Novel genetic effects on amyloid and tau protein levels in cerebrospinal fluid: Towards a better knowledge of the genetics of Alzheimer's disease, the European Alzheimer Disease Biobank (EADB) Consortium. (7th December 2020)

• Record Type: Journal Article
• Authors: Jansen, Iris E.; Van Der Lee, Sven J.; Bellenguez, Céline; Grenier‐Boley, Benjamin; de Rojas, Itziar; Zettergren, Anna; Kleineidam, Luca
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.037973
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Assuming measurable biological properties to be more strongly related to the underlying Alzheimer's disease (AD) pathogenesis than the diagnostic classification, we studied the genetics of AD‐relevant protein levels in cerebrospinal fluid (CSF). Initiated by the European Alzheimer's disease DNA biobank (EADB), we established the largest collaborative effort on CSF amyloid beta and tau, and aimed to improve the current understanding on the genetic etiology of AD, including the identification of novel genetic risk factors. Method: A collection of 10 European dementia cohorts was explored to study the genetic effects on CSF amyloid beta (n = 6529 individuals), tau (n = 6455 individuals) and phosphorylated tau (n = 5865). Most of the genetic data was generated with Illumina Global Screening Array, and imputed with TOPMed reference genome. The protein level data was log transformed and normalized. Per variant linear regressions were performed within cohorts using PLINK v2.0, followed by meta‐analysis. We corrected for population structure (principal components), gender, age and biomarker assay type (if applicable within a cohort). Results: Besides APOE ( p = 3.16 × 10 −251 ), no other loci reached genome‐wide significance for amyloid beta protein levels. For tau protein levels, we discovered 5 loci, including the known AD loci APOE ( p = 1.61 × 10 −61 ) and HLA‐DRB1 ( p = 4.67 × 10 −8 ). We additionally confirm the GMNC locus ( p = 1.23 × 10 −12 ) that previously was associated with CSF tau by an independent consortium. Two novel loci are seen on chromosome 9 ( p = 5.76 × 10 −8 ) and chromosome 16 ( p = 3.67 × 10 −8 ). These tau findings are strengthened by the identification of these same 5 loci for phosphorylated tau which has been measured by a different protein level assay. Both novel loci have shown associations with brain ventricular volume in previous large‐scale studies performed by other consortia, such as CHARGE and ADNI. Conclusion: The novel loci identified for CSF tau protein levels suggest an overlap in genetic etiology for tau and brain ventricular volume, thereby strengthening the theory that neurodegeneration and tau pathology are highly correlated in dementia patients.