APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline

doi:10.1038/s41586-020-2247-3

. 2020 May;581(7806):71-76.

doi: 10.1038/s41586-020-2247-3. Epub 2020 Apr 29.

APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline

Axel Montagne^#¹, Daniel A Nation^#^{1

2

3

4}, Abhay P Sagare^#¹, Giuseppe Barisano^#¹, Melanie D Sweeney^#¹, Ararat Chakhoyan¹, Maricarmen Pachicano¹, Elizabeth Joe^{2

5}, Amy R Nelson¹, Lina M D'Orazio^{2

5}, David P Buennagel⁶, Michael G Harrington⁶, Tammie L S Benzinger^{7

8}, Anne M Fagan^{8

9

10}, John M Ringman^{2

5}, Lon S Schneider^{2

5

11}, John C Morris^{9

10}, Eric M Reiman¹², Richard J Caselli¹³, Helena C Chui^{2

5}, Julia Tcw^{14

15}, Yining Chen¹, Judy Pa^{2

16}, Peter S Conti¹⁷, Meng Law^{2

18

19}, Arthur W Toga^{2

16}, Berislav V Zlokovic^{20

21}

Affiliations

¹ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Psychological Science, University of California, Irvine, Irvine, CA, USA.
⁴ Institute for Memory Disorders and Neurological Impairments, University of California, Irvine, Irvine, CA, USA.
⁵ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Huntington Medical Research Institutes, Pasadena, CA, USA.
⁷ Department of Radiology, Washington University School of Medicine, St Louis, MO, USA.
⁸ The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St Louis, MO, USA.
⁹ Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
¹⁰ The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
¹² Banner Alzheimer Institute, Phoenix, AZ, USA.
¹³ Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
¹⁴ Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Laboratory of Neuroimaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁷ Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸ Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁹ Department of Neuroscience and Radiology, Monash University, Alfred Health, Melbourne, Victoria, Australia.
²⁰ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.
²¹ Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.

^# Contributed equally.

PMID: 32376954
PMCID: PMC7250000
DOI: 10.1038/s41586-020-2247-3

APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline

Axel Montagne et al. Nature. 2020 May.

. 2020 May;581(7806):71-76.

doi: 10.1038/s41586-020-2247-3. Epub 2020 Apr 29.

Authors

Affiliations

¹ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Psychological Science, University of California, Irvine, Irvine, CA, USA.
⁴ Institute for Memory Disorders and Neurological Impairments, University of California, Irvine, Irvine, CA, USA.
⁵ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Huntington Medical Research Institutes, Pasadena, CA, USA.
⁷ Department of Radiology, Washington University School of Medicine, St Louis, MO, USA.
⁸ The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St Louis, MO, USA.
⁹ Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
¹⁰ The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
¹² Banner Alzheimer Institute, Phoenix, AZ, USA.
¹³ Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
¹⁴ Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Laboratory of Neuroimaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁷ Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸ Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁹ Department of Neuroscience and Radiology, Monash University, Alfred Health, Melbourne, Victoria, Australia.
²⁰ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.
²¹ Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. zlokovic@usc.edu.

^# Contributed equally.

PMID: 32376954
PMCID: PMC7250000
DOI: 10.1038/s41586-020-2247-3

Abstract

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 dysfunction⁷, 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 tomography²³. 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 pathway¹⁹ 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.

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Conflict of interest statement

Competing Interests

The authors declare no competing interests.

Figures

**Extended Data Figure 1.. Regional BBB *K_trans* constant in eight additional brain regions in *APOE4* carriers and non-carriers (*APOE3*) with CDR status 0 and 0.5.**
DCE-MRI BBB permeability, *K_trans* constant, in the inferior temporal gyrus (ITG, a), superior frontal gyrus (SFG, b), caudate nucleus (CN, c), thalamus (Thal, d), striatum (Str, e), subcortical watershed normal-appearing white matter (Subcort. WS NAWM, f), corpus callosum (CC, g), and internal capsule (IC, h) in CDR 0 *APOE3* (black, n=128) and *APOE4* (red, n=68) carriers, CDR 0.5 *APOE3* (black, n=14) and *APOE4* (red, n=25) carriers. Violin plot continuous lines indicate median values and dotted lines indicate interquartile range. Significance by ANCOVAs for main effects and post-hoc comparisons controlling for age, sex, and education.

