Caspase-1 genetic variation is not associated with Alzheimer's disease risk.

BACKGROUND: Interleukin (IL)-1beta is a potent proinflammatory cytokine markedly overexpressed in the brains of patients with Alzheimer's disease (AD), and also involved in development of atherosclerosis and coronary artery disease. Caspase-1 (CASP1), formerly called IL-1beta converting enzyme (ICE), mediates the cleavage of the inactive precursor of IL-1beta into the biologically active form. CASP1 genetic variation (G+7/in6A, rs501192) has been associated with susceptibility to myocardial infarction and cardiovascular death risk. We examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of CASP1 by genotyping haplotype tagging SNPs (htSNPs) (rs501192, rs556205 and rs530537) in a group of 628 Spanish AD cases and 722 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by age, gender or APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that CASP1 genetic variations are causally related to AD risk.

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk.

Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.

DYRK1A genetic variants are not linked to Alzheimer's disease in a Spanish case-control cohort.

BACKGROUND: As dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of DYRK1A by genotyping haplotype tagging SNPs (htSNPs) (rs11701483, rs2835740, rs1137600, rs2835761, rs2835762, rs2154545 and rs8132976) in a group of 634 Spanish AD cases and 733 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that DYRK1A genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between DYRK1A gene and AD risk in the Japanese population exists.

Presenilin 1 polymorphism associated with Alzheimer's disease in apolipoprotein E4 carriers.

Mutations of presenilin 1 (PSEN1) are associated with monogenic Alzheimer's disease (AD); polymorphisms at this gene may therefore be associated with the sporadic form of the disease. In fact, recent meta-analyses and whole-genome association studies indicate PSEN1 as one of the few genes significantly associated with AD risk. Several polymorphisms have been analyzed in PSEN1. The present work examined the possible modulation of the risk of AD by a PSEN1 polymorphism (dbSNP rs3025786) located in intron 7, which we found during a denaturing gradient gel electrophoresis mutation screening of the gene, and which was previously reported as 'suspected' in the public databases. The study of a Spanish case-control sample of 1,183 individuals showed this polymorphism to be associated with AD in an apolipoprotein E (APOE)-specific manner: more specifically, to carry the PSEN1 C allele was associated with a decreased AD risk among carriers of the APOE4 allele. Thus, the present results reinforce the possible involvement of PSEN1 in sporadic AD.

Vascular biomarkers and ApoE4 expression in mild cognitive impairment and Alzheimer's disease.

Vascular pathology and genetic markers such as apolipoprotein E allele ε4 (ApoE ε4) are risk factors for the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). In Panama, a high prevalence of vascular risk factors and an increase in the aging population, generate the need to investigate biomarkers using specific, sensitive, non-invasive and cost-efficient methods that could be used in primary care. The main objective of this study was to explore the association between vascular biomarkers such as intima-media thickness (IMT) and stenosis, ApoΕ Îµ4 and cognitive function in a sample of older adults, including healthy controls (n = 41), MCI (n = 33), and AD (n = 12). A descriptive and cross-sectional study was conducted. Participants were part of the Panama Aging Research Initiative (PARI), the first prospective study in aging in Panama. Assessments included a neuropsychological battery, ApoΕ Îµ4 genotyping and a Doppler ultrasound of the left carotid artery to examine the presence of vascular risk factors. Neuropsychological tests were combined to form six cognitive domains: Global cognition, language, visuospatial abilities, learning and memory, attention and executive functions. Multivariable analyses (using age, education, and ApoE ε4 expression as covariates) were conducted. Participants with increased IMT showed poorer performance in memory and those with carotid stenosis showed poorer performance in language, visuospatial abilities and attention, independent of age, education or ApoΕ Îµ4 expression. The results support the use of vascular markers in cognitive assessments of aged individuals.

Effectiveness and limitations of an incident-reporting system analyzed by local clinical safety leaders in a tertiary hospital: Prospective evaluation through real-time observations of patient safety incidents.

