PLoS Genetics: SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease

SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease

Carlos Cruchaga1,2#*, John S. K. Kauwe3#, Kevin Mayo1,2, Noah Spiegel1,2, Sarah Bertelsen1, Petra Nowotny1,2, Aarti R. Shah2,4, Richard Abraham9, Paul Hollingworth5, Denise Harold5, Michael M. Owen5, Julie Williams5, Simon Lovestone6, Elaine R. Peskind7,8, Ge Li7,8, James B. Leverenz7,8,9, Douglas Galasko10, The Alzheimer's Disease Neuroimaging Initiative¶, John C. Morris4,11,6, Anne M. Fagan2,4,13, David M. Holtzman2,4,12,13, Alison M. Goate1,2,4,13

1 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 The Hope Center Program on Protein Aggregation and Neurodegeneration (HPAN), Washington University School of Medicine, St. Louis, Missouri, United States of America, 3 Department of Biology, Brigham Young University, Provo, Utah, United States of America, 4 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 5 Department of Psychological Medicine, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom, 6 Kings College, London, United Kingdom, 7 Departments of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, United States of America, 8 Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle, Washington, United States of America, 9 Department of Neurology, University of Washington School of Medicine, Seattle, Washington, United States of America, 10 Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America, 11 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 12 Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 13 Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America


Abstract
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 (ptau181) 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 ptau181 levels in two independent CSF series . 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 . Our analyses suggest that genetic variants associated with CSF ptau181 levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ42 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 Aβ42 levels. Finally, we believe genome-wide association studies of CSF tau/ptau181 levels should identify novel genetic variants which will likely influence rate of progression of AD.


Author Summary
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 4.5 million people in the US. Genetic studies of AD have previously identified pathogenic mutations in three genes (APP, PSEN1 and PSEN2) and polymorphisms in APOE as risk factors. These findings have led to a better understanding of the underlying disease mechanisms. However, half of all AD cases have no known genetic risk factors for disease. Most studies are designed to identify variants associated with risk or age at onset, but rarely cover other important facets of AD, such as disease progression or duration. In this study we have used an established AD biomarker (cerebrospinal fluid tau phosphorylated at threonine 181, ptau181) to find genetic variants that influence levels of ptau181 in the cerebrospinal fluid. This novel and powerful approach has allowed us to identify a genetic factor located in the regulatory subunit of the calcineurin that is also strongly associated with rate of progression of AD. This study is important because it defines a strategy to find novel genetic factors influencing different facets of AD pathobiology including risk, onset and progression.

Citation: Cruchaga C, Kauwe JSK, Mayo K, Spiegel N, Bertelsen S, et al. (2010) SNPs A
full-text:
PLoS Genetics: SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease




PLoS Genetics

NEUROLOGÍA
Actualidad Ultimas noticias - JANOes y agencias -
Hallado un marcador genético asociado a la progresión de la enfermedad de Alzheimer

JANO.es y agencias · 17 Septiembre 2010 12:05

El descubrimiento puede ayudar a determinar la rapidez con que los enfermos podrían desarrollar demencia al completo después de ser diagnosticados

Investigadores de la Facultad de Medicina de la Universidad de Washington en Saint Louis (Estados Unidos) han identificado una variante genética que parece predecir la tasa a la que progresará la enfermedad de Alzheimer. Los resultados del estudio se publican en PLoS Genetics.

El hallazgo puede ayudar a determinar la rapidez con que los enfermos de Alzheimer podrían desarrollar demencia al completo después de ser diagnosticados.

Estudios recientes han descubierto que la presencia de una forma particular de la proteína tau -tau fosforilada o ptau- en el líquido cefalorraquídeo es un indicador de la enfermedad de Alzheimer. Los investigadores examinaron variantes de ADN en 846 pacientes e identificaron un marcador genético vinculado a niveles elevados de ptau, asociados a una progresión rápida de la enfermedad.

Según explica el Dr. Carlos Cruchaga, responsable del estudio, “hemos examinado datos de tres estudios internacionales independientes y en todos ellos descubrimos la misma asociación. Por ello confiamos en que es real y que esta variante genética se asocia con la progresión de la enfermedad de Alzheimer”.

Los autores apuntan que el descubrimiento genético, en combinación con la capacidad de medir ptau en el fluido cerebroespinal, podría significar que la inhibición farmacológica de la acumulación de ptau en el líquido cefalorraquídeo podría evitar o retrasar algunos de los efectos devastadores del Alzheimer.

Según explican los investigadores, el conocimiento por anticipado de los pacientes que van a pasar por una progresión rápida podría permitir evaluar mejor los efectos de los fármacos diseñados para ralentizar la progresión de la enfermedad.

PLoS Genet 6(9): e1001101. doi:10.1371/journal.pgen.1001101
http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001101


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Washington University School of Medicine in St. Louis
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