Journal of Alzheimer's Disease - Volume 23, issue 2

Authors: Aznar, Susana | Knudsen, Gitte M.

Article Type: Review Article

Abstract: The existence of a high co-morbidity between Alzheimer's disease (AD) and depression has been known for a long time. More interesting though are recent studies indicating that depression and number of depressive episodes earlier in life is associated with increased risk of AD development. This suggests the existence of common neuropathological mechanisms behind depression and AD. Here we propose that the brain changes associated with depressive episodes that compromise the brain's ability to cope with stress may constitute risk factors for development of AD. Furthermore, in individuals with a genetic linkage to depression, there may be an increased vulnerability towards …the initiation of a detrimental neurodegenerative cascade. The following review will deal with the various observations reported within the different neurobiological systems known to be involved and affected in depression, like serotonergic and cholinergic system, hypothalamic-pituitary-adrenal axis and brain derived neurotrophic factor, and discussed in relation to AD. Show more

Keywords: 5-HT 1A, 5-HT 2A, BDNF, depression, HPA-axis, monoaminergic hypothesis, serotonin, stress

DOI: 10.3233/JAD-2010-100390

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 177-193, 2011

Authors: Cuadrado-Tejedor, Mar | Vilariño, Marcos | Cabodevilla, Felipe | Del Río, Joaquín | Frechilla, Diana | Pérez-Mediavilla, Alberto

Article Type: Research Article

Abstract: The mitochondrial voltage-dependent anion channel 1 (VDAC1) is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology. Through proteomic analysis followed by Western blotting and immunohistochemical techniques, we have found that VDAC1 is overexpressed in the hippocampus from amyloidogenic AD transgenic mice models. VDAC1 was also overexpressed in postmortem brain tissue from AD patients at an advanced stage of the disease. Interestingly, amyloid-β (Aβ) soluble oligomers were able to induce upregulation of VDAC1 in a human neuroblastoma cell line, further supporting a correlation between Aβ levels and VDAC1 expression. In hippocampal extracts from transgenic …mice, a significant increase was observed in the levels of VDAC1 phosphorylated at an epitope that is susceptible to phosphorylation by glycogen synthase kinase-3β, whose activity was also increased. The levels of hexokinase I (HXKI), which interacts with VDAC1 and affects its function, were decreased in mitochondrial samples from AD models. Since phospho-VDAC and reduced HXKI levels favors a VDAC1 conformational state more prone to the release proapoptotic factors, regulation of the function of this channel may be a promising therapeutic approach to combat AD. Show more

Keywords: Alzheimer's disease, amyloid-β, hexokinase I, phospho-VDAC1, voltage-dependent anion channel 1 (VDAC1)

DOI: 10.3233/JAD-2010-100966

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 195-206, 2011

Authors: Dursun, Erdinç | Gezen-Ak, Duygu | Yilmazer, Selma

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is the core component of amyloid plaques of Alzheimer's disease (AD). The effects of Aβ include damage to neuronal plasma membrane, disruption of Ca2+ homeostasis, and alterations of neurotrophic factor levels. The aim of this study was to determine the effects of Aβ treatment on vitamin D receptor (VDR), L-type voltage sensitive calcium channels A1C (LVSCC A1C), NGF, and observing the effects of vitamin D treatment on Aβ induced alterations in primary cortical neurons. As to the latter, we aimed to test the suggested neuroprotective role of vitamin D as a neglected neurosteroid. The expressions of VDR …and LVSCC A1C were studied with qRT-PCR and Western blotting. NGF and cytotoxicity levels were determined by ELISA. Apoptotic cell death was investigated with caspase-3 protein expression by Western blotting. Our results showed that the Aβ triggers neurodegeneration not only by inducing LVSCC A1C expression and NGF levels and but also by dramatically suppressing VDR expression. Administration of vitamin D to this model protected neurons by preventing cytotoxicity and apoptosis, and also by downregulating LVSCC A1C and upregulating VDR. Additionally, vitamin D brought NGF expression to a state of equilibrium and did not show its apoptosis inducing effects. Consequently, prevention of Aβ toxicity which was one of the major component of AD type pathology by vitamin D treatment and understanding how Aβ effects vitamin D related pathways, might open up new frontiers in clarifying molecular mechanisms of neurodegeneration and provide basis for novel perspectives in both preventing and treating AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein, calcium channels, nerve growth factor vitamin D, vitamin D 3 receptor