The effectiveness of a hospital incident-reporting system (IRS) on improve patient safety is unclear. This study objective was to assess which implemented improvement actions after the analysis of the incidents reported were effective in reduce near-misses or adverse events.Patient safety incidents (PSIs), near misses and adverse events, notified to the IRS were analyzed by local clinical safety leaders (CSLs) who propose and implement improvement actions. The local CSLs received training workshops in patient safety and analysis tools. Following the notification of a PSI in the IRS, prospective real-time observations with external staff were planned to record and rated the frequency of that PSI. This methodology was repeated after the implementation of the improvement actions.Ultimately, 1983 PSIs were identified. Surgery theaters, emergency departments, intensive care units, and general adult care units comprised 82% of all PSIs. The PSI rate increased from 0.39 to 3.4 per 1000 stays in 42 months. A significant correlation was found between the reporting rate per month and the number of workshop-trained local CSLs (Spearman coefficient = 0.874; P = .003). A total of 24,836 real-time observations showed a statistically significant reduction in PSIs observed in 63.15% (categories: medication P = .044; communication P = .037; technology P = .009) of the implemented improvements actions, but not in the organization category (P = .094). In the multivariate analyses, the following factors were associated with the reduction in near misses or adverse events after the implementation of the improvement actions: "adverse event" type of PSI (odds ratio [OR], 3.67; 95% confidence interval [CI], 1.93-5.74), "disussion group" type of analysis (OR, 2.45; 95% CI, 1.52-3.76), and root cause type of analysis (OR, 2.32; 95% CI: 1.17-3.90).The implementation of a hospital IRS, together with the systematization of the method and analysis of PSIs by workshop-trained local CSLs led to an important reduction in the frequency of PSIs.

Mortalidade infantil em crianças menores de um ano na região noroeste do estado do Paraná / Child mortality in children under one year of age in the northwest region of the state of Paraná

A mortalidade infantil é considerada um fator relevante para avaliar condições de saúde de uma população, uma temática bem esclarecida na literatura, no entanto, carece de informações sobre a causalidade em localidades específicas. Logo, a pesquisa tem por objetivo analisar a taxa e as causas de mortalidade infantil em alguns municípios da 12a Regional de Saúde do Paraná, no período de 2015 a 2019. Trata-se de um estudo de caráter epidemiológico, transversal realizado na plataforma digital DATASUS. A amostra foi constituída por 191 óbitos, dos quais, a média da taxa de mortalidade infantil entre os anos variou de 14,92 a 26,98/mil nascidos vivos. A causa mais frequente foi identificada como afecções originadas no período perinatal (72,0%), que teve associação significativa pelo teste Wilcoxon/Mann-Whiney quando comparada a causa de anomalias congênitas (21,9%). A qualidade da assistência ofertada durante o pré-natal e puerpério pode ter relação com a causa encontrada, o que intriga na avaliação de programas e projetos na regional em questão

Infant mortality is considered a relevant factor to assess the health conditions of a population. A well-understood theme in the literature, however, lacking information on causality in specific locations. Therefore, the research aims to analyze the rate and causes of infant mortality in some municipalities of the 12th Health Regional of Paraná, from 2015 to 2019. This is an epidemiological, cross-sectional and quantitative study, carried out on the DATASUS digital platform. The sample consisted of 191 deaths, of which the average infant mortality rate between the years ranged from 14.92 to 26.98/ thousand live births. The most frequent cause was identified as conditions originated during the perinatal period (72.0%), which had a significant association by the Wilcoxon/Man-Whiney test when compared to the cause of congenital anomalies (21,9%). The quality of the care offered during prenatal and postpartum periods may be related to the cause found, which intrigues the evaluation of programs and projects in the region in question.

Association of DSC1, a gene modulated by adrenergic stimulation, with Alzheimer's disease.

