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The Journal of Alzheimer’s Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer’s disease.
The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer’s disease.
Authors: Chan, Amy | Shea, Thomas B.
Article Type: Research Article
Abstract: Gain-of-function mutations in the presenilin-1 (PS-1) promote Alzheimer's disease (AD) by increasing reactive oxygen species, at least part of which is derived by an accompanying increase in generation of amyloid-β (Aβ). Additional studies indicate that impaired Apolipoprotein E function, which also increases oxidative stress and is also associated with AD, potentiates the deleterious activity of PS-1. Folate deficiency is also associated with AD and potentiates the impact of both ApoE deficiency and β exposure. More recently, folate deficiency has been shown to increase PS-1 expression. Since dietary supplementation with apple juice provides neuroprotection against ApoE deficiency, Aβ exposure and folate …deficiency, we examined the impact of apple juice on PS-1 overexpression. Herein, we demonstrate that dietary deficiency in folate and vitamin E increased PS-1 expression in juvenile and adult normal C57B1/6J and ApoE-/- mice and in aged normal mice. Supplementation with apple juice concentrate (AJC) attenuated or prevent these increases. Prior studies demonstrate that impaired DNA methylation resulting from a deficiency in S-adenosylmethionine (SAM, which is rapidly depleted following folate deprivation) leads to PS-1 overexpression, and that direct supplementation with SAM attenuates PS-1 overexpression. We determined that AJC contained levels of SAM comparable to those capable of suppressing PS-1 overexpression, suggesting that the SAM content of AJC represents a potential mechanism for preventing PS-1 overexpression, and further highlighting the possibility that AJC provides neuroprotection by mechanisms in addition to its antioxidant potential. Show more
Keywords: Alzheimer disease, antioxidants, apolipoprotein E, oxidative stress, presenilin, s-adenosylmethionine
DOI: 10.3233/JAD-2006-10401
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 353-358, 2006
Authors: Lahiri, Debomoy K.
Article Type: Article Commentary
DOI: 10.3233/JAD-2006-10402
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 359-361, 2006
Authors: Shea, Thomas B. | Chan, Amy
Article Type: Article Commentary
DOI: 10.3233/JAD-2006-10403
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 363-364, 2006
Authors: Barbosa, Fábio Augusto Freiria | de Labio, Roger Willian | de Oliveira S. Rigolin, Valdeci | Minett, Thais | Bertolucci, Paulo Henrique Ferreira | de Arruda Cardoso Smith, Marília | Payão, Spencer Luiz Marques
Article Type: Research Article
Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly and is also considered a progeroid genetic syndrome. The etiology of AD is complex and the mechanisms underlying its pathophysiology remain to be clarified. It has been suggested that a high serum cholesterol level is a risk factor for (AD), and that some polymorphisms of genes encoding proteins regulating cholesterol metabolism are associated with AD development. APOA5 is a recently discovered apolipoprotein involved primarily with triglyceride (TG) metabolism disorder. This study investigates the association of AD with the APOA5 gene –1131T>C polymorphisms in samples of 106 patients with …Alzheimer's disease (AD), 76 elderly healthy controls and 93 young healthy controls. DNA samples were isolated from blood cells, amplified by PCR and digested with Tru1l. We observed that the genotype distributions of APOA5 variants were within Hardy-Weinberg equilibrium in all subject samples. Furthermore, chi-square test comparison for genotype distributions and allele frequencies did not reveal any significant difference among the three groups of subjects P>0.05). These results support the idea that these variants are not involved as a risk factor for developing AD. Show more
Keywords: Ageing, Alzheimer's disease, apolipoprotein A5, –1131T→C polymorphisms, risk factor
DOI: 10.3233/JAD-2006-10404
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 365-369, 2006
Authors: Micheli, D. | Bonvicini, C. | Rocchi, A. | Ceravolo, R. | Mancuso, M. | Tognoni, G. | Gennarelli, M. | Siciliano, G. | Murri, L.
Article Type: Research Article
Abstract: Patients with Alzheimer disease (AD) often exhibit psychiatric symptoms associated with cognitive impairment. The serotoninergic system may be involved in the development of depressive symptoms in AD patients, as suggested by the evidence that antidepressant drugs having the serotonin transporter as their target are effectively used to treat depressive AD patients. The aim of this study was to investigate the role of serotonin in depression, searching for association of two serotoninergic polymorphisms (T102C of serotonin receptor 5-HT2A and serotonin transporter linked polymorphic region -5-HTTLPR- of SLC6A4 gene) with depressive symptoms and considering their possible interactions with Apolipoprotein E …(ApoE) and between themselves, in a sample of 208 sporadic AD patients and 116 normal controls from Italy. 5-HTTLPR and T102C are not associated with AD when separately analysed. However, we found out an interaction between the two polymorphisms in L/L and C/C genotype carriers increasing the risk for the disease (p=0.015, OR=8.048; 95% CI: 1.497–43.262). No association of the polymorphisms was detected with depression linked to AD. No interaction between 5-HTTLPR and T102C was detected in depressive AD subjects, even after stratification according to the presence of ApoE4 allele. These results suggest that the serotoninergic system may be not involved in the pathogenesis of depressive symptoms in AD patients, and it may be involved in other aspects of disease pathophysiology like cognitive symptoms and psychosis. Show more
Keywords: Serotoninergic system, polymorphisms, depression, 5-HTTLPR, T102C
DOI: 10.3233/JAD-2006-10405
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 371-378, 2006
Authors: Thomas, Rhian S. | Liddell, J. Eryl | Murphy, Lynne S. | Pache, David M. | Kidd, Emma J.