**Extended Data Figure 2.. BBB breakdown in the hippocampus and parahippocampal gyrus in *APOE4* carriers increases with cognitive domain impairment.**
(**a,b**) DCE-MRI BBB permeability, *K_trans* constant, in the hippocampus (HC, a) and parahippocampal gyrus (PHG, b) in individuals with 0 cognitive domain impaired that are *APOE3* (black, n=70) and *APOE4* (red, n=40) carriers, 1 cognitive domain impaired that are *APOE3* (black, n=18) and *APOE4* (red, n=21) carriers, and 2+ cognitive domains impaired that are *APOE3* (black, n=7) and *APOE4* (red, n=12) carriers. (**c,d**) *K_trans* (estimated marginal means ± SEM from ANCOVA models corrected for age, sex, education, CSF Aβ_1-42 and pTau status, and HC and PHG volumes) in the HC (c) and PHG (d) in individuals with 0 cognitive domain impaired that are *APOE3* (black, n=70) and *APOE4* (red, n=40) carriers, 1 cognitive domain impaired that are *APOE3* (black, n=18) and *APOE4* (red, n=21) carriers, and 2+ cognitive domains impaired that are *APOE3* (black, n=7) and *APOE4* (red, n=12) carriers. Panels a and b: Violin plot continuous lines indicate median values and dotted lines indicate interquartile range. Significance by ANCOVA for main effects and post-hoc comparisons controlling for age, sex, and education. All ANCOVA omnibus tests remained significant at false discovery rate threshold of 0.05.

**Extended Data Figure 3.. Regional BBB *K_trans* constant in eight additional brain regions in *APOE4* carriers and non-carriers (*APOE3*) with different degree of cognitive domain impairment.**
DCE-MRI BBB permeability, *K_trans* constant, in the inferior temporal gyrus (ITG, a), superior frontal gyrus (SFG, b), caudate nucleus (CN, c), thalamus (Thal, d), striatum (Str, e), subcortical watershed normal-appearing white matter (Subcort. WS NAWM, f), corpus callosum (CC, g), and internal capsule (IC, h) in individuals with 0 cognitive domain impaired that are *APOE3* (black, n=70) and *APOE4* (red, n=40) carriers, 1 cognitive domain impaired that are *APOE3* (black, n=18) and *APOE4* (red, n=21) carriers, and 2+ cognitive domains impaired that are *APOE3* (black, n=7) and *APOE4* (red, n=12) carriers. Violin plot continuous lines indicate median values and dotted lines indicate interquartile range. Significance tests from ANCOVAs for main effects and post-hoc comparisons controlling for age, sex, and education.

**Extended Data Figure 4.. Regional BBB *K_trans* constant in all studied brain regions in *APOE4* carriers and non-carriers (*APOE3*) in relation to vascular risk factors.**
DCE-MRI BBB permeability, *K_trans* constant, in the hippocampus (HC, a), parahippocampal gyrus (PHG, b), inferior temporal gyrus (ITG, c), superior frontal gyrus (SFG, d), caudate nucleus (CN, e), thalamus (Thal, f), striatum (Str, g), subcortical watershed normal-appearing white matter (Subcort. WS NAWM, h), corpus callosum (CC, i), and internal capsule (IC, j) in *APOE3* (black, n=80) and *APOE4* (red, n=42) carriers with 0-1 vascular risk factors (VRFs), and *APOE3* (black, n=58) and *APOE4* (red, n=51) carriers with 2+ VRFs. Violin plot continuous lines indicate median values and dotted lines indicate interquartile range. Significance by ANCOVAs for main effects and post-hoc comparisons controlling for age, sex, and education (ns=non-significant).