DOI: 10.3233/JAD-2010-101377

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 207-219, 2011

Authors: Teipel, Stefan J. | Kaza, Evangelia | Hadlich, Stefan | Bauer, Alexandra | Brüning, Thomas | Plath, Anne-Sophie | Krohn, Markus | Scheffler, Katja | Walker, Lary C. | Lotze, Martin | Pahnke, Jens

Article Type: Research Article

Abstract: In vivo imaging of amyloid-β (Aβ) load as a biomarker of Alzheimer's disease (AD) would be of considerable clinical relevance for the early diagnosis and monitoring of treatment effects. Here, we investigated automated quantification of in vivo T2 relaxation time as a surrogate measure of plaque load in the brains of ten AβPP/PS1 transgenic mice (age 20 weeks) using in vivo MRI acquisitions on a 7T Bruker ClinScan magnet. AβPP/PS1 mice present with rapid-onset cerebral β-amyloidosis, and were compared with eight age-matched, wild-type control mice (C57Bl/6J) that do not develop Aβ-deposition in brain. Data were analyzed with a novel automated …voxel-based analysis that allowed mapping the entire brain for significant signal changes. In AβPP/PS1 mice, we found a significant decrease in T2 relaxation times in the deeper neocortical layers, caudate-putamen, thalamus, hippocampus, and cerebellum compared to wildtype controls. These changes were in line with the histological distribution of cerebral Aβ plaques and activated microglia. Grey matter density did not differ between wild-type mice and AβPP/PS1 mice, consistent with a lack of neuronal loss in histological investigations. High-field MRI with automated mapping of T2 time changes may be a useful tool for the detection of plaque load in living transgenic animals, which may become relevant for the evaluation of amyloid lowering intervention effects in future studies. Show more

Keywords: Alzheimer's disease, amyloid-β, high-field MRI, iron deposition, transgenic mouse models, T2 relaxation time

DOI: 10.3233/JAD-2010-101035

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 221-237, 2011

Authors: Squitti, Rosanna | Ghidoni, Roberta | Scrascia, Federica | Benussi, Luisa | Panetta, Valentina | Pasqualetti, Patrizio | Moffa, Filomena | Bernardini, Silvia | Ventriglia, Mariacarla | Binetti, Giuliano | Rossini, Paolo Maria

Article Type: Research Article

Abstract: In patients affected by Alzheimer's disease (AD), serum copper not bound to ceruloplasmin (‘free’ copper) appears elevated, slightly but significantly enough to distinguish AD patients from healthy elderly subjects. In this paper we tested the hypothesis that this is also the case for individuals affected by mild cognitive impairment (MCI). A sample of 83 MCI subjects were compared with 100 elderly control subjects in terms of levels of serum copper, free copper, ceruloplasmin, apolipoprotein E4 genotype (APOE4), iron, transferrin, and total antioxidant capacity (TRAP). The groups were also compared in terms of demographic and cardiovascular risk factors. The comparison with …an additional group of 105 mild to moderate AD patients was also evaluated. The possible effects of copper dysfunction on cognitive decline were evaluated by multinomial logistic regression analysis. A linear regression model was applied to define the role of metals and antioxidant dysfunction in explaining Mini-Mental Status Examination (MMSE) variations. APOE4 and free copper differentiated the MCI group from the healthy control group. The probability of aquiring MCI increased by about 24% for each free copper unit (μmol/L) increment. APOE4 and free copper differentiated the MCI group also from the AD group. APOE4 and free copper appeared associated to MMSE worsening, as did age and gender. These results suggest that free copper can help in discriminating MCI subjects from healthy controls, but not on an individual basis. Show more

