Quantitative genetics validates previous genetic variants and identifies novel genetic players influencing Alzheimer's disease cerebrospinal fluid biomarkers

Mafalda Ramos De Matos, Catarina Ferreira, Sanna Kaisa Herukka, Hilkka Soininen, André Janeiro, Isabel Santana, Inês Baldeiras, Maria Rosário Almeida, Alberto Lleó, Oriol Dols-Icardo, Daniel Alcolea, Luisa Benussi, Giuliano Binetti, Anna Paterlini, Roberta Ghidoni, Benedetta Nacmias, Olga Meulenbroek, Linda J.C. Van Waalwijk Van Doorn, H. Bea J. Kuiperi, Lucrezia HausnerGunhild Waldemar, Anja Hviid Simonsen, Magda Tsolaki, Olymbia Gkatzima, Catarina Resende De Oliveira, Marcel M. Verbeek, Jordi Clarimon, Mikko Hiltunen, Alexandre De Mendonça, Madalena Martins

Research output: Contribution to journalArticlepeer-review

Abstract

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ 1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ 1-42 is decreased due to the accumulation of Aβ 1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ 1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers. Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Original languageEnglish
Pages (from-to)639-652
Number of pages14
JournalJournal of Alzheimer's Disease
Volume66
Issue number2
DOIs
Publication statusPublished - Jan 1 2018

Keywords

  • Alzheimer's disease
  • cerebrospinal fluid biomarkers
  • endophenotypes
  • European multicenter study
  • quantitative trait loci

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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