**Extended Data Figure 5.. Amyloid and tau PET analysis in *APOE4* carriers and correction of ¹⁸F-AV1451 off-target binding in the choroid plexus.**
All studies were performed in individuals with clinical dementia rating score 0. Amyloid and tau PET studies were conducted using ¹⁸F-Florbetaben (FBB) or ¹⁸F-Florbetapir (FBP), and ¹⁸F-Flortaucipir (AV1451), respectively. For amyloid PET data analysis, FBP and FBB datasets were combined. (a) Uptake of amyloid tracers by the orbital frontal cortex (OFC) in *APOE4* (n=29) relative to *APOE3* (n=45) carriers (voxel-wise 2-sample one-tailed t-tests). (b) Representative amyloid PET Standardized Uptake Value Ratios (SUVR) maps from *APOE3* homozygote (*APOE3*) (*upper*) and *APOE4* carrier (*APOE4*) (*lower*). Slices 1 and 2, regions-of-interest (ROIs) for amyloid PET and BBB DCE-MRI scans (see e). Arrow, amyloid tracer uptake by OFC. The *APOE3* and *APOE4* representative images used FBP. (c) Uptake of tau tracer shows undetectable tau accumulation in *APOE3* (n=60) or *APOE4* (n=37) carriers (voxel-wise 2-sample one-tailed t-tests). (d) Representative tau PET SUVR maps from *APOE3* (*upper*) and *APOE4* (*lower*) carriers. Slice 1 and slice 1’, ROIs for tau PET and BBB DCE-MRI scans (see e). (e) Coronal 3D scans of regions studied in main Figure 2: hippocampus (HC; red), parahippocampal gyrus (PHG; green), medial orbital frontal cortex (OFC; yellow), and inferior temporal gyrus (ITG; blue). (f) Correction of ¹⁸F-AV1451 off-target binding in the choroid plexus: *Step 1*) Hippocampus (HC) masks were generated from the 3D T1-weighted MP-RAGE; *Step 2*) Choroid plexus (CP) masks were generated from the T1-weighted VIBE image post-GBCA (flip angle = 15°) image; *Step 3*) HC and CP masks were overlaid (arrowheads, red); and *Step 4*) CP overlap with HC masks (arrowheads, yellow) were subtracted to obtain CP-corrected HC tau PET signal after adding 6-mm voxel size on top of CP mask generated from DCE data. (g) Representative images of HC tau PET signal before (*left*) and after (*right*) applying the CP correction (arrows and white dotted lines = overlap between HC and CP).

**Extended Data Figure 6.. CSF biomarkers of glia and inflammatory response and endothelial and neuronal cell injury in *APOE4* carriers and non-carriers (*APOE3*).**
(a) CSF astrocytic S100 calcium-binding protein B (S100B) levels in CDR 0 *APOE3* (black, n=77) and *APOE4* (red, n=41) carriers, and CDR 0.5 *APOE3* (black, n=39) and *APOE4* (red, n=32) carriers. (b) CSF interleukin 6 (IL6) levels in CDR 0 *APOE3* (black, n=71) and *APOE4* (red, n=47) carriers, and CDR 0.5 *APOE3* (black, n=34) and *APOE4* (red, n=32) carriers. (c) CSF interferon gamma (IFNγ) levels in CDR 0 *APOE3* (black, n=54) and *APOE4* (red, n=29) carriers, and CDR 0.5 *APOE3* (black, n=25) and *APOE4* (red, n=17) carriers. (d) CSF interleukin 1β (IL1β) levels in CDR 0 *APOE3* (black, n=43) and *APOE4* (red, n=18) carriers, and CDR 0.5 *APOE3* (black, n=17) and *APOE4* (red, n=13) carriers. (e) CSF tumor necrosis factor α (TNFα) levels in CDR 0 *APOE3* (black, n=70) and *APOE4* (red, n=46) carriers, and CDR 0.5 *APOE3* (black, n=34) and *APOE4* (red, n=32) carriers. (f) CSF soluble intercellular adhesion molecule 1 (sICAM1) levels in CDR 0 *APOE3* (black, n=77) and *APOE4* (red, n=40) carriers, and CDR 0.5 *APOE3* (black, n=39) and *APOE4* (red, n=33) carriers. (g) CSF Neuron-Specific Enolase (NSE) levels in CDR 0 *APOE3* (black, n=47) and *APOE4* (red, n=32) carriers, and CDR 0.5 *APOE3* (black, n=29) and *APOE4* (red, n=29) carriers. Violin plot continuous lines indicate median values and dotted lines indicate interquartile range. Panels a and b had one outlier each, which were removed prior to statistical analysis using methods described in Statistical Analyses section. Significance by ANCOVAs for main effects and post-hoc comparisons controlling for age, sex, and education (ns=non-significant).

