RESUMEN

Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S' 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo/genética , Depresión/genética , Polimorfismo de Nucleótido Simple , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Estrés Psicológico/genética , Adulto , Anciano , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/metabolismo , Depresión/psicología , Femenino , Genotipo , Fracturas de Cadera/metabolismo , Fracturas de Cadera/psicología , Humanos , Masculino , Persona de Mediana Edad , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/genética , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estrés Psicológico/metabolismo

RESUMEN

The apolipoprotein E (ApOE) ε4 allele is associated with neuropathological buildup of amyloid in the brain, and with lower performance on some laboratory measures of memory in some populations. In two studies, we tested whether ApOE genotype affects memory for everyday activities. In Study 1, participants aged 20-79 years old (n = 188) watched movies of actors engaged in daily activities and completed memory tests for the activities in the movies. In Study 2, cognitively healthy and demented older adults (n = 97) watched and remembered similar movies, and also underwent structural MRI scanning. All participants provided saliva samples for genetic analysis. In both samples we found that, in older adults, ApOE ε4 carriers demonstrated worse everyday memory performance than did ε4 noncarriers. In Study 2, ApOE ε4 carriers had smaller medial temporal lobes (MTL) volumes, and MTL volume mediated the relationship between ApOE genotype and everyday memory performance. These everyday memory tasks measure genetically determined cognitive decline that can occur prior to a clinical diagnosis of dementia. Further, these tasks are easily administered and may be a useful clinical tool in identifying ε4 carriers who may be at risk for MTL atrophy and further cognitive decline that is a common characteristic of the earliest stages of Alzheimer's disease.

Asunto(s)

Actividades Cotidianas , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Memoria Episódica , Adulto , Anciano , Enfermedad de Alzheimer/patología , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Lóbulo Temporal/patología , Adulto Joven

RESUMEN

OBJECTIVE: Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. METHODS: Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively). RESULTS: Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. CONCLUSION: Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care.

Asunto(s)

Antidepresivos/efectos adversos , Trastornos de Ansiedad/genética , Citalopram/efectos adversos , Polimorfismo Genético , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT2A/genética , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Anciano , Antidepresivos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Citalopram/sangre , Citalopram/uso terapéutico , Método Doble Ciego , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico

RESUMEN

Older adults are among the most vulnerable to adverse cognitive effects of psychotropic medications and, therefore, the personalization of psychotropic treatment based on adverse drug reactions in this demographic is of great importance. We examined changes on neuropsychological tests of attention attributable to selective serotonin reuptake inhibitor (SSRI) treatment in anxious older adults. We also examined whether variation in serotonin receptor genes was associated with reduced attentional performance with SSRIs. We examined change from pre- to post-treatment in two attention measures - digit span and coding - in 133 adults aged ≥60 yr with generalized anxiety disorder in a 12-wk trial of escitalopram vs. placebo. We also examined attentional change in relation to genetic variability in four central serotonin receptors: the serotonin transporter and serotonin 1A, 2A and 1B receptors. Digit span scores were significantly lowered in patients receiving escitalopram relative to placebo, indicating reduced attentional performance attributable to the SSRI. Individuals with high-transcription variants in the receptors 5-HTR2A rs6311 and 5-HTR1B rs11568817 had greater reductions in attention with SSRI treatment compared to placebo. We conclude that SSRIs reduce attention in older adults, particularly in those with high-expression genetic variants at the serotonin 2A and 1B receptors. Analysing neuropsychological changes with SSRIs in relation to genetic variation in the serotonin system may be a useful strategy for detecting subgroups of older adults who are more susceptible to side-effects of SSRIs. These results, if confirmed, could lead to the personalization of SSRI use to reduce adverse neurocognitive effects.

Asunto(s)

Ansiedad , Atención/efectos de los fármacos , Citalopram/efectos adversos , Polimorfismo de Nucleótido Simple/genética , Receptor de Serotonina 5-HT1B/genética , Receptor de Serotonina 5-HT2A/genética , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Anciano , Anciano de 80 o más Años , Ansiedad/tratamiento farmacológico , Ansiedad/genética , Ansiedad/fisiopatología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios Retrospectivos , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Factores de Tiempo

RESUMEN

Late onset Alzheimer's disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.

Asunto(s)

Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Transportadoras de Casetes de Unión a ATP/genética , Edad de Inicio , Anciano de 80 o más Años , Estudios de Casos y Controles , Clusterina/genética , Femenino , Humanos , Inmunidad/genética , Masculino , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados , Factores de Riesgo , Sinapsis/genética , Sinapsis/patología

RESUMEN

The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aß(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aß(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aß(42) levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10(-13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ε4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10(-6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10(-9)).

Asunto(s)

Enfermedad de Alzheimer/genética , Apolipoproteínas E/líquido cefalorraquídeo , Apolipoproteínas E/genética , Fenotipo , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

BACKGROUND: Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene. OBJECTIVE: To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset. DESIGN: We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue. SETTING: Alzheimer's Disease Research Center. PARTICIPANTS: Research volunteers who were cognitively normal or had Alzheimer disease. MAIN OUTCOME MEASURES: Disease status and age at onset. RESULTS: We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or ß-amyloid 42 levels or TOMM40 or APOE gene expression. CONCLUSIONS: Although we did not replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.