Alzheimer's disease (AD) is a complex multifactorial disorder involving a number of genetic and environmental factors, with severe head injury consistently reported as a major non-genetic risk factor. The adrenergic activation that occurs during major trauma increases cAMP levels, therefore the cAMP signaling pathway might be involved in AD pathogenesis. Time course of candidate gene expression following adrenergic stimulation with isoproterenol was assayed in neuroblastoma cells by quantitative reverse transcription (RT)-PCR. Then, genetic association studies of polymorphisms in several of these candidate genes were performed. Association studies in two independent case-control samples showed a polymorphism in DSC1, encoding desmocollin 1--a member of the desmosomal cadherins--which modulated AD susceptibility in a gender-specific manner. These results are in accordance with the potential involvement of the adrenergic signaling pathway in AD pathogenesis.

Diagnostic accuracy of the Eurotest for dementia: a naturalistic, multicenter phase II study.

BACKGROUND: Available screening tests for dementia are of limited usefulness because they are influenced by the patient's culture and educational level. The Eurotest, an instrument based on the knowledge and handling of money, was designed to overcome these limitations. The objective of this study was to evaluate the diagnostic accuracy of the Eurotest in identifying dementia in customary clinical practice. METHODS: A cross-sectional, multi-center, naturalistic phase II study was conducted. The Eurotest was administered to consecutive patients, older than 60 years, in general neurology clinics. The patients' condition was classified as dementia or no dementia according to DSM-IV diagnostic criteria. We calculated sensitivity (Sn), specificity (Sp) and area under the ROC curves (aROC) with 95% confidence intervals. The influence of social and educational factors on scores was evaluated with multiple linear regression analysis, and the influence of these factors on diagnostic accuracy was evaluated with logistic regression. RESULTS: Sixteen neurologists recruited a total of 516 participants: 101 with dementia, 380 without dementia, and 35 who were excluded. Of the 481 participants who took the Eurotest, 38.7% were totally or functionally illiterate and 45.5% had received no formal education. Mean time needed to administer the test was 8.2+/-2.0 minutes. The best cut-off point was 20/21, with Sn = 0.91 (0.84-0.96), Sp = 0.82 (0.77-0.85), and aROC = 0.93 (0.91-0.95). Neither the scores on the Eurotest nor its diagnostic accuracy were influenced by social or educational factors. CONCLUSION: This naturalistic and pragmatic study shows that the Eurotest is a rapid, simple and useful screening instrument, which is free from educational influences, and has appropriate internal and external validity.

The partial volume effect in the quantification of 1H magnetic resonance spectroscopy in Alzheimer's disease and aging.

1H-MRS variability increases due to normal aging and also as a result of atrophy in grey and white matter caused by neurodegeneration. In this work, an automatic process was developed to integrate data from spectra and high-resolution anatomical images to quantify metabolites, taking into account tissue partial volumes within the voxel of interest avoiding additional spectra acquisitions required for partial volume correction. To evaluate this method, we use a cohort of 135 subjects (47 male and 88 female, aged between 57 and 99 years) classified into 4 groups: 38 healthy participants, 20 amnesic mild cognitive impairment patients, 22 multi-domain mild cognitive impairment patients, and 55 Alzheimer's disease patients. Our findings suggest that knowing the voxel composition of white and grey matter and cerebrospinal fluid is necessary to avoid partial volume variations in a single-voxel study and to decrease part of the variability found in metabolites quantification, particularly in those studies involving elder patients and neurodegenerative diseases. The proposed method facilitates the use of 1H-MRS techniques in statistical studies in Alzheimer's disease, because it provides more accurate quantitative measurements, reduces the inter-subject variability, and improves statistical results when performing group comparisons.