**Extended Data Figure 7.. Lower CSF Aβ_1-42 and increased pTau levels in *APOE4* carriers with cognitive impairment.**
(a) CSF Aβ_1-42 levels in CDR 0 *APOE3* (black, n=141) and *APOE4* (red, n=83) and CDR 0.5 *APOE3* (black, n=39) and *APOE4* (red, n=41) carriers. (b) CSF Aβ_1-42 levels in *APOE3* (black, n=89) and *APOE4* (red, n=55) carriers with 0 cognitive domain impaired, *APOE3* (black, n=29) and *APOE4* (red, n=31) carriers with 1 cognitive domain impaired, and *APOE3* (black, n=17) and *APOE4* (red, n=14) carriers with 2+ cognitive domains impaired. (c) CSF Aβ_1-42 levels (estimated marginal means ± SEM from ANCOVA models corrected for age, sex, education, and CSF sPDGFRβ levels) in CDR 0 *APOE3* (black, n=141) and *APOE4* (red, n=83) and CDR 0.5 *APOE3* (black, n=39) and *APOE4* (red, n=41) carriers. (d) CSF pTau levels in CDR 0 *APOE3* (black, n=141) and *APOE4* (red, n=82) and CDR 0.5 *APOE3* (black, n=39) and *APOE4* (red, n=43) carriers. (e) CSF pTau levels in *APOE3* (black, n=89) and *APOE4* (red, n=56) carriers with 0 cognitive domain impaired, *APOE3* (black, n=29) and *APOE4* (red, n=30) carriers with 1 cognitive domain impaired, and *APOE3* (black, n=17) and *APOE4* (red, n=15) carriers with 2+ cognitive domains impaired. (f) CSF pTau levels (estimated marginal means ± SEM from ANCOVA models corrected for age, sex, education, and CSF sPDGFRβ levels) in CDR 0 *APOE3* (black, n=141) and *APOE4* (red, n=82) and CDR 0.5 *APOE3* (black, n=39) and *APOE4* (red, n=43) carriers. Violin plot continuous lines indicate median values and dotted lines indicate interquartile range. CSF Aβ_1-42 and pTau values were log10-transformed due to non-normal distribution prior to statistical analysis. Significance tests from ANCOVAs for main effects and post-hoc comparisons controlling for age, sex, and education.

**Extended Data Figure 8.. Full scans of western blots.**
Full scans of western blots for CypA shown in Figure 4 panel m (top).

**Figure 1.. Blood-brain barrier breakdown in the hippocampus and parahippocampal gyrus in *APOE4* carriers increases with cognitive impairment independently of CSF Aβ and tau status.**
(a,b) Blood-brain barrier (BBB) permeability *K_trans* maps generated by dynamic contrast-enhanced magnetic resonance imaging in the hippocampus (HC) of *APOE3* homozygotes (*APOE3*) and *APOE4* carriers (*APOE4*) with clinical dementia rating (CDR) score 0 or 0.5. (c,d) BBB permeability, *K_trans* constant, in the HC (c) and parahippocampal gyrus (PHG, d) in CDR 0 *APOE3* (black, n=128) and *APOE4* (red, n=68) and CDR 0.5 *APOE3* (black, n=14) and *APOE4* (red, n=25) carriers. (e,f) *K_trans* values in the HC (e) and PHG (f) in *APOE4* carriers CDR 0 Aβ_1-42 negative (Aβ-; n=37) or positive (Aβ+; n=16), and CDR 0.5 Aβ- (n=7) or Aβ+ (n=10). (g,h) *K_trans* values in the HC (g) and PHG (h) in *APOE4* carriers CDR 0 pTau negative (pTau−; n=42) or positive (pTau+; n=10), and CDR 0.5 pTau− (n=13) or pTau+ (n=5). (i) HC (blue) and PHG (orange) overlaid on a 3D template. (j,k) HC (j) and PHG (k) volumes in CDR 0 *APOE3* (n=124) and *APOE4* (n=75) and CDR 0.5 *APOE3* (n=13) and *APOE4* (n=20) carriers. (l,m) *K_trans* (estimated marginal means ± SEM from ANCOVA models corrected for age, sex, education, CSF Aβ_1-42 and pTau status, and HC and PHG volumes) in the HC (l) and PHG (m) in CDR 0 *APOE3* (black, HC n=125; PHG n=128) and *APOE4* (red, HC and PHG n=68) and CDR 0.5 *APOE3* (black, HC n=12; PHG n=14) and *APOE4* (red, HC n=20; PHG n=25) carriers. In **c-h**, j, and k, continuous line indicates median value; dotted line indicates interquartile range. Significance by ANCOVA for main effects and post-hoc comparisons controlling for age, sex, and education. All ANCOVA omnibus tests remained significant at false discovery rate threshold of 0.05.