Asunto(s)

Enfermedad de Alzheimer/genética , Apolipoproteína E3/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Transporte de Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo/métodos , Haplotipos/genética , Homocigoto , Humanos , Masculino , Proteínas de Transporte de Membrana/deficiencia , Persona de Mediana Edad , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Poli T/genética

RESUMEN

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Proteínas del Citoesqueleto/genética , Proteínas de la Membrana/genética , Receptor EphA1/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Familia de Multigenes , Polimorfismo de Nucleótido Simple , Lectina 3 Similar a Ig de Unión al Ácido Siálico

RESUMEN

BACKGROUND: Generalized anxiety disorder (GAD) is a common disorder in older adults, which has been linked to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this age group. The authors examined whether treatment of GAD in older adults with a selective serotonin reuptake inhibitor (SSRI) corrects this HPA axis hyperactivity. METHODS: The authors examined adults aged 60 years and older with GAD in a 12-week randomized controlled trial comparing the SSRI escitalopram with placebo. The authors collected salivary cortisol at six daily time points for 2 consecutive days to assess peak and total (area under the curve) cortisol, both at baseline and posttreatment. RESULTS: Compared with placebo-treated patients, SSRI-treated patients had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to patients with elevated (above the median) baseline cortisol, in whom SSRI-treated patients showed substantially greater reduction in cortisol than did placebo-treated patients. Reductions in cortisol were associated with improvements in anxiety. Additionally, genetic variability at the serotonin transporter promoter predicted cortisol changes. CONCLUSIONS: SSRI treatment of GAD in older adults reduces HPA axis hyperactivity. Further research should determine whether these treatment-attributable changes are sustained and beneficial.

Asunto(s)

Trastornos de Ansiedad/tratamiento farmacológico , Citalopram/uso terapéutico , Hidrocortisona/análisis , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Anciano , Anciano de 80 o más Años , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/psicología , Citalopram/farmacología , Femenino , Genotipo , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/fisiopatología , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Saliva/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Resultado del Tratamiento

RESUMEN

OBJECTIVE: Generalized anxiety disorder (GAD) is common in older adults and can be treated with selective serotonin reuptake inhibitors (SSRIs). Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy: 2 polymorphisms (5-HTTLPR S/L and rs25531 g/a) form a haplotype with the La combination having higher transcription activity than other haplotypes. We hypothesized that GAD patients with no La haplotypes (La⁻) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes (La+). METHOD: The study enrolled subjects aged 60 years or older with a principal diagnosis of GAD into a 12-week, randomized trial of escitalopram versus placebo. One hundred fifty subjects were genotyped for the serotonin transporter promoter region haplotype and were divided into La⁻ and La+ genotype groups; the primary analyses were done in European Americans only (n = 125; n = 59 with escitalopram and n = 66 with placebo). RESULTS: Escitalopram had no efficacy in the La⁻ group versus moderate efficacy in the La+ group. This genetic moderation of SSRI efficacy was due to a higher placebo response in La⁻ subjects, compared with La+ subjects. Drug concentration did not affect the genetic results. Exploratory analyses suggest that La⁻ subjects had greater variability of anxiety symptoms unrelated to treatment. CONCLUSIONS: The serotonin transporter promoter haplotype is associated with variability in SSRI efficacy for late-life GAD. The variability may result from a genetic effect on anxiety symptom variability unrelated to treatment, rather than a pharmacodynamic effect that has been previously assumed. Further research is needed to understand the pharmacogenetic mechanism of this haplotype.

Asunto(s)

Trastornos de Ansiedad/tratamiento farmacológico , Citalopram/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Resultado del Tratamiento

RESUMEN

Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aß(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aß(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.

Asunto(s)

Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Fosfoproteínas/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Proteínas tau/líquido cefalorraquídeo , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Calcineurina/genética , Calcineurina/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/metabolismo , Fosfoproteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factores de Riesgo , Análisis de Supervivencia , Washingtón/epidemiología , Proteínas tau/metabolismo

RESUMEN

Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-ß (Aß) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aß or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aß42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aß42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aß levels in vitro and provides support for an Aß-related mechanism for modulating risk for Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Proteínas Adaptadoras Transductoras de Señales/genética , Anciano , Anciano de 80 o más Años , Alelos , Análisis de Varianza , Biomarcadores/líquido cefalorraquídeo , Canales de Calcio/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Fosforilación , Polimorfismo de Nucleótido Simple

RESUMEN

There is substantial evidence that cerebrospinal fluid (CSF) levels of both Abeta42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Abeta and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Abeta42 levels were used to stratify the sample into those with and without likely Abeta deposition in the brain the association was only observed in individuals with evidence of Abeta deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Abeta deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (Abeta deposition) interaction that places changes in CSF tau after Abeta deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.