Keywords: Alzheimer's disease, apolipoprotein E, copper, mild cognitive impairment

DOI: 10.3233/JAD-2010-101098

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 239-248, 2011

Authors: Wilson, Robert S. | Barral, Sandra | Lee, Joseph H. | Leurgans, Sue E. | Foroud, Tatiana M. | Sweet, Robert A. | Graff-Radford, Neill | Bird, Thomas D. | Mayeux, Richard | Bennett, David A. | for the National Institute on Aging Late-Onset Alzheimer's Disease Genetics Study

Article Type: Research Article

Abstract: The study aim was to estimate the genetic contribution to individual differences in different forms of memory in a large family-based group of older adults. As part of the Late Onset Alzheimer's Disease Family Study, 899 persons (277 with Alzheimer's disease, 622 unaffected) from 325 families completed a battery of memory tests from which previously established composite measures of episodic memory, semantic memory, and working memory were derived. Heritability in these measures was estimated using the maximum likelihood variance component method, controlling for age, gender, and education. In analyses of unaffected family members, the adjusted heritability estimates were 0.62 for …episodic memory, 0.49 for semantic memory, and 0.72 for working memory, where a heritability estimate of 1 indicates that genetic factors explain all of the phenotypic variance and a heritability of 0 indicates that genetic factors explain none. Adjustment for APOE genotype had little effect on these estimates. When analyses included affected and unaffected family members, adjusted heritability estimates were lower (0.47 for episodic memory, 0.32 for semantic memory, 0.42 for working memory). Adjusting for APOE slightly reduced the estimate for episodic memory (0.40) but had no effect on the remaining estimates. The results indicate that memory functions are under strong genetic influence in older persons with and without AD, and are only partly attributable to APOE. This suggests that genetic analyses of memory endophenotypes may help to identify genetic variants associated with AD. Show more

Keywords: Alzheimer's disease, apolipoprotein E, heritability, memory

DOI: 10.3233/JAD-2010-101515

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 249-255, 2011

Authors: Aluise, Christopher D. | Robinson, Renã A.S. | Cai, Jian | Pierce, William M. | Markesbery, William R. | Butterfield, D. Allan

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a central nervous system disorder pathologically characterized by senile plaques, neurofibrillary tangles, and synapse loss. A small percentage of individuals with normal antemortem psychometric scores, after adjustments for age and education, meet the neuropathological criteria for amnestic mild cognitive impairment (MCI) or AD; these individuals have been termed ‘preclinical’ or ‘asymptomatic’ AD (PCAD). In this study, we employed the immunochemical slot-blot method and two-dimensional gel-based redox proteomics to observe differences in protein levels and oxidative modifications between groups with equal levels of AD pathology who differ in regards to clinical symptoms of memory impairment. Results of …global oxidative stress measurements revealed significantly higher levels of protein carbonyls in the MCI inferior parietal lobule (IPL) relative to PCAD (and controls), despite equal levels of neuropathology. Proteomics analysis of the IPL revealed differences in protein levels and specific carbonylation that are consistent with preservation of memory in PCAD and apparent memory decline in MCI. Our data suggest that marked changes occur at the protein level in MCI that may cause or reflect memory loss and other AD symptoms. Show more

Keywords: Alzheimer's disease, brain, mild cognitive impairment, oxidative stress, preclinical Alzheimer's, proteomics, redox proteomics, two dimensional gel electrophoresis

DOI: 10.3233/JAD-2010-101083

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 257-269, 2011

Authors: Liu, Ying | Lee, Michael K. | James, Maria M. | Price, Donald L. | Borchelt, David R. | Troncoso, Juan C. | Oh, Esther S.