**Figure 2.. Blood-brain barrier breakdown in *APOE4* carriers is independent of amyloid and tau brain accumulation.**
All studies were performed in individuals with clinical dementia rating score 0. (a) Representative superimposed left-hippocampus (HC) amyloid PET (*top*), tau PET (*middle*), and BBB *K_trans* maps (*bottom*) from *APOE3* (*left*) and *APOE4* (*right*) carriers. (b,c) HC: amyloid and tau tracer uptake (b) and BBB *K_trans* constant (c) in *APOE3* (n=45, 60, and 65) and *APOE4* (n=29, 37, and 31) carriers. (d) Representative superimposed left-parahippocampal gyrus (PHG) amyloid PET (*top*), tau PET (*middle*), and BBB *K_trans* maps (*bottom*) from *APOE3* (*left*) and *APOE4* (*right*) carriers. (e,f) PHG: amyloid and tau tracer uptake (e) and BBB *K_trans* constant (f) in *APOE3* (n=45, 60, and 65) and *APOE4* (n=29, 37, and 31) carriers. (g) Representative superimposed left-medial orbital frontal cortex (OFC) amyloid PET (*top*) and BBB *K_trans* maps (*bottom*) from *APOE3* (*left*) and *APOE4* (*right*) carriers. (h,i) OFC: amyloid tracer uptake (h) and BBB *K_trans* constant (i) in *APOE3* (n=45 and 44) and *APOE4* (n=29 and 23) carriers. (j) Representative superimposed left-inferior temporal gyrus (ITG) tau PET (*top*) and BBB *K_trans* maps (*bottom*) from *APOE3* (*left*) and *APOE4* (*right*) carriers. (k,l) ITG: tau tracer uptake (l) and BBB *K_trans* constant (l) in *APOE3* (n=60 and 59) and *APOE4* (n=37 and 28) carriers. In b, c, e, f, h, i, k, and l, continuous lines indicate median values and dotted lines indicate interquartile range. The BBB *K_trans* constant was determined in all participants (see Extended Data Tables 2a,b) who received either both amyloid and tau tracers (n=58), only amyloid tracer (n=9) or only tau tracer (n= 29). Significance by ANCOVA for group comparisons controlling for age, sex, and education, and one-tailed t-tests for comparison of PET values to SUVR = 1.

**Figure 3.. Elevated baseline CSF levels of pericyte injury biomarker sPDGFRβ predict cognitive decline in *APOE4* carriers.**
(a) Histogram frequency distribution of CSF sPDGFRβ values using median split to divide participants into two groups with high (*blue*, above median 600-2,000 ng/ml) and low (*grey*, below median; 0-600 ng/ml) baseline CSF sPDGFRβ levels. All longitudinal analyses used baseline CSF sPDGFRβ as a continuous predictor of future cognitive decline. (**b-c**) Linear mixed model analysis of all studied participants (n=146) followed over 2-year intervals for up to 4.5 years after baseline lumbar puncture (LP) shows that higher baseline CSF sPDGFRβ (*blue*) predicts greater decline in demographically-corrected mental status exam scores over time (p=0.01), which remains significant after controlling for CSF Aβ (p=0.002) and pTau (p=0.002) status (b), and in global cognitive composite scores (p=0.01), which also remains significant after controlling for CSF Aβ (p=0.017) and pTau (p=0.01) status (c). (**d-e**) Higher CSF sPDGFRβ (*blue*) in *APOE4* carriers (n=58) predicts future decline in mental status exam scores (p=0.005) after controlling for CSF Aβ (p=0.004) and pTau (p=0.003) status (d), and in global cognitive composite scores (p=0.02) after controlling for CSF Aβ (p=0.02) and pTau (p=0.01) status (e). (**f-g**) Baseline CSF sPDGFRβ does not predict decline in *APOE3* homozygotes (n=88) on either mental status (f) or global composite (g) scores regardless of CSF Aβ or pTau status. Panels **b-g**, for graphical depiction, separate lines indicate median split of baseline CSF sPDGFRβ (*grey*, below median; *blue*, above median). ∆ slopes provided for median split of baseline CSF sPDGFRβ groups (*grey*, below median; *blue*, above median). Time was modeled as t₀ = −1 to 0.5 years post-LP, t₁ = 0.5 to 2.5 years post-LP, and t₂ = 2.5 to 4.5 years post-LP. The error bars are SE of the estimate. In panels **b-g**, significance by linear mixed model analysis; no multiple comparison correction applied. See Supplementary Information Tables 2–4 for detailed statistics.

