Version history

{
  "pmid": "32376954",
  "doi": "10.1038/s41586-020-2247-3",
  "abstract": "1. Nature. 2020 May;581(7806):71-76. doi: 10.1038/s41586-020-2247-3. Epub 2020\nApr  29.\n\nAPOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.\n\nMontagne A(#)(1), Nation DA(#)(1)(2)(3)(4), Sagare AP(#)(1), Barisano G(#)(1), \nSweeney MD(#)(1), Chakhoyan A(1), Pachicano M(1), Joe E(2)(5), Nelson AR(1), \nD'Orazio LM(2)(5), Buennagel DP(6), Harrington MG(6), Benzinger TLS(7)(8), Fagan \nAM(8)(9)(10), Ringman JM(2)(5), Schneider LS(2)(5)(11), Morris JC(9)(10), Reiman \nEM(12), Caselli RJ(13), Chui HC(2)(5), Tcw J(14)(15), Chen Y(1), Pa J(2)(16), \nConti PS(17), Law M(2)(18)(19), Toga AW(2)(16), Zlokovic BV(20)(21).\n\nAuthor information:\n(1)Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, \nKeck School of Medicine, University of Southern California, Los Angeles, CA, \nUSA.\n(2)Alzheimer's Disease Research Center, Keck School of Medicine, University of \nSouthern California, Los Angeles, CA, USA.\n(3)Department of Psychological Science, University of California, Irvine, \nIrvine, CA, USA.\n(4)Institute for Memory Disorders and Neurological Impairments, University of \nCalifornia, Irvine, Irvine, CA, USA.\n(5)Department of Neurology, Keck School of Medicine, University of Southern \nCalifornia, Los Angeles, CA, USA.\n(6)Huntington Medical Research Institutes, Pasadena, CA, USA.\n(7)Department of Radiology, Washington University School of Medicine, St Louis, \nMO, USA.\n(8)The Hope Center for Neurodegenerative Disorders, Washington University School \nof Medicine, St Louis, MO, USA.\n(9)Department of Neurology, Washington University School of Medicine, St Louis, \nMO, USA.\n(10)The Knight Alzheimer's Disease Research Center, Washington University School \nof Medicine, St Louis, MO, USA.\n(11)Department of Psychiatry and Behavioral Sciences, University of Southern \nCalifornia, Los Angeles, CA, USA.\n(12)Banner Alzheimer Institute, Phoenix, AZ, USA.\n(13)Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.\n(14)Department of Neuroscience & Friedman Brain Institute, Icahn School of \nMedicine at Mount Sinai, New York, NY, USA.\n(15)Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at \nMount Sinai, New York, NY, USA.\n(16)Laboratory of Neuroimaging, USC Stevens Neuroimaging and Informatics \nInstitute, Keck School of Medicine, University of Southern California, Los \nAngeles, CA, USA.\n(17)Molecular Imaging Center, Department of Radiology, Keck School of Medicine, \nUniversity of Southern California, Los Angeles, CA, USA.\n(18)Department of Neurological Surgery, Keck School of Medicine, University of \nSouthern California, Los Angeles, CA, USA.\n(19)Department of Neuroscience and Radiology, Monash University, Alfred Health, \nMelbourne, Victoria, Australia.\n(20)Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, \nKeck School of Medicine, University of Southern California, Los Angeles, CA, \nUSA. zlokovic@usc.edu.\n(21)Alzheimer's Disease Research Center, Keck School of Medicine, University of \nSouthern California, Los Angeles, CA, USA. zlokovic@usc.edu.\n(#)Contributed equally\n\nComment in\n    Nature. 2020 May;581(7806):31-32. doi: 10.1038/d41586-020-01152-8.\n    Nat Rev Neurol. 2020 Jul;16(7):350. doi: 10.1038/s41582-020-0367-x.\n    J Cereb Blood Flow Metab. 2020 Sep;40(9):1912-1914. doi: \n10.1177/0271678X20938146.\n\nVascular contributions to dementia and Alzheimer's disease are increasingly \nrecognized1-6. Recent studies have suggested that breakdown of the blood-brain \nbarrier (BBB) is an early biomarker of human cognitive dysfunction7, including \nthe early clinical stages of Alzheimer's disease5,8-10. The E4 variant of \napolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's \ndisease11-14, leads to accelerated breakdown of the BBB and degeneration of \nbrain capillary pericytes15-19, which maintain BBB integrity20-22. It is \nunclear, however, whether the cerebrovascular effects of APOE4 contribute to \ncognitive impairment. Here we show that individuals bearing APOE4 (with the \nε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by \nbreakdown of the BBB in the hippocampus and medial temporal lobe. This finding \nis apparent in cognitively unimpaired APOE4 carriers and more severe in those \nwith cognitive impairment, but is not related to amyloid-β or tau pathology \nmeasured in cerebrospinal fluid or by positron emission tomography23. High \nbaseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the \ncerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not \nin non-carriers, even after controlling for amyloid-β and tau status, and were \ncorrelated with increased activity of the BBB-degrading cyclophilin A-matrix \nmetalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that \nbreakdown of the BBB contributes to APOE4-associated cognitive decline \nindependently of Alzheimer's disease pathology, and might be a therapeutic \ntarget in APOE4 carriers.\n\nDOI: 10.1038/s41586-020-2",
  "journal": "Nature",
  "year": 2020,
  "authors": "Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Pachicano M, Joe E, Nelson AR, D'Orazio LM",
  "url": "https://pubmed.ncbi.nlm.nih.gov/32376954",
  "external_ids": {
    "doi": "10.1038/s41586-020-2247-3",
    "pmid": "32376954"
  },
  "citation_count": 1,
  "domain": "neurodegeneration"
}