Article Type: Research Article

Abstract: The role of amyloid-β (Aβ) in the neurodegeneration of Alzheimer's disease remains controversial, to a large extent because of the lack of robust neurodegeneration in mouse models of AD. To address this question, we examined the effects of Aβ antibodies in the recently described monoaminergic (MAergic) axonal degeneration in AβPPswe/PS1dE9 mice. To determine if Aβ accumulation is directly involved in degeneration of MAergic axons, we examined the effects of passive anti-Aβ antibody (7B6) administration on Aβ pathology and MAergic degeneration in AβPPswe/PS1dE9 mice. Injections of monoclonal antibody (mAb) 7B6 into mice (6 to 9 months of age) resulted in a …modest reduction of Aβ load in the brains of AβPPswe/PS1dE9 mice. In addition, 7B6 treated AβPPswe/PS1dE9 mice had significantly higher densities of MAergic axons in both cortex and in hippocampus as compared to untreated mutant mice. For example, 7B6 treated mice showed almost 2-fold greater densities of serotonergic (5-HT) axons in the cortex compared to saline treated mice. Similar findings were observed in the catecholaminergic (TH) axons. Our results demonstrate that lowering of Aβ levels via passive Aβ immunotherapy ameliorates ongoing degenerative processes, supporting a causal link between Aβ and neurodegeneration. Show more

Keywords: Amyloid-β, axon, immunotherapy, neurodegeneration, serotonergic

DOI: 10.3233/JAD-2010-101602

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 271-279, 2011

Authors: Kim, Ki Woong | Park, Joon Hyuk | Kim, Myoung-Hee | Kim, Moon Doo | Kim, Bong-Jo | Kim, Shin-Kyum | Kim, Jeong Lan | Moon, Seok Woo | Bae, Jae Nam | Woo, Jong Inn | Ryu, Seung-Ho | Yoon, Jong Chul | Lee, Nam-Jin | Lee, Dong Young | Lee, Dong Woo | Lee, Seok Bum | Lee, Jung Jae | Lee, Jun-Young | Lee, Chang-Uk | Chang, Sung Man | Jhoo, Jin Hyeong | Cho, Maeng Je

Article Type: Research Article

Abstract: We investigated the prevalence of dementia and mild cognitive impairment (MCI) and the factors associate with risk of dementia from a representative nationwide sample of Korean elders. 8,199 randomly-sampled Koreans aged 65 years or older were invited to participate in the Phase I screening assessment using Mini-Mental State Examination by door-to-door home visit, and 6,141 subjects (response rate = 74.9%) responded. Among them, 2,336 subjects were invited to participate in the Phase II diagnostic assessment for dementia and MCI, and 1,673 subjects responded (response rate = 71.6%). Diagnostic assessments were administered using the Korean version of the Consortium to Establish …a Registry for Alzheimer's Disease Assessment Packet (CERAD-K) Clinical Assessment Battery. The CERAD-K Neuropsychological Assessment Battery was used for diagnosing MCI. Age-, gender-, education-, and urbanicity-standardized prevalence of dementia was estimated to be 8.1% (95% CI = 6.9–9.2) for overall dementia and 24.1% (95% CI = 21.0–27.2) for MCI. Alzheimer's disease (AD) was the most prevalent type (5.7%) followed by vascular dementia (2.0%). Amnestic subtype (20.1%) was much more prevalent than nonamnestic subtype in MCI (4.0%). Older age, being male, lower education level, illiteracy, smoking, and histories of head trauma or depression were associated with increased dementia risk, and alcohol use and moderately intense exercise were associated with decreased dementia risk. We expect numbers of dementia patients to double every 20 years until 2050 in Korea and expect AD to account for progressively more dementia cases in the future. Show more

Keywords: Dementia, mild cognitive impairment (MCI), prevalence, risk, South Korea

DOI: 10.3233/JAD-2010-101221

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 281-291, 2011

Authors: Miller, David L. | Potempska, Anna | Wegiel, Jerzy | Mehta, Pankaj D.

