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

Eva Louwersheimer, Steffen Wolfsgruber, Ana Espinosa, Andre Lacour, Stefanie Heilmann-Heimbach, Montserrat Alegret, Isabel Hernandez, Maitee Rosende-Roca, Lluis Tarraga, Merce Boada, Johannes Kornhuber, Oliver Peters, Lutz Frolich, Michael Hull, Eckart Ruther, Jens Wiltfang, Martin Scherer, Steffi Riedel-Heller, Frank Jessen, Markus M. NothenWolfgang Maier, Ted Koene, Philip Scheltens, Henne Holstege, Michael Wagner, Agustin Ruiz, Wiesje M. van der Flier, Tim Becker, Alfredo Ramirez

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We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI).


We 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).


PGS 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).


In 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.
Original languageEnglish
Pages (from-to)872-881
JournalAlzheimers & Dementia
Issue number8
Publication statusPublished - Aug 2016


  • Alzheimer's disease
  • Endophenotypes
  • Genetic risk variants
  • Mild cognitive impairment
  • Polygenic risk score

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