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Journal Article
APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline
2020
Overview
Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized
1
–
6
. Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction
7
, including the early clinical stages of Alzheimer’s disease
5
,
8
–
10
. The E4 variant of
apolipoprotein E
(
APOE4
), the main susceptibility gene for Alzheimer’s disease
11
–
14
, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes
15
–
19
, which maintain BBB integrity
20
–
22
. It is unclear, however, whether the cerebrovascular effects of
APOE4
contribute to cognitive impairment. Here we show that individuals bearing
APOE4
(with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without
APOE4
(ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired
APOE4
carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography
23
. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ
7
,
8
in the cerebrospinal fluid predicted future cognitive decline in
APOE4
carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway
19
in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to
APOE4
-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in
APOE4
carriers.
Breakdown of the blood–brain barrier in individuals carrying the ε4 allele of the
APOE
gene, but not the ε3 allele, increases with and predicts cognitive impairment and is independent of amyloid β or tau pathology.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 59/78
/ 82/1
/ 82/80
/ Alleles
/ Alzheimer Disease - genetics
/ Alzheimer Disease - pathology
/ Amyloid
/ Amyloid beta-Peptides - cerebrospinal fluid
/ Amyloid beta-Peptides - metabolism
/ Apolipoprotein E4 - genetics
/ Blood-Brain Barrier - pathology
/ Cognitive Dysfunction - genetics
/ Cognitive Dysfunction - pathology
/ Cyclophilin A - cerebrospinal fluid
/ Dementia
/ Female
/ Humanities and Social Sciences
/ Humans
/ Male
/ Matrix Metalloproteinase 9 - cerebrospinal fluid
/ Matrix Metalloproteinase 9 - metabolism
/ Parahippocampal Gyrus - blood supply
/ Positron-Emission Tomography
/ Receptor, Platelet-Derived Growth Factor beta - cerebrospinal fluid
/ Science
/ tau Proteins - cerebrospinal fluid