Article Type: Research Article
Abstract: Proteolytic cleavage of amyloid-β-protein precursor (AβPP) by β- and γ-secretases results in production of the amyloid-β peptide (Aβ) that accumulates in the brains of sufferers of Alzheimer's disease (AD). We have developed a monoclonal antibody, 2B12, which binds in the vicinity of the β-secretase cleavage site on AβPP but does not bind within the Aβ region. We hypothesised that this antibody, directed against the substrate rather than the enzyme, could inhibit cleavage of AβPP by β-secretase via steric hindrance and thus reduce downstream production of Aβ. The antibody would enter cells by binding to AβPP when it is at the …cell surface and then be internalised with the protein. We subsequently demonstrated that, after addition of 2B12 to standard growth media, this antibody was indeed capable of inhibiting Aβ40 production in neuroblastoma and astrocytoma cells expressing native AβPP, as measured by an ELISA. This inhibition was both concentration- and time-dependent and was specific to 2B12. We were only able to inhibit approximately 50% of Aβ40 production suggesting that not all AβPP is trafficked to the cell surface. We propose that this antibody could be used as a novel, putative therapy for the treatment of AD. Show more
Keywords: Alzheimer's disease, monoclonal antibodies, amyloid β, β-secretase, amyloid β-protein precursor, steric hindrance
DOI: 10.3233/JAD-2006-10406
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 379-390, 2006
Authors: Butterfield, D. Allan | Gnjec, Anastazija | Poon, H. Fai | Castegna, Alessandra | Pierce, William M. | Klein, Jon B. | Martins, Ralph N.
Article Type: Research Article
Abstract: Objective: To identify oxidatively modified proteins in brains of persons with inherited Alzheimer's disease. Methods: Redox proteomics was used to identify oxidatively modified brain proteins in persons with mutations in the genes for presenilin-1 (PS-1). Results: An initial redox proteomics assessment of oxidatively modified proteins from brains of individuals with PS-1 mutations was performed. These PS1 mutations, Q222H and M233T, are completely penetrant causing early-onset familial AD as previously reported in these Australian families. We show that oxidative modifications of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), γ-enolase, actin, and dimethylarginine dimethylaminohydrolase 1 (DMDMAH-1) are present in the brain of familial AD …subjects. Conclusions: These initial results suggest that oxidatively modified proteins are important common features in both familial and sporadic AD. Show more
Keywords: Redox proteomics, familial Alzheimer's disease, oxidatively modified brain proteins
DOI: 10.3233/JAD-2006-10407
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 391-397, 2006
Authors: Riekse, Robert G. | Li, Ge | Petrie, Eric C. | Leverenz, James B. | Vavrek, Darcy | Vuletic, Simona | Albers, John J. | Montine, Thomas J. | Lee, Virginia M.-Y. | Lee, Michael | Seubert, Peter | Galasko, Douglas | Schellenberg, Gerard D. | Hazzard, William R. | Peskind, Elaine R.
Article Type: Research Article
Abstract: Background: Treatment with HMG-CoA reductase inhibitors ("statins") has been variably associated with a reduced risk of Alzheimer's disease (AD) in epidemiologic studies and reduced amyloid-β (Aβ) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS). Methods: We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n=10) at 40 mg/day or pravastatin (a CNS impermeant statin; n=13) at 80 mg/day in hypercholesterolemic subjects without dementia. Results: Simvastatin, but not pravastatin, reduced CSF levels …of phospho-tau-181 (p-tau181 ) in all subjects. There were no differences in CSF levels of total tau, Aβ42 , Aβ40 , soluble amyloid β protein precursor (sAβPP) α or β, or F2 -isoprostanes. Conclusions: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD. Show more
Keywords: Alzheimer's disease, statins, tau, clinical trial, CSF
DOI: 10.3233/JAD-2006-10408
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 399-406, 2006
Authors: Ghribi, Othman
Article Type: Article Commentary
DOI: 10.3233/JAD-2006-10409
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 407-408, 2006
Authors: Villanueva, Vicent | Garcia, Ana M.
Article Type: Research Article
Abstract: This study is aimed to investigate proxy respondent's information usefulness in retrospective studies by comparing information obtained with a questionnaire (with a total of 171 items) from controls and their proxy respondents in a case-control study on Alzheimer's disease. Kappa indices and intraclass correlation coefficients were calculated to assess reliability, and bias factor and mean differences were calculated to assess validity. Proxy respondent's personal features (gender, age and relationship with the index subject) were also studied. Kappa indices and intraclass correlation coefficients were in general good or very good (>0.6), specially regarding control's personal and family data (ranges 0.45-1 for …Kappa and 0.86–0.99 for intraclass correlation coefficient) and occupational exposures (range for Kappa 0.48–1). No systematic biases were found (range for bias factor 0.65–4.12 and range for mean differences −1.81–1.30, none of them statistically significant). Proxy respondent's individual features were not found to systematically affect reliability. The use of surrogate information for controls in etiologic case-control studies of Alzheimer's disease may be useful without unacceptable loss of information or systematic biases. Show more
Keywords: Alzheimer disease, epidemiology, case-control studies, proxy-respondents, questionnaires, reliability, validity
DOI: 10.3233/JAD-2006-10410
Citation: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 409-416, 2006
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