Completude das cadernetas de gestantes: realidade da região noroeste do Paraná / Completeness of the booklets of pregnant women: reality of the northwest region of Paraná / Completud de las cadernetas de gestantes: realidad de La región noroeste del Paraná

Objetivo: Este estudo tem por objetivo avaliar a completude do preenchimento das carteiras de gestante, verificando o preenchimento das informações por parte da equipe de saúde. Método: Trata-se de uma pesquisa de campo baseada em documentos de natureza quali-quantitativa, realizada em uma Maternidade da região noroeste do Paraná. Resultados: Realizou-se uma análise nos registros de perfil, antecedentes obstétricos, exame físico, consultas e exames. Os registros incompletos e a ausência de preenchimento das informações relevantes à saúde demonstra que existem falhas na assistência oferecida, bem como que o atendimento a gestante não está sendo integralizado e condizente com as recomendações vigentes. Conclusão: Evidencia-se que a carência de informações nas cadernetas de gestante interfere significativamente no desfecho final do processo gestacional e no resultado de toda assistência, sendo fundamental que os profissionais de saúde, estejam em conhecimento da real situação para que possam melhorar a qualidade de atendimento ofertada (AU)

Objective: This study aims to evaluate the completeness of completing the pregnant woman's portfolios, verifying the completeness of the information by the health team. Method: This is a field research based on qualitative and quantitative documents, carried out in a Maternity from northwestern Paraná. Results: An analysis was performed in the profile records, obstetric history, physical examination, consultations and examinations. Incomplete records and the lack of completeness of information relevant to health demonstrates that there are failures in the care offered, as well as that care for pregnant women is not being paid and consistent with current recommendations. Conclusion: It is evident that the lack of information on pregnant woman's handbooks interferes significantly in the final outcome of the gestational process and in the outcome of all care, being essential that health professionals are aware of the real situation so that they can improve the quality of care service offered (AU)

Objetivo: Este estudio tiene como objetivo evaluar la integridad de completar las carteras de la mujer embarazada, verificando la integridad de la información por parte del equipo de salud. Método: Esta es una investigación de campo basada en documentos cualitativos y cuantitativos, realizada en una Maternidad del noroeste de Paraná. Resultados: se realizó un análisis en los registros de perfil, antecedentes obstétricos, examen físico, consultas y exámenes. Los registros incompletos y la falta de integridad de la información relevante para la salud demuestra que hay fallas en la atención ofrecida, así como que la atención a las mujeres embarazadas no se paga y es consistente con las recomendaciones actuales. Conclusión: se evidencia que la falta de información en los manuales de las mujeres embarazadas interfiere significativamente en el resultado final del proceso gestacional y en el resultado de toda la atención servicio ofrecido (AU)

Machine learning and social network analysis applied to Alzheimer's disease biomarkers.

Due to the fact that the number of deaths due Alzheimer is increasing, the scientists have a strong interest in early stage diagnostic of this disease. Alzheimer's patients show different kind of brain alterations, such as morphological, biochemical, functional, etc. Currently, using magnetic resonance imaging techniques is possible to obtain a huge amount of biomarkers; being difficult to appraise which of them can explain more properly how the pathology evolves instead of the normal ageing. Machine Learning methods facilitate an efficient analysis of complex data and can be used to discover which biomarkers are more informative. Moreover, automatic models can learn from historical data to suggest the diagnostic of new patients. Social Network Analysis (SNA) views social relationships in terms of network theory consisting of nodes and connections. The resulting graph-based structures are often very complex; there can be many kinds of connections between the nodes. SNA has emerged as a key technique in modern sociology. It has also gained a significant following in medicine, anthropology, biology, information science, etc., and has become a popular topic of speculation and study. This paper presents a review of machine learning and SNA techniques and then, a new approach to analyze the magnetic resonance imaging biomarkers with these techniques, obtaining relevant relationships that can explain the different phenotypes in dementia, in particular, different stages of Alzheimer's disease.

Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimer's disease patients alter calcium homeostasis.

Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca(2+) influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+) influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.

