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. Nothen; Wolfgang Maier; Ted Koene; Philip Scheltens; Henne Holstege; Michael Wagner; Agustin Ruiz; Wiesje M. van der Flier; Tim Becker; Alfredo Ramirez

doi:https://doi.org/10.1016/j.jalz.2016.01.006

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

Research output: Contribution to journal › Article › Academic › peer-review

29 Citations (Scopus)

Abstract

Introduction

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).

Methods

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).

Results

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).

Discussion

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 language	English
Pages (from-to)	872-881
Journal	Alzheimers & Dementia
Volume	12
Issue number	8
DOIs	https://doi.org/10.1016/j.jalz.2016.01.006
Publication status	Published - Aug 2016

Keywords

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

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https://doi.org/10.1016/j.jalz.2016.01.006

Cite this

Louwersheimer, E., Wolfsgruber, S., Espinosa, A., Lacour, A., Heilmann-Heimbach, S., Alegret, M., Hernandez, I., Rosende-Roca, M., Tarraga, L., Boada, M., Kornhuber, J., Peters, O., Frolich, L., Hull, M., Ruther, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Jessen, F., ... Ramirez, A. (2016). Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment. Alzheimers & Dementia, 12(8), 872-881. https://doi.org/10.1016/j.jalz.2016.01.006

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title = "Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment",

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.",

keywords = "Alzheimer's disease, Endophenotypes, Genetic risk variants, Mild cognitive impairment, Polygenic risk score",

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

year = "2016",

month = aug,

doi = "https://doi.org/10.1016/j.jalz.2016.01.006",

language = "English",

volume = "12",

pages = "872--881",

journal = "Alzheimers & Dementia",

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Louwersheimer, E, Wolfsgruber, S, Espinosa, A, Lacour, A, Heilmann-Heimbach, S, Alegret, M, Hernandez, I, Rosende-Roca, M, Tarraga, L, Boada, M, Kornhuber, J, Peters, O, Frolich, L, Hull, M, Ruther, E, Wiltfang, J, Scherer, M, Riedel-Heller, S, Jessen, F, Nothen, MM, Maier, W, Koene, T, Scheltens, P , Holstege, H, Wagner, M, Ruiz, A, van der Flier, WM, Becker, T & Ramirez, A 2016, 'Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment', Alzheimers & Dementia, vol. 12, no. 8, pp. 872-881. https://doi.org/10.1016/j.jalz.2016.01.006

TY - JOUR

T1 - Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment

AU - Louwersheimer, Eva

AU - Wolfsgruber, Steffen

AU - Espinosa, Ana

AU - Lacour, Andre

AU - Heilmann-Heimbach, Stefanie

AU - Alegret, Montserrat

AU - Hernandez, Isabel

AU - Rosende-Roca, Maitee

AU - Tarraga, Lluis

AU - Boada, Merce

AU - Kornhuber, Johannes

AU - Peters, Oliver

AU - Frolich, Lutz

AU - Hull, Michael

AU - Ruther, Eckart

AU - Wiltfang, Jens

AU - Scherer, Martin

AU - Riedel-Heller, Steffi

AU - Jessen, Frank

AU - Nothen, Markus M.

AU - Maier, Wolfgang

AU - Koene, Ted

AU - Scheltens, Philip

AU - Holstege, Henne

AU - Wagner, Michael

AU - Ruiz, Agustin

AU - van der Flier, Wiesje M.

AU - Becker, Tim

AU - Ramirez, Alfredo

PY - 2016/8

Y1 - 2016/8

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Endophenotypes

KW - Genetic risk variants

KW - Mild cognitive impairment

KW - Polygenic risk score

U2 - https://doi.org/10.1016/j.jalz.2016.01.006

DO - https://doi.org/10.1016/j.jalz.2016.01.006

M3 - Article

C2 - 26921674

SN - 1552-5260

VL - 12

SP - 872

EP - 881

JO - Alzheimers & Dementia

JF - Alzheimers & Dementia

IS - 8

ER -