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

Neurobiol Aging. 2020 Jan:85:96-103. doi: 10.1016/j.neurobiolaging.2019.09.020. Epub 2019 Oct 15.

Authors

Joost M Riphagen¹, Inez H G M Ramakers², Whitney M Freeze², Linda H G Pagen², Bernard J Hanseeuw³, Marcel M Verbeek⁴, Frans R J Verhey², Heidi I L Jacobs⁵

Affiliations

¹ Department of Psychiatry & Neuropsychology, Maastricht University, School for Mental Health & Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands; Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Electronic address: joost.riphagen@maastrichtuniversity.nl.
² Department of Psychiatry & Neuropsychology, Maastricht University, School for Mental Health & Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.
³ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Cliniques Universitaires Saint-Luc and Institute of Neurosciences, Université Catholique de Louvain, Brussels, Belgium.
⁴ Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Department of Psychiatry & Neuropsychology, Maastricht University, School for Mental Health & Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands; Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

PMID: 31733942
DOI: 10.1016/j.neurobiolaging.2019.09.020

Abstract

The APOE-ε4 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-ε4 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-1β, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau₁₈₁ and amyloid-β_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-ε4 genotype. This suggests that APOE-ε4-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.

Keywords: APOE; Alzheimer's disease; Blood-brain barrier; Inflammation; Vascular.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Alzheimer Disease / genetics
Alzheimer Disease / pathology*
Apolipoproteins E / genetics*
Blood-Brain Barrier / physiopathology*
Cyclophosphamide / analogs & derivatives
Female
Humans
Inflammation
Interleukin-6 / cerebrospinal fluid
Male
Middle Aged
Risk

Substances

Apolipoproteins E
IL6 protein, human
Interleukin-6
Cyclophosphamide
trofosfamide