**Figure 4.. Elevated CSF sPDGFRβ, cyclophilin A and matrix metalloproteinase-9 in *APOE4* carriers.**
(a) CSF sPDGFRβ in CDR 0 *APOE3* (black, n=152) and *APOE4* (red, n=95) and CDR 0.5 *APOE3* (black, n=42) and *APOE4* (red, n=45) carriers. (b) CSF sPDGFRβ (estimated marginal means ± SEM from ANCOVA models corrected for age, sex, education, CSF Aβ_1-42 and pTau status) in CDR 0 *APOE3* (black, n=152) and *APOE4* (red, n=95) and CDR 0.5 *APOE3* (black, n=42) and *APOE4* (red, n=45) carriers. (**c,d**) CSF sPDGFRβ and BBB *K_trans* correlation in the hippocampus (HC, n=65; c) and parahippocampal gyrus (PHG, n=65; d) in *APOE4* carriers. (**e-g**) Correlations between CSF sPDGFRβ and albumin quotient (Qalb, n=92; e), fibrinogen (n=93; f), and plasminogen (n=57; g) in *APOE4* carriers. (h) CSF cyclophilin A (CypA) in CDR 0 *APOE3* (black, n=75) and *APOE4* (red, n=62) and CDR 0.5 *APOE3* (black, n=33) and *APOE4* (red, n=45) carriers. (i) CSF CypA (estimated marginal means ± SEM from ANCOVA models corrected for age, sex, education, CSF Aβ_1-42 and pTau status) in CDR 0 *APOE3* (black, n=75) and *APOE4* (red, n=62) and CDR 0.5 *APOE3* (black, n=33) and *APOE4* (red, n=45) carriers. (j) CSF CypA and sPDGFRβ correlation in *APOE4* carriers (n=96). (k) CSF matrix metalloproteinase-9 (MMP9) in CDR 0 *APOE3* (black, n=72) and *APOE4* (red, n=68) and CDR 0.5 *APOE3* (black, n=33) and *APOE4* (red, n=45) carriers. (l) CSF MMP9 and CypA correlation in *APOE4* carriers (n=104). (**m,n**) CypA (m; see Extended Data Fig. 8), and secreted MMP9 in the culture medium (n), in human iPSC-derived *APOE3* (ε3/ε3) and *APOE4* (ε4/ε4) pericytes. Mean + SEM from four independent culture replicates. In **a, h** and k, continuous lines indicate median values and dotted lines interquartile range. Significance by ANCOVA for main effects and post-hoc comparisons controlling for age, sex, and education. Panels **c-g**, j, and l: two-tailed simple linear regression; Pearson correlation coefficient (r). Panels m and n, unpaired one-tailed Student t-test.

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Comment in

Risk factor for Alzheimer's disease breaks the blood-brain barrier.
Ishii M, Iadecola C. Ishii M, et al. Nature. 2020 May;581(7806):31-32. doi: 10.1038/d41586-020-01152-8. Nature. 2020. PMID: 32350425 Free PMC article.
APOE*ε4 is linked to BBB breakdown.
Wood H. Wood H. Nat Rev Neurol. 2020 Jul;16(7):350. doi: 10.1038/s41582-020-0367-x. Nat Rev Neurol. 2020. PMID: 32393877 No abstract available.
Leaky memories: Impact of APOE4 on blood-brain barrier and dementia.
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References

1. Wardlaw JM et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013). - PMC - PubMed
1. Kapasi A, DeCarli C & Schneider JA Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. (Berl.) 134, 171–186 (2017). - PMC - PubMed
1. Iadecola C The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96, 17–42 (2017). - PMC - PubMed
1. Iturria-Medina Y et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun 7, 11934 (2016). - PMC - PubMed
1. Sweeney MD, Sagare AP & Zlokovic BV Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol 14, 133–150 (2018). - PMC - PubMed

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[1] Wardlaw JM et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013). - PMC - PubMed

[2] Wardlaw JM et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013). - PMC - PubMed

[3] Kapasi A, DeCarli C & Schneider JA Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. (Berl.) 134, 171–186 (2017). - PMC - PubMed

[4] Kapasi A, DeCarli C & Schneider JA Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. (Berl.) 134, 171–186 (2017). - PMC - PubMed

[5] Iadecola C The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96, 17–42 (2017). - PMC - PubMed

[6] Iadecola C The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96, 17–42 (2017). - PMC - PubMed

[7] Iturria-Medina Y et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun 7, 11934 (2016). - PMC - PubMed

[8] Iturria-Medina Y et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun 7, 11934 (2016). - PMC - PubMed

[9] Sweeney MD, Sagare AP & Zlokovic BV Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol 14, 133–150 (2018). - PMC - PubMed

[10] Sweeney MD, Sagare AP & Zlokovic BV Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol 14, 133–150 (2018). - PMC - PubMed

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APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline

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APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline

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