Asunto(s)

Péptidos beta-Amiloides/metabolismo , Polimorfismo de Nucleótido Simple/genética , Proteínas tau/líquido cefalorraquídeo , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Regulación de la Expresión Génica , Haplotipos , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Supervivencia , Proteínas tau/genética

RESUMEN

Alzheimer's disease (AD) pathology is associated with two proteins, the microtubule-binding protein tau and the beta-amyloid-precursor protein (APP). When tau becomes hyperphosphorylated, it forms neuritic aggregates, called neurofibrillary tangles. APP is cleaved by several enzymes to generate Abeta peptides, which are - depending on their length - more or less amyloidogenic and form senile plaques. Pin1, a peptidyl-propyl cis/trans-isomerase, seems to be involved in both pathologies. Pin1 may facilitate dephosphorylation of tau by PP2A phosphatase, while cellular overexpression of Pin1 causes a reduction in the amyloidogenic processing of APP, making this enzyme an interesting target for pharmaceutical intervention. The gene encoding Pin1 maps to 19p13.2, a region previously linked to late-onset Alzheimer's disease (LOAD). Therefore, Pin1 is an excellent positional and functional candidate for LOAD. In this study, we investigated whether common single nucleotide polymorphisms (SNPs) in Pin1 can influence the risk for developing late-onset Alzheimer's disease. No association was observed with any of six polymorphisms or their resulting haplotypes. A meta-analysis of two promoter SNPs, which combined the data from this study with two previous ones, did not show any association either suggesting that common SNPs in Pin1 do not increase the risk for LOAD.

Asunto(s)

Enfermedad de Alzheimer/genética , Isomerasa de Peptidilprolil/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Peptidilprolil Isomerasa de Interacción con NIMA

RESUMEN

Linkage studies have suggested a susceptibility locus for late-onset Alzheimer's disease (LOAD) on chromosome 21. A functional candidate gene in this region is the beta-amyloid precursor protein (APP) gene. Previously, coding mutations in APP have been associated with early onset Alzheimer's Disease (EOAD). Three copies of APP are associated with AD pathology in Down's syndrome and in EOAD, suggesting that overexpression of APP may be a risk factor for LOAD. Although APP is a strong functional and positional candidate, to date there has been no thorough investigation using a dense map of SNPs across the APP gene. In order to investigate the role of common variation in the APP gene in the risk of LOAD, we genotyped 44 SNPs, spanning 300 kb spanning the entire gene, in a large case-control series of 738 AD cases and 657 healthy controls. The SNPs showed no association in genotypic or allelic tests, even after stratification for presence or absence of the APOE 4 allele. Haplotype analysis also failed to reveal significant association with any common haplotypes. These results suggest that common variation in the APP gene is not a significant risk factor for LOAD. However, we cannot rule out the possibility that multiple rare variants that increase APP expression or Abeta production might influence the risk for LOAD.

Asunto(s)

Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Apolipoproteínas E/genética , Femenino , Haplotipos , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estados Unidos/epidemiología

RESUMEN

This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P = 6.94E - 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEepsilon4 and epsilon2/3 variants (0.09 < D'<1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P = 0.00005, OR = 1.2, false positive rate = 0.87).

Asunto(s)

Enfermedad de Alzheimer/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Anciano , Estudios de Casos y Controles , Mapeo Cromosómico , Femenino , Silenciador del Gen , Marcadores Genéticos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reino Unido , Estados Unidos

RESUMEN

Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control sample set (WU) and replicated in each of two initial validation case-control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.

Asunto(s)

Enfermedad de Alzheimer/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Predisposición Genética a la Enfermedad , Alelos , Sitios de Unión , Estudios de Casos y Controles , Cromosomas Humanos Par 9/genética , Bases de Datos de Ácidos Nucleicos , Proteínas Quinasas Asociadas a Muerte Celular , Femenino , Frecuencia de los Genes , Ligamiento Genético , Marcadores Genéticos , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple

RESUMEN

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Asunto(s)

Alelos , Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 10/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad , Proteínas Ribosómicas/genética , Marcadores Genéticos/genética , Haplotipos/genética , Humanos , Missouri , Polimorfismo de Nucleótido Simple , Población Blanca/genética

RESUMEN

Several studies have reported evidence for linkage of late-onset Alzheimer's disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ-8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls. We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD.

Asunto(s)

Enfermedad de Alzheimer/genética , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Polimorfismo Genético , Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer/metabolismo , Proteínas Relacionadas con la Autofagia , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Femenino , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Persona de Mediana Edad , Factores de Riesgo

RESUMEN

Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Abeta. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three "tagging" SNPs identified in an earlier study. We used four case-control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P-value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over-represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.

Asunto(s)

Enfermedad de Alzheimer/genética , Insulisina/genética , Polimorfismo de Nucleótido Simple , Alelos , Enfermedad de Alzheimer/enzimología , Apolipoproteínas E/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Marcadores Genéticos/genética , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Factores de Riesgo