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

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