Article Type: Research Article

Abstract: Antibodies that specifically bind to either amyloid-β peptide (Aβ) isoform Aβ40 or Aβ42 contribute to the study of Alzheimer's disease (AD) pathology and to the development of cerebrospinal fluid-based tests for the probable diagnosis of AD. Polyclonal rabbit anti-Aβ antibodies possess high affinity and specificity, but their generation requires a long immunization period, and the resulting antibodies exhibit variable specificities and affinities. To secure a continuing supply of antibodies with uniform properties, we generated and partially characterized rabbit monoclonal antibodies specific for either Aβ40 or Aβ42 . These antibodies possess nanomolar or sub-nanomolar dissociation constants and are …at least 3,000-fold more selective for one isoform over the other. These antibodies are suitable for immunoblotting and, in a sandwich ELISA, RabmAb42 (anti-Aβ42 ) is sensitive enough to measure plasma levels of Aβ42 . In addition, these antibodies have been applied to the immunohistology of Down syndrome and AD brain tissues, where they reveal fibrillar and diffuse amyloid deposits and are almost free of non-specific staining. The data indicate that diffuse amyloid deposits contain only minute amounts of Aβ40 . Thus these rabbit monoclonal anti-Aβ antibodies can be widely applied in AD and Down syndrome research and diagnosis. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, anti-Aβ antibodies, ELISA, immunohistology, peptide-antibody dissociation constants, rabbit monoclonal antibodies

DOI: 10.3233/JAD-2010-101341

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 293-305, 2011

Authors: Sierra, Saleta | Ramos, Maria C. | Molina, Pilar | Esteo, Cynthia | Vázquez, Jose Antonio | Burgos, Javier S.

Article Type: Research Article

Abstract: There is growing evidence to support the hypothesis that statins may act as neuroprotectants in several neuropathological conditions, including Alzheimer's disease. The mechanisms for neuroprotection are only partially understood, however, and pleiotropic phenomena could be involved. We have made a comparative study of 9 statins (lovastatin, mevastatin, pravastatin, simvastatin, cerivastatin, atorvastatin, fluvastatin, pitavastatin, and rosuvastatin), analyzing several parameters that could be related to neuroprotection, such as chemical structure, lipophilicity, potential blood-brain-barrier penetration (BBB), 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibition, cholesterol modulation in neurons, glia, and human hepatocyte cell lines, and protection against neurodegeneration caused by tau hyperphosphorylation induced by okadaic acid. …Our results indicate that monacolin J derivatives (natural and semi-synthetic statins) are the best candidates for the prevention of neurodegenerative conditions due to their higher potential BBB penetration capacity, cholesterol lowering effect on neurons with a satisfactory safety profile, and in vitro protection against cell death caused by okadaic acid in culture. Among the nine statins studied, simvastatin presented the best characteristics for preventing neurodegenerative conditions. Show more

Keywords: Blood brain barrier, cholesterol, HMG-CoA reductase, in vitro, neuroprotection, okadaic acid, statins

DOI: 10.3233/JAD-2010-101179

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 307-318, 2011

Authors: Rami, Lorena | Fortea, Juan | Bosch, Beatriz | Solé-Padullés, Cristina | Lladó, Albert | Iranzo, Alex | Sánchez-Valle, Raquel | Molinuevo, Jose Luis

Article Type: Research Article

Abstract: The objective was to study the association between cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)1-42 , t-tau, and p-tau and cognitive performance along the Alzheimer's disease (AD) continuum from healthy subjects to AD patients and, specifically, among patients in the pre-dementia stage of the disease. A total of 101 subjects were studied: 19 healthy controls (CTR), 17 subjects with subjective memory complaints (SMC), 47 with mild cognitive impairment (MCI), and 18 AD patients. Only memory performance significantly correlated with CSF levels of Aβ1-42 , t-tau, and p-tau along the AD continuum. Subgroup analyses revealed that in SMC patients Aβ1-42 …levels positively correlated with the total recall score of the Free and Cued Selective Reminding Test (FCRST) (r = 0.666; p < 0.005), Digit Span (r = 0.752; p < 0.005), and CERAD world list learning (r = 0.697; p < 0.005). In MCI patients, a significant inverse correlation was found between the word list recall score from the CERAD and t-tau (r = −0.483; p < 0.005) and p-tau levels (r = −0.495; p < 0.005), as well as between the total recall subtest score from the FCRST and both t-tau (r = −0.420; p < 0.005) and p-tau levels (r = −0.422; p < 0.005). No significant correlations were found between other aspects of cognition and CSF levels in CTR or AD patients. These results indicate that memory performance is related to Aβ1-42 levels in SMC, while it is associated with tau in the prodromal stage of the disease. This suggests that in the continuum from healthy aging to AD, memory performance is first related with Aβ1-42 levels and then with t-tau or p-tau, before becoming independent of biomarker levels in the dementia stage. Show more

