APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.

1. Nature. 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. Montagne A(#)(1), Nation DA(#)(1)(2)(3)(4), Sagare AP(#)(1), Barisano G(#)(1), Sweeney MD(#)(1), Chakhoyan A(1), Pachicano M(1), Joe E(2)(5), Nelson AR(1), D'Orazio LM(2)(5), Buennagel DP(6), Harrington MG(6), Benzinger TLS(7)(8), Fagan AM(8)(9)(10), Ringman JM(2)(5), Schneider LS(2)(5)(11), Morris JC(9)(10), Reiman EM(12), Caselli RJ(13), Chui HC(2)(5), Tcw J(14)(15), Chen Y(1), Pa J(2)(16), Conti PS(17), Law M(2)(18)(19), Toga AW(2)(16), Zlokovic BV(20)(21). Author information: (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 Comment in Nature. 2020 May;581(7806):31-32. doi: 10.1038/d41586-020-01152-8. Nat Rev Neurol. 2020 Jul;16(7):350. doi: 10.1038/s41582-020-0367-x. J Cereb Blood Flow Metab. 2020 Sep;40(9):1912-1914. doi: 10.1177/0271678X20938146. 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-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 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. DOI: 10.1038/s41586-020-2