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APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.
Montagne, Axel; Nation, Daniel A; Sagare, Abhay P; Barisano, Giuseppe; Sweeney, Melanie D; Chakhoyan, Ararat; Pachicano, Maricarmen; Joe, Elizabeth; Nelson, Amy R; D'Orazio, Lina M; Buennagel, David P; Harrington, Michael G; Benzinger, Tammie L S; Fagan, Anne M; Ringman, John M; Schneider, Lon S; Morris, John C; Reiman, Eric M; Caselli, Richard J; Chui, Helena C; Tcw, Julia; Chen, Yining; Pa, Judy; Conti, Peter S; Law, Meng; Toga, Arthur W; Zlokovic, Berislav V.
Affiliation
  • Montagne A; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Nation DA; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Sagare AP; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Barisano G; Department of Psychological Science, University of California, Irvine, Irvine, CA, USA.
  • Sweeney MD; Institute for Memory Disorders and Neurological Impairments, University of California, Irvine, Irvine, CA, USA.
  • Chakhoyan A; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Pachicano M; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Joe E; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Nelson AR; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • D'Orazio LM; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Buennagel DP; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Harrington MG; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Benzinger TLS; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Fagan AM; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Ringman JM; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Schneider LS; Huntington Medical Research Institutes, Pasadena, CA, USA.
  • Morris JC; Huntington Medical Research Institutes, Pasadena, CA, USA.
  • Reiman EM; Department of Radiology, Washington University School of Medicine, St Louis, MO, USA.
  • Caselli RJ; The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St Louis, MO, USA.
  • Chui HC; The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St Louis, MO, USA.
  • Tcw J; Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
  • Chen Y; The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA.
  • Pa J; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Conti PS; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Law M; Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Toga AW; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Zlokovic BV; Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
Nature ; 581(7806): 71-76, 2020 05.
Article in En | MEDLINE | ID: mdl-32376954
ABSTRACT
Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. 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 disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. 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-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß 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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Blood-Brain Barrier / Apolipoprotein E4 / Cognitive Dysfunction Type of study: Prognostic_studies / Risk_factors_studies Limits: Female / Humans / Male Language: En Journal: Nature Year: 2020 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Blood-Brain Barrier / Apolipoprotein E4 / Cognitive Dysfunction Type of study: Prognostic_studies / Risk_factors_studies Limits: Female / Humans / Male Language: En Journal: Nature Year: 2020 Document type: Article Affiliation country: Estados Unidos