Keywords: Alzheimer's disease, amyloid, cerebrospinal fluid, cognition, neuropsychological tests

DOI: 10.3233/JAD-2010-101422

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 319-326, 2011

Authors: Reif, Andreas | Grünblatt, Edna | Herterich, Sabine | Wichart, Ildiko | Rainer, Michael K. | Jungwirth, Susanne | Danielczyk, Walter | Deckert, Jürgen | Tragl, Karl-Heinz | Riederer, Peter | Fischer, Peter

Article Type: Research Article

Abstract: NO synthase, type I (NOS-I) has been suggested to play a role in the etiology of Alzheimer's disease (AD). The gene encoding NOS-I harbors at least nine alternative first exons; in the promoter region of exon 1f, a polymorphic repeat (NOS1 ex1f-VNTR) has been described which influences gene expression and neuronal transcriptome. We have shown that short alleles of this repeat are associated with AD. Here, we sought to further explore this finding by investigating a longitudinal cohort sample from the Vienna-Transdanube-Aging (VITA) study consisting of 606 subjects enrolled at the age of 75 (of these, genotypes were available for …574 subjects) and followed up for 60 months. The ex1f-VNTR risk genotype was associated with AD in the total sample and at the second follow-up. Thus, either long alleles of NOS1 ex1f-VNTR are protective against disease or conversely, short alleles predispose to earlier onset of disease. As demonstrated, ex1f-VNTR interacted with the apolipoprotein E ε4 risk allele (OR in the presence of both risk alleles 3.63; 95% CI: 1.45–9.12). These findings provide further evidence for an association of NOS1 with AD. Show more

Keywords: Alzheimer's disease, genetics, neuronal nitric oxide synthase (NOS1), polymorphism, risk factor, VITA study

DOI: 10.3233/JAD-2010-101491

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 327-333, 2011

Authors: Lilja, Anna M. | Porras, Omar | Storelli, Elisa | Nordberg, Agneta | Marutle, Amelia

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptides in the brain of patients with Alzheimer's disease (AD) assemble into various aggregation forms that differ in size, structure, and functional properties. Previous studies have shown that Aβ binds to nicotinic acetylcholine receptors (nAChRs) and activates signaling cascades that result in the disruption of synaptic functions. These findings suggest a possible link between impaired cholinergic neurotransmitter function in AD and Aβ pathogenesis. However, it is not yet known how the different Aβ assemblies interact with specific nAChR subtypes. In the present study, we demonstrate that neurotoxicity in neuronal cells in culture induced by fibrillar Aβ1-40 is …prevented through an α7 nAChR-dependent mechanism. The α7 nAChR agonists varenicline and JN403 increased binding of the amyloid ligand [3 H]PIB to fibrillar Aβ in AD frontal cortex autopsy tissue. This suggests that the presence of nAChR agonists may inhibit interaction of Aβ with α7 nAChRs and prevent the formation of Aβ/α7 nAChR complexes. This interaction was confirmed in binding assays with [125 I]Aβ1-40 and α7 nAChRs in autopsy brain tissue homogenates from the frontal cortex. The functional effects of Aβ fibrils and oligomers on nAChRs were examined by measuring intracellular calcium ([Ca2+ ]i levels. Oligomeric, but not fibrillar Aβ1-40 , increased [Ca2+ ]\i in neuronal cells, and this effect was attenuated by varenicline. Our findings demonstrate that fibrillar Aβ exerts neurotoxic effects mediated partly through a blockade of α7 nAChRs, whilst oligomeric Aβ may act as a ligand activating α7 nAChRs, thereby stimulating downstream signaling pathways. Show more

