New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Equidad en salud

•Acceso a diagnóstico y tratamiento para depresión según posición social en países seleccionados de Latinoamérica •Análisis narrativo de experiencias de chilenos exiliados políticos con discapacidad física en Malmö, Suecia •Caracterización y comparación de puérperas peruanas y chilenas atendidas en el Hospital San José •Conocimientos y prácticas de estudiantes de 7º y 8º básico, de ambos sexos, de Curacaví •Desarrollo económico y mortalidad prematura, Chile, 1994-2003 •Determinación nacional del Índice Significante de Caries (SIC) en adolescentes de 12 años, Chile 2010 •Diagnóstico de salud bucal en niños 2 y 4 años asistentes a la educación preescolar, zonas norte y centro •El GES promueve la equidad en el tratamiento del gran quemado de la tercera edad •Evaluación del nivel de conocimiento en salud bucal de la comunidad educativa preescolar •Factores psicosociales y culturales que inciden en embarazo adolescente en niñas menores de 15 años •Índice Significante de Caries en niños de 6 años, Chile 2010 •La mortalidad por cáncer del cuello uterino en Río de Janeiro: Estudio ecológico •Nivel de desarrollo psicomotor y su relación con el score de riesgo DSM •Perfil en interconsultas dermatológicas del consultorio Padre Esteban Gumucio Vives de Santiago de Chile, 2010 •Prevalencia caries, pérdida de dientes, necesidad de tratamiento en adultos mapuche - huilliches de Isla Huapi •Recursos humanos odontológicos para tratamiento de caries en adolescentes de 12 años, Chile 2010 •Retraso del diagnóstico de tuberculosis en la percepción de los representantes de ONG en Río de Janeiro •Rol de la escuela en promoción de salud y reducción de vulnerabilidad social en salud •Tendencia de las tasas de mortalidad fetal e infantil y sus componentes, Chile 1996- 2006 •Implementación de un mamógrafo móvil para la Región de los Río

Equidad en salud

•Acceso a diagnóstico y tratamiento para depresión según posición social en países seleccionados de Latinoamérica •Análisis narrativo de experiencias de chilenos exiliados políticos con discapacidad física en Malmö, Suecia •Caracterización y comparación de puérperas peruanas y chilenas atendidas en el Hospital San José •Conocimientos y prácticas de estudiantes de 7º y 8º básico, de ambos sexos, de Curacaví •Desarrollo económico y mortalidad prematura, Chile, 1994-2003 •Determinación nacional del Índice Significante de Caries (SIC) en adolescentes de 12 años, Chile 2010 •Diagnóstico de salud bucal en niños 2 y 4 años asistentes a la educación preescolar, zonas norte y centro •El GES promueve la equidad en el tratamiento del gran quemado de la tercera edad •Evaluación del nivel de conocimiento en salud bucal de la comunidad educativa preescolar •Factores psicosociales y culturales que inciden en embarazo adolescente en niñas menores de 15 años •Índice Significante de Caries en niños de 6 años, Chile 2010 •La mortalidad por cáncer del cuello uterino en Río de Janeiro: Estudio ecológico •Nivel de desarrollo psicomotor y su relación con el score de riesgo DSM •Perfil en interconsultas dermatológicas del consultorio Padre Esteban Gumucio Vives de Santiago de Chile, 2010 •Prevalencia caries, pérdida de dientes, necesidad de tratamiento en adultos mapuche - huilliches de Isla Huapi •Recursos humanos odontológicos para tratamiento de caries en adolescentes de 12 años, Chile 2010 •Retraso del diagnóstico de tuberculosis en la percepción de los representantes de ONG en Río de Janeiro •Rol de la escuela en promoción de salud y reducción de vulnerabilidad social en salud •Tendencia de las tasas de mortalidad fetal e infantil y sus componentes, Chile 1996- 2006 •Implementación de un mamógrafo móvil para la Región de los Río

Nat Commun

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele