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

Eva Louwersheimer; Steffen Wolfsgruber; Ana Espinosa; André Lacour; Stefanie Heilmann-Heimbach; Montserrat Alegret; Isabel Hernández; Maitée Rosende-Roca; Lluís Tárraga; Mercè Boada; Johannes Kornhuber; Oliver Peters; Lutz Frölich; Michael Hüll; Eckart Rüther; Jens Wiltfang; Martin Scherer; Steffi Riedel-Heller; Frank Jessen; Markus M. Nöthen; Wolfgang Maier; Ted Koene; Philip Scheltens; Henne Holstege; Michael Wagner; Agustín Ruiz; Wiesje M. van der Flier; Tim Becker; Alfredo Ramirez

doi:10.1016/j.jalz.2016.01.006

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

Eva Louwersheimer
, Steffen Wolfsgruber
, Ana Espinosa
, André Lacour
, Stefanie Heilmann-Heimbach
, Montserrat Alegret
, Isabel Hernández
, Maitée Rosende-Roca
, Lluís Tárraga
, Mercè Boada
, Johannes Kornhuber
, Oliver Peters
, Lutz Frölich
, Michael Hüll
, Eckart Rüther
, Jens Wiltfang
, Martin Scherer
, Steffi Riedel-Heller
, Frank Jessen
, Markus M. Nöthen

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

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

31 Scopus citations

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 (US)
Pages (from-to)	872-881
Number of pages	10
Journal	Alzheimer's and Dementia
Volume	12
Issue number	8
DOIs	https://doi.org/10.1016/j.jalz.2016.01.006
State	Published - Aug 1 2016
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1016/j.jalz.2016.01.006

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

Louwersheimer, E, Wolfsgruber, S, Espinosa, A, Lacour, A, Heilmann-Heimbach, S, Alegret, M, Hernández, I, Rosende-Roca, M, Tárraga, L, Boada, M, Kornhuber, J, Peters, O, Frölich, L, Hüll, M, Rüther, E, Wiltfang, J, Scherer, M, Riedel-Heller, S, Jessen, F, Nöthen, 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', Alzheimer's and Dementia, vol. 12, no. 8, pp. 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 = "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.",

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

author = "Eva Louwersheimer and Steffen Wolfsgruber and Ana Espinosa and Andr{\'e} Lacour and Stefanie Heilmann-Heimbach and Montserrat Alegret and Isabel Hern{\'a}ndez and Mait{\'e}e Rosende-Roca and Llu{\'i}s T{\'a}rraga and Merc{\`e} Boada and Johannes Kornhuber and Oliver Peters and Lutz Fr{\"o}lich and Michael H{\"u}ll and Eckart R{\"u}ther and Jens Wiltfang and Martin Scherer and Steffi Riedel-Heller and Frank Jessen and N{\"o}then, \{Markus M.\} and Wolfgang Maier and Ted Koene and Philip Scheltens and Henne Holstege and Michael Wagner and Agust{\'i}n Ruiz and \{van der Flier\}, \{Wiesje M.\} and Tim Becker and Alfredo Ramirez",

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doi = "10.1016/j.jalz.2016.01.006",

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

AU - Louwersheimer, Eva

AU - Wolfsgruber, Steffen

AU - Espinosa, Ana

AU - Lacour, André

AU - Heilmann-Heimbach, Stefanie

AU - Alegret, Montserrat

AU - Hernández, Isabel

AU - Rosende-Roca, Maitée

AU - Tárraga, Lluís

AU - Boada, Mercè

AU - Kornhuber, Johannes

AU - Peters, Oliver

AU - Frölich, Lutz

AU - Hüll, Michael

AU - Rüther, Eckart

AU - Wiltfang, Jens

AU - Scherer, Martin

AU - Riedel-Heller, Steffi

AU - Jessen, Frank

AU - Nöthen, Markus M.

AU - Maier, Wolfgang

AU - Koene, Ted

AU - Scheltens, Philip

AU - Holstege, Henne

AU - Wagner, Michael

AU - Ruiz, Agustín

AU - van der Flier, Wiesje M.

AU - Becker, Tim

AU - Ramirez, Alfredo

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Endophenotypes

KW - Genetic risk variants

KW - Mild cognitive impairment

KW - Polygenic risk score

UR - https://www.scopus.com/pages/publications/84989937910

UR - https://www.scopus.com/pages/publications/84989937910#tab=citedBy

U2 - 10.1016/j.jalz.2016.01.006

DO - 10.1016/j.jalz.2016.01.006

M3 - Article

C2 - 26921674

AN - SCOPUS:84989937910

SN - 1552-5260

VL - 12

SP - 872

EP - 881

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 8

ER -

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

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