Keywords: Alzheimer's disease, amyloid-β fibrils, amyloid-β oligomers, nicotinic acetylcholine receptors

DOI: 10.3233/JAD-2010-101242

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 335-347, 2011

Authors: Sherva, Richard | Baldwin, Clinton T. | Inzelberg, Rivka | Vardarajan, Badri | Cupples, L. Adrienne | Lunetta, Kathryn | Bowirrat, Abdalla | Naj, Adam | Pericak-Vance, Margaret | Friedland, Robert P. | Farrer, Lindsay A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is highly prevalent in Wadi Ara despite the low frequency of apolipoprotein E ε4 in this genetically isolated Arab community in northern Israel. We hypothesized that the reduced genetic variability in combination with increased homozygosity would facilitate identification of genetic variants that contribute to the high rate of AD in this community. AD cases (n = 124) and controls (n = 142) from Wadi Ara were genotyped for a genome-wide set of more than 300,000 single nucleotides polymorphisms (SNPs) which were used to calculate measures of population stratification and inbreeding, and to identify regions of autozygosity. Although …a high degree of relatedness was evident in both AD cases and controls, controls were significantly more related and contained more autozygous regions than AD cases (p = 0.004). Eight autozygous regions on seven different chromosomes were more frequent in controls than the AD cases, and 116 SNPs in these regions, primarily on chromosomes 2, 6, and 9, were nominally associated with AD. The association with rs3130283 in AGPAT1 on chromosome 6 was observed in a meta-analysis of seven genome-wide association study (GWAS) datasets. Analysis of the full Wadi Ara GWAS dataset revealed 220 SNP associations with AD at p ≤ 10 −5 , and seven of these were confirmed in the replication GWAS datasets (p < 0.05). The unique population structure of Wadi Ara enhanced efforts to identify genetic variants that might partially explain the high prevalence of AD in the region. Several of these variants show modest evidence for association in other Caucasian populations. Show more

Keywords: Alzheimer's disease, genome-wide association study, meta-analysis, population groups

DOI: 10.3233/JAD-2010-100714

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 349-359, 2011

Authors: Eriksson, Ulrika K. | Pedersen, Nancy L. | Reynolds, Chandra A. | Hong, Mun-Gwan | Prince, Jonathan A. | Gatz, Margaret | Dickman, Paul W. | Bennet, Anna M.

Article Type: Research Article

Abstract: Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and dementia. We therefore sought to study DNA sequence variation and serum levels of the potent inflammatory mediators Interleukin-6 (IL6) and C-reactive protein (CRP) in relation to AD and dementia. Tagging single nucleotide polymorphisms (tagSNPs) were chosen to capture most variation in and around CRP and IL6 in 3937 elderly Swedish men and women (1,265 AD cases). A sub-set of the population (n = 723) with serum measurements of CRP and IL6 was included in 1) a nested case-control study of incident dementia cases, and 2) a case-control study of prevalent …dementia cases. None of the SNPs or haplotypes was significantly associated with AD or dementia after correcting for multiple testing nor were elevated baseline levels of hsCRP or IL6 (measured on average 4.3 years before dementia onset) significantly associated with risk of future AD or dementia. However, prevalent AD cases had higher levels of IL6 (measured on average 5.5 years after dementia onset) than age- and gender-matched controls, OR 2.24 (95% CI 1.27–3.95), p-value 0.006. In summary, this data suggests that AD patients have an altered immune profile with higher circulating levels of IL6 than age- and gender-matched controls. However, neither variation in the CRP and IL6 genes nor circulating levels of their respective protein products were associated with an increased risk of developing late-life dementias. Show more

Keywords: Alzheimer's disease, dementia, inflammation, interleukin-6, C-reactive protein, biological markers, candidate gene analysis, matched case-control studies, nested case-control studies

DOI: 10.3233/JAD-2010-101671

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 361-369, 2011

Article Type: Other

DOI: 10.3233/JAD-2010-100895

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 371-373, 2011