TY - JOUR
T1 - Quantitative genetics validates previous genetic variants and identifies novel genetic players influencing Alzheimer's disease cerebrospinal fluid biomarkers
AU - Ramos De Matos, Mafalda
AU - Ferreira, Catarina
AU - Herukka, Sanna Kaisa
AU - Soininen, Hilkka
AU - Janeiro, André
AU - Santana, Isabel
AU - Baldeiras, Inês
AU - Almeida, Maria Rosário
AU - Lleó, Alberto
AU - Dols-Icardo, Oriol
AU - Alcolea, Daniel
AU - Benussi, Luisa
AU - Binetti, Giuliano
AU - Paterlini, Anna
AU - Ghidoni, Roberta
AU - Nacmias, Benedetta
AU - Meulenbroek, Olga
AU - Van Waalwijk Van Doorn, Linda J.C.
AU - Kuiperi, H. Bea J.
AU - Hausner, Lucrezia
AU - Waldemar, Gunhild
AU - Simonsen, Anja Hviid
AU - Tsolaki, Magda
AU - Gkatzima, Olymbia
AU - Resende De Oliveira, Catarina
AU - Verbeek, Marcel M.
AU - Clarimon, Jordi
AU - Hiltunen, Mikko
AU - De Mendonça, Alexandre
AU - Martins, Madalena
PY - 2018/1/1
Y1 - 2018/1/1
N2 - © 2018 - IOS Press and the authors. All rights reserved. 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.
AB - © 2018 - IOS Press and the authors. All rights reserved. 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.
KW - Alzheimer's disease
KW - European multicenter study
KW - cerebrospinal fluid biomarkers
KW - endophenotypes
KW - quantitative trait loci
U2 - 10.3233/JAD-180512
DO - 10.3233/JAD-180512
M3 - Article
C2 - 30320580
SN - 1387-2877
VL - 66
SP - 639
EP - 652
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 2
ER -