Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Acta neuropathologica

Acta Neuropathol. 2022 Sep 6. doi: 10.1007/s00401-022-02454-z. Online ahead of print.

ABSTRACT

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

PMID:36066633 | DOI:10.1007/s00401-022-02454-z

Authors

Iris E Jansen
Sven J van der Lee
Duber Gomez-Fonseca
Itziar de Rojas
Maria Carolina Dalmasso
Benjamin Grenier-Boley
Anna Zettergren
Aniket Mishra
Muhammad Ali
Victor Andrade
Céline Bellenguez
Luca Kleineidam
Fahri Küçükali
Yun Ju Sung
Niccolo Tesí
Ellen M Vromen
Douglas P Wightman
Daniel Alcolea
Montserrat Alegret
Ignacio Alvarez
Philippe Amouyel
Lavinia Athanasiu
Shahram Bahrami
Henri Bailly
Olivia Belbin
Sverre Bergh
Lars Bertram
Geert Jan Biessels
Kaj Blennow
Rafael Blesa
Mercè Boada
Anne Boland
Katharina Buerger
Ángel Carracedo
Laura Cervera-Carles
Geneviève Chene
Jurgen A H R Claassen
Stephanie Debette
Jean-Francois Deleuze
Peter Paul de Deyn
Janine Diehl-Schmid
Srdjan Djurovic
Oriol Dols-Icardo
Carole Dufouil
Emmanuelle Duron
Emrah Düzel
EADB consortium
Tormod Fladby
Juan Fortea
Lutz Frölich
Pablo García-González
Maria Garcia-Martinez
Ina Giegling
Oliver Goldhardt
Johan Gobom
Timo Grimmer
Annakaisa Haapasalo
Harald Hampel
Olivier Hanon
Lucrezia Hausner
Stefanie Heilmann-Heimbach
Seppo Helisalmi
Michael T Heneka
Isabel Hernández
Sanna-Kaisa Herukka
Henne Holstege
Jonas Jarholm
Silke Kern
Anne-Brita Knapskog
Anne M Koivisto
Johannes Kornhuber
Teemu Kuulasmaa
Carmen Lage
Christoph Laske
Ville Leinonen
Piotr Lewczuk
Alberto Lleó
Adolfo López de Munain
Sara Lopez-Garcia
Wolfgang Maier
Marta Marquié
Merel O Mol
Laura Montrreal
Fermin Moreno
Sonia Moreno-Grau
Gael Nicolas
Markus M Nöthen
Adelina Orellana
Lene Pålhaugen
Janne M Papma
Florence Pasquier
Robert Perneczky
Oliver Peters
Yolande A L Pijnenburg
Julius Popp
Danielle Posthuma
Ana Pozueta
Josef Priller
Raquel Puerta
Inés Quintela
Inez Ramakers
Eloy Rodriguez-Rodriguez
Dan Rujescu
Ingvild Saltvedt
Pascual Sanchez-Juan
Philip Scheltens
Norbert Scherbaum
Matthias Schmid
Anja Schneider
Geir Selbæk
Per Selnes
Alexey Shadrin
Ingmar Skoog
Hilkka Soininen
Lluís Tárraga
Stefan Teipel
GR@ACE study group
Betty Tijms
Magda Tsolaki
Christine Van Broeckhoven
Jasper Van Dongen
John C van Swieten
Rik Vandenberghe
Jean-Sébastien Vidal
Pieter J Visser
Jonathan Vogelgsang
Margda Waern
Michael Wagner
Jens Wiltfang
Mandy M J Wittens
Henrik Zetterberg
Miren Zulaica
Cornelia M van Duijn
Maria Bjerke
Sebastiaan Engelborghs
Frank Jessen
Charlotte E Teunissen
Pau Pastor
Mikko Hiltunen
Martin Ingelsson
Ole A Andreassen
Jordi Clarimón
Kristel Sleegers
Agustín Ruiz
Alfredo Ramirez
Carlos Cruchaga
Jean-Charles Lambert
Wiesje van der Flier