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Principal Investigator  
Principal Investigator's Name: Alfredo Ramirez
Institution: University of Bonn
Department: Division Neurogenetics at the Dept. of Psychiatry
Proposed Analysis: Alzheimer disease (AD) is the most common form of neurodegeneration. In the majority of cases, the disease shows a complex mode of inheritance with a late disease onset (> 65 years). Until recently, only variants in the gene encoding Apoliprotein E (APOE) have been consistently identified as a genetic risk factor for AD. In this regard, recent genome-wide association studies (GWAS) have led to the identification of several new genes that are implicated in the aetiology of AD (Harold et al. and Lambert et al. Nat Genetics 2009). These studies reported genome-wide significant association of CLU and 5’ to PICALM with AD. In addition, Lambert and colleagues reported a genome-wide significance at the CR1 gene locus. Interestingly, recent meta-analyses have added further risk variants in the BIN1 gene and the locus containing EXOC3L2/BLOC1S3/MARK4 genes. These novel discoveries have shed lights into the genetics, neuropathologic mechanisms and the molecular pathways associated with AD. However, the case-control approach have an inherent confound in that a proportion of the apparently normal controls will already harbour disease due to the long pre-symptomatic phase of the disease. In this regard, using markers of pathology (endophenotypes) that can distinguish in vivo diseased from normal individuals might help to address this issue. This strategy, also called quantitative trait analysis, led already to identify genetic factors involved in different diseases. Cerebrospinal fluid (CSF) markers such as, Aβ1-42 and phosphorylated Tau (pTau181), have been proposed as potential biomarkers in AD. The Aβ1-42 fragment is decreased and pTau181 is increased in the CSF of AD patients. Unravelling genes that modulate levels of these biomarkers will be critical to further our knowledge on pathophysiological pathways related to Aβ1-42 and pTau in AD. In this regard, GWAS of CSF biomarkers in the ANDI cohort have provided additional genes to the growing list of AD loci. However, these studies were based on one single sample with a modest sample size limiting, thereby, the statistical power of the analyses. In addition, confirmation of these findings in independent and larger samples is still an important issue not addressed so far. For this reason, we sought to investigate genetic variants modulating levels of Aβ1-42 and pTau181 in a sample of 280 AD patients of German origin. To this end, we performed a QT analysis combining measures of these two CSF biomarkers and genome-wide common variation data in this sample. Now, we would like to use the CSF biomarkers (Aβ1-42,t-Tau, and pTau181) and genome-wide genotype data from the ADNI cohort to replicate our results. Additionally, it is also expected that previously unidentified genes will appear by increasing the sample size (i.e. combining both samples). Therefore, we will also perform a metaanalysis with both samples after the second GWAS of CSF biomarkers in the ADNI sample was ran. In this concern, applying similar QC algorithms and normalization procedures to both German and ADNI datasets will reduce the signal-to-noise ratio. This will certainly improve the results of the metaanalysis. Using the genome-wide genotype and CSF data of both samples, we will also search for epistatic gene effects with our INTERSNP software for genome-wide interaction analysis [Herold C, Steffens M, Brockschmidt FF, Baur MP, Becker T (2009) INTERSNP: Genome-wide Interaction Analysis Guided by A Priori Information. Bioinformatics. 2009 Dec 15;25(24):3275-81]. In order to guarantee computability, we would first focus on interaction partners of APOE.
Additional Investigators  
Investigator's Name: Pamela Matino Adami
Proposed Analysis: Identification and characterization of genetics and epigenetics underpinning of plasma and CSF biomarkers and their correlation with brain structures and cognitive performance