The effects of different attentional demands in the identification of emotional facial expressions in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the progressive impairment of mental and emotional functions, including the processing of emotional facial expression (EFE). Deficits in decoding EFE are relevant in social contexts in which information from 2 or more sources may be processed simultaneously. To assess the role of contextual stimuli on EFE processing in AD, we analyzed the ability of patients with AD and healthy elderly adults to identify EFE when simultaneously performing another task. Each of the 6 basic EFEs was presented to 15 patients with AD and 35 controls in a dual task paradigm that is in parallel with a visuospatial or a semantic task. Results show that the decoding of EFEs was impaired in patients with AD when they were simultaneously processing additional visuospatial information, yet not when they were performed in conjunction with a semantic task. These findings suggest that the capacity to interpret emotional states is impaired in AD.

Decline of executive processes affects identification of emotional facial expression in aging.

The current study examined the hypothesis that old people have a selective deficit in the identification of emotional facial expressions (EFEs) when the task conditions require the mechanism of the central executive. We have used a Dual Task (DT) paradigm to assess the role of visuo-spatial interference of working memory when processing emotional faces under two conditions: DT at encoding and DT at retrieval. Previous studies have revealed a loss of the ability to identify specific emotional facial expressions (EFEs) in old age. This has been consistently associated with a decline of the ability to coordinate the performance of two tasks concurrently. Working memory is usually tested using DT paradigms. Regarding to aging, there is evidence that with DT performance during encoding the costs are substantial. In contrast, the introduction of a secondary task after the primary task (i.e. at retrieval), had less detrimental effects on primary task performance in either younger or older adults. Our results demonstrate that aging is associated with higher DT costs when EFEs are identified concurrently with a visuo-spatial task. In contrast, there was not a significant age-related decline when the two tasks were presented sequentially. This suggests a deficit of the central executive rather than visuo-spatial memory deficits. The current data provide further support for the hypothesis that emotional processing is "top-down" controlled, and suggest that the deficits in emotional processing of old people depend, above all, on specific cognitive impairment.

Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.

Neurofibrillary tangles, one of the characteristic neuropathological lesions found in Alzheimer's disease (AD) brains, are composed of abnormally hyperphosphorylated tau protein. Tau-tubulin kinase-1 (TTBK1) is a brain-specific protein kinase involved in tau phosphorylation at AD-related sites. We examined genetic variations of TTBK1 by genotyping nine haplotype tagging SNPs (htSNPs) (rs2104142, rs2651206, rs10807287, rs7764257, rs3800294, rs1995300, rs2756173, rs6936397, and rs6458330) in a group of 645 Spanish late-onset AD patients and 738 healthy controls. Using a recessive genetic model, minor allele homozygotes for rs2651206 in intron 1 (OR=0.50, p=0.0003), rs10807287 in intron 5 (OR=0.49, p=0.0002), and rs7764257 in intron 9 (OR=0.57, p=0.023), which are in strong linkage disequilibrium, had a lower risk of developing AD than subjects homozygotes and heterozygotes for the major allele. TTBK1 is a promising new candidate tau phosphorylation-related gene for AD risk.

IGF-I gene variability is associated with an increased risk for AD.

Insulin-like growth factor I (IGF-I), a neuroprotective factor with a wide spectrum of actions in the adult brain, is involved in the pathogenesis of Alzheimer's disease (AD). Circulating levels of IGF-I change in AD patients and are implicated in the clearance of brain amyloid beta (Aß) complexes. To investigate this hypothesis, we screened the IGF-I gene for various well known single nucleotide polymorphisms (SNPs) covering % of the gene variability in a population of 2352 individuals. Genetic analysis indicated different distribution of genotypes of 1 single nucleotide polymorphism, and 1 extended haplotype in the AD population compared with healthy control subjects. In particular, the frequency of rs972936 GG genotype was significantly greater in AD patients than in control subjects (63% vs. 55%). The rs972936 GG genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype, and with enhanced circulating levels of IGF-I. These findings suggest that polymorphisms within the IGF-I gene could infer greater risk for AD through their effect on IGF-I levels, and confirm the physiological role IGF-I in the pathogenesis of AD.

