OBJECTIVE: Aggregation and deposition of amyloid beta (Abeta) in the brain is thought to be central to the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) Abeta levels are strongly correlated with AD status and progression, and may be a meaningful endophenotype for AD. Mutations in presenilin 1 (PSEN1) are known to cause AD and change Abeta levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Abeta levels as an endophenotype for AD. METHODS: We sequenced the exons and flanking intronic regions of PSEN1 in clinically characterized research subjects with extreme values of CSF Abeta levels. RESULTS: This novel approach led directly to the identification of a disease-causing mutation in a family with late-onset AD. INTERPRETATION: This finding suggests that CSF Abeta may be a useful endophenotype for genetic studies of AD. Our results also suggest that PSEN1 mutations can cause AD with a large range in age of onset, spanning both early- and late-onset AD.
OBJECTIVE: Aggregation and deposition of amyloid beta (Abeta) in the brain is thought to be central to the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) Abeta levels are strongly correlated with AD status and progression, and may be a meaningful endophenotype for AD. Mutations in presenilin 1 (PSEN1) are known to cause AD and change Abeta levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Abeta levels as an endophenotype for AD. METHODS: We sequenced the exons and flanking intronic regions of PSEN1 in clinically characterized research subjects with extreme values of CSF Abeta levels. RESULTS: This novel approach led directly to the identification of a disease-causing mutation in a family with late-onset AD. INTERPRETATION: This finding suggests that CSF Abeta may be a useful endophenotype for genetic studies of AD. Our results also suggest that PSEN1 mutations can cause AD with a large range in age of onset, spanning both early- and late-onset AD.
Authors: Bruno A Benitez; Celeste M Karch; Yefei Cai; Sheng Chih Jin; Breanna Cooper; David Carrell; Sarah Bertelsen; Lori Chibnik; Julie A Schneider; David A Bennett; Anne M Fagan; David Holtzman; John C Morris; Alison M Goate; Carlos Cruchaga Journal: PLoS Genet Date: 2013-08-22 Impact factor: 5.917
Authors: John S K Kauwe; Jun Wang; Sumi Chakraverty; Alison M Goate; Andres F Henao-Martinez Journal: Neurosci Lett Date: 2008-04-15 Impact factor: 3.046
Authors: Jeremy Koppel; Fabien Campagne; Valérie Vingtdeux; Ute Dreses-Werringloer; Michael Ewers; Dan Rujescu; Harald Hampel; Marc L Gordon; Erica Christen; Julien Chapuis; Blaine S Greenwald; Peter Davies; Philippe Marambaud Journal: Mol Med Date: 2011-05-24 Impact factor: 6.354
Authors: Carlos Cruchaga; Petra Nowotny; John S K Kauwe; Perry G Ridge; Kevin Mayo; Sarah Bertelsen; Anthony Hinrichs; Anne M Fagan; David M Holtzman; John C Morris; Alison M Goate Journal: Arch Neurol Date: 2011-08
Authors: John S K Kauwe; Jun Wang; Kevin Mayo; John C Morris; Anne M Fagan; David M Holtzman; Alison M Goate Journal: Neurogenetics Date: 2008-09-24 Impact factor: 2.660
Authors: Minji Kim; Jaehong Suh; Donna Romano; Mimy H Truong; Kristina Mullin; Basavaraj Hooli; David Norton; Giuseppina Tesco; Kathy Elliott; Steven L Wagner; Robert D Moir; K David Becker; Rudolph E Tanzi Journal: Hum Mol Genet Date: 2009-07-15 Impact factor: 6.150
Authors: Carlos Cruchaga; John S K Kauwe; Kevin Mayo; Noah Spiegel; Sarah Bertelsen; Petra Nowotny; Aarti R Shah; Richard Abraham; Paul Hollingworth; Denise Harold; Michael M Owen; Julie Williams; Simon Lovestone; Elaine R Peskind; Ge Li; James B Leverenz; Douglas Galasko; John C Morris; Anne M Fagan; David M Holtzman; Alison M Goate Journal: PLoS Genet Date: 2010-09-16 Impact factor: 5.917