Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment

ISSN
1552-5260
Date Issued
2016
Author(s)
Louwersheimer, Eva
Wolfsgruber, Steffen
Espinosa, Ana
Lacour, André
Heilmann-Heimbach, Stefanie
Alegret, Montserrat
Hernández, Isabel
Rosende-Roca, Maitée
Tárraga, Lluís
Boada, Mercè
Peters, Oliver
Frölich, Lutz
Hüll, Michael
Scherer, Martin
Riedel-Heller, Steffi
Jessen, Frank
Nöthen, Markus M.
Maier, Wolfgang
Koene, Ted
Scheltens, Philip
Holstege, Henne
Wagner, Michael
Ruiz, Agustín
van der Flier, Wiesje M.
Becker, Tim
Ramirez, Alfredo
DOI
10.1016/j.jalz.2016.01.006
Abstract
IntroductionWe evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI).MethodsWe selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aβ, tau, ptau).ResultsPGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (β ± SE:−0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10−4; ptau: 1.40 ± 0.36, P = 1.02 × 10−4).DiscussionIn MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.