Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer's pathology

Joost M. Riphagen; Inez H. G. M. Ramakers; Whitney M. Freeze; Linda H. G. Pagen; Bernard J. Hanseeuw; Marcel M. Verbeek; Frans R. J. Verhey; Heidi I. L. Jacobs

doi:10.1016/j.neurobiolaging.2019.09.020

Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer's pathology

Joost M. Riphagen^*, Inez H. G. M. Ramakers, Whitney M. Freeze, Linda H. G. Pagen, Bernard J. Hanseeuw, Marcel M. Verbeek, Frans R. J. Verhey, Heidi I. L. Jacobs

^*Corresponding author for this work

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

Abstract

The APOE-epsilon 4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-epsilon 4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1 beta, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau(181) and amyloid-beta(1-42) (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-epsilon 4 genotype. This suggests that APOE-epsilon 4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. (C) 2019 The Author(s). Published by Elsevier Inc.

Original language	English
Pages (from-to)	96-103
Number of pages	8
Journal	Neurobiology of Aging
Volume	85
DOIs	https://doi.org/10.1016/j.neurobiolaging.2019.09.020
Publication status	Published - Jan 2020

Keywords

Alzheimer's disease
Inflammation
Blood-brain barrier
APOE
Vascular
MILD COGNITIVE IMPAIRMENT
CEREBROSPINAL-FLUID
SAMPLE-SIZE
ASSOCIATION WORKGROUPS
DIAGNOSTIC GUIDELINES
NATIONAL INSTITUTE
DISEASE
DEMENTIA
INTERLEUKIN-6
TAU

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Cite this

@article{4ea5611cccdc49c2aa53a1327030659f,

title = "Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer's pathology",

abstract = "The APOE-epsilon 4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-epsilon 4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1 beta, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau(181) and amyloid-beta(1-42) (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-epsilon 4 genotype. This suggests that APOE-epsilon 4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. (C) 2019 The Author(s). Published by Elsevier Inc.",

keywords = "Alzheimer's disease, Inflammation, Blood-brain barrier, APOE, Vascular, MILD COGNITIVE IMPAIRMENT, CEREBROSPINAL-FLUID, SAMPLE-SIZE, ASSOCIATION WORKGROUPS, DIAGNOSTIC GUIDELINES, NATIONAL INSTITUTE, DISEASE, DEMENTIA, INTERLEUKIN-6, TAU",

author = "Riphagen, {Joost M.} and Ramakers, {Inez H. G. M.} and Freeze, {Whitney M.} and Pagen, {Linda H. G.} and Hanseeuw, {Bernard J.} and Verbeek, {Marcel M.} and Verhey, {Frans R. J.} and Jacobs, {Heidi I. L.}",

note = "Funding Information: Authors' contributions: JMR and HILJ contributed to conception and design of study, conducted statistical analyses. IHGMR, LHGP, FRV, MMV, and WMF contributed to data acquisition and analyses. BJH assisted in data interpretation and revision for intellectual content. All authors contributed to drafting the text. This project was supported by Alzheimer Nederland (standard grant nr. 15007). Funding Information: Authors' contributions: JMR and HILJ contributed to conception and design of study, conducted statistical analyses. IHGMR, LHGP, FRV, MMV, and WMF contributed to data acquisition and analyses. BJH assisted in data interpretation and revision for intellectual content. All authors contributed to drafting the text. This project was supported by Alzheimer Nederland (standard grant nr. 15007 ). Appendix A Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2020",

month = jan,

doi = "10.1016/j.neurobiolaging.2019.09.020",

language = "English",

volume = "85",

pages = "96--103",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Science",

}

TY - JOUR

T1 - Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer's pathology

AU - Riphagen, Joost M.

AU - Ramakers, Inez H. G. M.

AU - Freeze, Whitney M.

AU - Pagen, Linda H. G.

AU - Hanseeuw, Bernard J.

AU - Verbeek, Marcel M.

AU - Verhey, Frans R. J.

AU - Jacobs, Heidi I. L.

N1 - Funding Information: Authors' contributions: JMR and HILJ contributed to conception and design of study, conducted statistical analyses. IHGMR, LHGP, FRV, MMV, and WMF contributed to data acquisition and analyses. BJH assisted in data interpretation and revision for intellectual content. All authors contributed to drafting the text. This project was supported by Alzheimer Nederland (standard grant nr. 15007). Funding Information: Authors' contributions: JMR and HILJ contributed to conception and design of study, conducted statistical analyses. IHGMR, LHGP, FRV, MMV, and WMF contributed to data acquisition and analyses. BJH assisted in data interpretation and revision for intellectual content. All authors contributed to drafting the text. This project was supported by Alzheimer Nederland (standard grant nr. 15007 ). Appendix A Publisher Copyright: © 2019 The Author(s)

PY - 2020/1

Y1 - 2020/1

N2 - The APOE-epsilon 4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-epsilon 4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1 beta, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau(181) and amyloid-beta(1-42) (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-epsilon 4 genotype. This suggests that APOE-epsilon 4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. (C) 2019 The Author(s). Published by Elsevier Inc.

AB - The APOE-epsilon 4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-epsilon 4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1 beta, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau(181) and amyloid-beta(1-42) (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-epsilon 4 genotype. This suggests that APOE-epsilon 4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. (C) 2019 The Author(s). Published by Elsevier Inc.

KW - Alzheimer's disease

KW - Inflammation

KW - Blood-brain barrier

KW - APOE

KW - Vascular

KW - MILD COGNITIVE IMPAIRMENT

KW - CEREBROSPINAL-FLUID

KW - SAMPLE-SIZE

KW - ASSOCIATION WORKGROUPS

KW - DIAGNOSTIC GUIDELINES

KW - NATIONAL INSTITUTE

KW - DISEASE

KW - DEMENTIA

KW - INTERLEUKIN-6

KW - TAU

U2 - 10.1016/j.neurobiolaging.2019.09.020

DO - 10.1016/j.neurobiolaging.2019.09.020

M3 - Article

C2 - 31733942

SN - 0197-4580

VL - 85

SP - 96

EP - 103

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -