tyrosine cross-linking. Using ESI-MS and a dityrosine specific antibody, we confirmed that Cu(II) (at concentrations lower than that associated with amyloid plaques) induces the generation of dityrosine-cross-linked, SDS-resistant oligomers of human, but not rat, A peptides. The addition of H 2 O 2 strongly promoted Cu-induced dityrosine cross-linking of A 1-28, A 1-40, and A 1-42, suggesting that the oxidative coupling is initiated by interaction of H 2 O 2 with a Cu(II) tyrosinate. The dityrosine modification is significant since it is highly resistant to proteolysis and is known to play a role in increasing structural strength. Given the elevated concentration of Cu in senile plaques, our results suggest that Cu interactions with A could be responsible for causing the covalent cross-linking of A in these structures.

Research paper thumbnail of An update on an AIBL blood-based biomarker panel for the prediction of Aβ burden

Alzheimer's & Dementia, 2012

Background: Evidence for the role of inflammation in Alzheimer's disease (AD) pathogenesis is inc... more Background: Evidence for the role of inflammation in Alzheimer's disease (AD) pathogenesis is increasing, with particular attention given to complement proteins that are involved in the clearance of amyloid plaque in addition to a causal role through chronic activation of the inflammatory response. Multiple studies suggest a role for both early and acute phase proteins within the complement network including Factor I, Factor H, C3 and C1 inhibitor all of which are altered in AD patient plasma. It is now necessary to study plasma complement proteome in depth to determine whether variation in complement proteins have sufficiently discriminatory power as an AD biomarker. Methods: Subjects were recruited from 2 large multi-centre cohorts with 399 cognitively normal subjects, 165 with mild cognitive impairment, and 411 Alzheimer's disease subjects that were gender-and age matched with an average age of 76.9 6 7.5 years. Plasma collected in EDTA tubes were anonymised and randomized. The concentration of 19 analytes was quantified using antibody-based multiplex assays on the Luminex and MSD platforms in 975 longitudinal samples using a case versus control design. Using the multiplex assays, we have at least 70% coverage of the complement cascade. Results: The intra-assay precision of the Luminex and MSD assays was calculated using coefficient of variation (%CV) showing <15% variation in duplicate samples. Univariate analyses to correlate protein expression levels with clinical parameters (MMSE, ADAS-cog, CDR) will be followed by multivariate analyses to identify the set of complement proteins that have discriminatory power. Conclusions: Peripheral inflammatory markers predictive of disease progression or with diagnostic power are of critical relevance for AD. This work aims to identify such markers within the complement cascade.

Research paper thumbnail of The effect of vascular risk factors on the rate of cognitive change in older adults: Data from the Australian Imaging Biomarkers and Lifestyle (AIBL) flagship study

Alzheimer's & Dementia, 2013

Research paper thumbnail of Change in cognition over 36 months in relation to blood biomarkers

Alzheimer's & Dementia, 2013

P1-149 CANADA-CHINA COHORT STUDY OF EARLY-ONSET FAMILIAL ALZHEIMER’S DISEASE Serge Gauthier, Jian... more P1-149 CANADA-CHINA COHORT STUDY OF EARLY-ONSET FAMILIAL ALZHEIMER’S DISEASE Serge Gauthier, Jianping Jia, Sylvie Belleville, Doris Doudet, Ging-Yuek Hsiung, A. Labbe, Dan Li, Wei Qin, Pedro Rosa-Neto, Dessa Sadovnick, Jean-Paul Soucy, Liyong Wu, McGill Centre for Studies in Aging, Montreal, Quebec, Canada; Xuan Wu Hospital of Capital Medical University, Beijing, China; Research Center, Institut Universitaire de G eriatrie de Montr eal, Montreal, Quebec, Canada; University of British Columbia, Vancouver, British Columbia, Canada; McGill Department of Biostatistics, Montreal, Quebec, Canada; Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China; Xuan Wu Hospital, Beijing, China; MCSA, Montreal, Quebec, Canada; University of British Columbia Hospital, Vancouver, British Columbia, Canada; McGill University, Montreal, Quebec, Canada; McGill Center for Studies in Aging, Verdun, Quebec, China. Contact e-mail: serge.gauthier@mcgill.ca

Research paper thumbnail of Alzheimer's disease is associated with lower hemoglobin levels and anemia: The Australian Imaging Biomarker Lifestyle (AIBL) study of aging

Alzheimer's & Dementia, 2010

Research paper thumbnail of Associations between gonadotropins, testosterone, plasma Aβ and PiB retention in men with subjective memory complaints or mild cognitive impairment

Alzheimer's & Dementia, 2010

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulat... more Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of b amyloid (Ab) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Ab levels have focused primarily on plasma Ab 1-40 and not on the more pathogenic Ab 1-42. Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Ab levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Ab 1-40 and Ab 1-42 levels (beta ¼ 0.163, Po0.001; beta ¼ 0.446, Po0.001). This held in subjective memory complainers (SMC) (Ab 1-40 ; beta ¼ 0.208, P ¼ 0.017; Ab 1-42 ; beta ¼ 0.215, P ¼ 0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-e4 allele (beta ¼ 0.536, Po0.001) and increasing serum LH levels (beta ¼ 0.421, P ¼ 0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-e4 allele copy number (beta ¼ 0.674, Po0.001) and decreasing calculated free testosterone (beta ¼ À 0.303, P ¼ 0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.