Prospective one-year cost-of-illness study in a cohort of patients with dementia of Alzheimer's disease type in Spain: the ECO study.

In this study, we analyzed the economic impact of one-year healthcare and non-healthcare resources utilization by patients with dementia of Alzheimer's disease (AD) under usual medical practice in Spain. A one-year, prospective, naturalistic, multicenter cohort study was designed to recruit patients with mild, moderate to severe, and severe AD according to Clinical Dementia Rating scale: the ECO study. Healthcare resources (medical visits, drugs and concomitant treatments, complementary and diagnostic tests, institutionalization and use of home-nursing facilities) and non-healthcare resources (inventory materials, consumables, professional and non-professional caregivers' time for care and supervision) were recorded and valued at 2006 prices. A total of 560 patients with possible/probable AD by DSM-IV-NINCDS-ADRDA criteria were included in the study: 68% women, 77 +/- 6 years old, 29% treatment naïve. Monthly average cost per patient was 1,425.73 euro, and increased 10.08% at the end of the study (baseline monthly cost; 1,316.22 euro). Non-healthcare costs 1059.00 euro, 74.30% of total cost) decreased 4.30 euro/month (0.40%) at the end of the year, while healthcare costs, which presented a total average of 366.66 euro, grew by 136.94 euro in the period (54.06%), mainly due to cost of drugs, nursing home utilization, and institutionalization. The 87.26% of the overall cost (1,244.22 euro) was not financed by National Health Service (NHS), and the majority of this cost corresponded to caregiver-associated cost. The caregiver's total burden represented 70.86% of the overall cost-of-illness. In conclusion, monthly overall mean cost of dementia of AD type was high in Spain (1,412.73 euro). Almost 88% of the cost-of-illness is funded by the patient's own family, adding a financial burden to the suffering of these families.

Epistasis between intracellular cholesterol trafficking-related genes (NPC1 and ABCA1) and Alzheimer's disease risk.

Aberrant cholesterol metabolism has been implicated in Alzheimer's disease (AD). Recent findings have suggested an interaction of Niemann-Pick C1 (NPC1) and ATP-binding cassette transporter A1 (ABCA1) proteins in intracellular cholesterol transport and in maintaining cell cholesterol balance. Underexpression of NPC1 in concert with under-expression of ABCA1 would result in increased cholesterol accumulation and increased AD risk. We examined a functional polymorphism in the ABCA1 promoter region (-477, rs2422493), and four NPC1 polymorphisms in exon 6 (rs18050810), intron 20 (rs4800488), intron 22 (rs2236707), and intron 24 (rs2510344) capturing 85% of genetic variability in the Hap Map Caucasian (CEU) population, in a group of 631 Spanish AD patients and 731 controls. Subjects carrying both the ABCA1 (-477) TT genotype and the NPC1 (exon 6) GG genotype (OR=1.89; 95% CI 1.04-3.41), NPC1 (intron 20) AA genotype (OR=2.05; 95% CI 1.26-3.33), NPC1 (intron 22) AA genotype (OR=2.05; 95% or NPC1 (intron 24) GG genotype (OR=1.89; 95% higher risk of developing AD than subjects without these risk genotypes. Testing for epistatic interaction between genes in the pathway of cholesterol metabolism might be useful for predicting AD risk.

PLA2G3, a gene involved in oxidative stress induced death, is associated with Alzheimer's disease.

Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging, the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking such stress in AD brains, are therefore of great interest. PLA2G3 is the most overexpressed gene in a human neuronal model of oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system, which provokes apoptotic cell death. In this work, we describe that PLA2G3 gene silencing produced a marked inhibition of X-XOD induced cell death, and that PLA2G3 polymorphisms are associated with AD in a Spanish case-control sample. The capacity to respond to oxidative stress may therefore modulate the risk of AD, and PLA2G3 is a potential target to regulate neuronal damage induced by free radicals.