TY - JOUR
T1 - APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline
AU - Montagne, Axel
AU - Nation, Daniel A.
AU - Sagare, Abhay P.
AU - Barisano, Giuseppe
AU - Sweeney, Melanie D.
AU - Chakhoyan, Ararat
AU - Pachicano, Maricarmen
AU - Joe, Elizabeth
AU - Nelson, Amy R.
AU - D’Orazio, Lina M.
AU - Buennagel, David P.
AU - Harrington, Michael G.
AU - Benzinger, Tammie L.S.
AU - Fagan, Anne M.
AU - Ringman, John M.
AU - Schneider, Lon S.
AU - Morris, John C.
AU - Reiman, Eric M.
AU - Caselli, Richard J.
AU - Chui, Helena C.
AU - Tcw, Julia
AU - Chen, Yining
AU - Pa, Judy
AU - Conti, Peter S.
AU - Law, Meng
AU - Toga, Arthur W.
AU - Zlokovic, Berislav V.
N1 - Funding Information:
Acknowledgements The work of B.V.Z. is supported by National Institutes of Health (NIH) grant nos. R01AG023084, R01NS034467, R01AG039452, 5P01AG052350 and 5P50AG005142, in addition to an Alzheimer’s Association strategic 509279 grant, Cure Alzheimer’s Fund, the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference no. 16 CVD 05, and Open Philanthropy. D.A.N. is supported by NIH grant nos. R01AG060049, R01AG064228, P01AG052350 and P50AG016573, Alzheimer’s Association grant AARG-17–532905 and Alzheimer’s Association strategic grant 509279. D.P.B and M.G.H. are supported by the L. K. Whittier Foundation, grant nos. P01AG052350, R01AG054434 and R01AG055770. Enrolment of participants into the WashU Knight ADRC is supported by NIH grant nos. P50AG05681, P01AG03991 and P01AG026276 (J.C.M.). E.M.R. is supported by National Institute of Aging (NIA) grant nos. P30AG19610 and R01AG031581, in addition to the state of Arizona. Enrolment of participants into the USC ADRC is supported by NIH grant no. 5P50AG005142 (H.C.C.). Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, provided doses of FBP and financial support for FBP scanning at the WashU site. Avid Radiopharmaceuticals also provided the WashU site with AV1451 precursor and technology transfer for producing the tracer on site. Avid Radiopharmaceuticals was not involved in data analysis or interpretation.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/5/7
Y1 - 2020/5/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85083961465&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2247-3
DO - 10.1038/s41586-020-2247-3
M3 - Article
C2 - 32376954
AN - SCOPUS:85083961465
VL - 581
SP - 71
EP - 76
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7806
ER -