@article{ec47e2f2bb304a15bd8cff25587e2595,
title = "In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer's disease pathology and cognitive decline",
abstract = "Several autopsy studies recognize the locus coeruleus (LC) as the initial site of hyperphosphorylated TAU aggregation, and as the number of LC neurons harboring TAU increases, TAU pathology emerges throughout the cortex. By conjointly using dedicated MRI measures of LC integrity and TAU and amyloid PET imaging, we aimed to address the question whether in vivo LC measures relate to initial cortical patterns of Alzheimer's disease (AD) fibrillar proteinopathies or cognitive dysfunction in 174 cognitively unimpaired and impaired older individuals with longitudinal cognitive measures. To guide our interpretations, we verified these associations in autopsy data from 1524 Religious Orders Study and Rush Memory and Aging Project and 2145 National Alzheimer's Coordinating Center cases providing three different LC measures (pigmentation, tangle density, and neuronal density), Braak staging, beta-amyloid, and longitudinal cognitive measures. Lower LC integrity was associated with elevated TAU deposition in the entorhinal cortex among unimpaired individuals consistent with postmortem correlations between LC tangle density and successive Braak staging. LC pigmentation ratings correlated with LC neuronal density but not with LC tangle density and were particularly worse at advanced Braak stages. In the context of elevated.-amyloid, lower LC integrity and greater cortical tangle density were associated with greater TAU burden beyond the medial temporal lobe and retrospective memory decline. These findings support neuropathologic data in which early LC TAU accumulation relates to disease progression and identify LC integrity as a promising indicator of initial AD-related processes and subtle changes in cognitive trajectories of preclinical AD.",
keywords = "SURFACE-BASED ANALYSIS, DATA SET UDS, TAU PATHOLOGY, HUMAN BRAIN, MEMORY RETRIEVAL, OLDER PERSONS, RUSH MEMORY, BETA, ASSOCIATION, IMPAIRMENT",
author = "H.I.L. Jacobs and J.A. Becker and K. Kwong and N. Engels-Dominguez and P.C. Prokopiou and K.V. Papp and M. Properzi and O.L. Hampton and F.D. Uquillas and J.S. Sanchez and D.M. Rentz and {El Fakhri}, G. and M.D. Normandin and J.C. Price and D.A. Bennett and R.A. Sperling and K.A. Johnson",
note = "Funding Information: We would like to thank all the participants of the HABS and all participants contributing to the ROSMAP and NACC datasets. We thank J. Riphagen for assistance in formatting the figures. This work was supported by NIH grant P01 AG036694 (to R.A.S. and K.A.J.); NIH grant R01 AG046396 (to K.A.J.); NIH grant R01 AG062559 (to H.I.L.J.); NIH grants P30AG10161 (to D.A.B.), R01AG15819 (to D.A.B.), and R01AG17917 (to D.A.B.); NIH grants P41 EB022544 (to G.E.F.) and S10OD018035 (to G.E.F.); NIH grants P41 EB01589 (to B. Rosen), S10RR021110 (to B. Rosen), and S10OD010364 (to B. Rosen); NIH grants 1S10RR019307 (to B. Fishl) and S10RR023401 (to B. Fishl); NIH grant R01 AG050436 (to J.C.P.); and NIH grant R01 AG052414 (to J.C.P.). The NACC database and associated data providing ADRCs are funded by NIH grants U01 AG016976 (to W. Kukull) and U01 AG032984 (to G. Schellenberg), NIH grant P30 AG019610 (to E. Reiman), NIH grant P30 AG013846 (to N. Kowall), NIH grant P30 AG062428-01 (to J. Leverenz), NIH grant P50 AG008702 (to S. Small), NIH grant P50 AG025688 (to A. Levey), NIH grant P50 AG047266 (to T. Golde), NIH grant P30 AG010133 (to A. Saykin), NIH grant P50 AG005146 (to M. Albert), NIH grant P30 AG062421-01 (to B. Hyman), NIH grant P30 AG062422-01 (to R. Petersen), NIH grant P50 AG005138 (to M. Sano), NIH grant P30 AG008051 (to T. Wisniewski), NIH grant P30 AG013854 (to R. Vassar), NIH grant P30 AG008017 (to Jeffrey Kaye), NIH grant P30 AG010161 (to D.A.B.), NIH grant P50 AG047366 (to V. Henderson), NIH grant P30 AG010129 (to C. DeCarli), NIH grant P50 AG016573 (to F. LaFerla), NIH grant P30 AG062429-01(to J. Brewer), NIH grant P50 AG023501 (to B. Miller), NIH grant P30 AG035982 (to R. Swerdlow), NIH grant P30 AG028383 (to L. Van Eldik), NIH grant P30 AG053760 (to H. Paulson), NIH grant P30 AG010124 (to J. Trojanowski), NIH grant P50 AG005133 (to O. Lopez), NIH grant P50 AG005142 (to H. Chui), NIH grant P30 AG012300 (to R. Rosenberg), NIH grant P30 AG049638 (to S. Craft), NIH grant P50 AG005136 (to T. Grabowski), NIH grant P30 AG062715-01 (to S. Asthana), NIH grant P50 AG005681 (to J. Morris), and NIH grant P50 AG047270 (to S. Strittmatter). H.I.L.J. received funding from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant agreement (IF-2015-GF, 706714). Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved;",
year = "2021",
month = sep,
day = "22",
doi = "10.1126/scitranslmed.abj2511",
language = "English",
volume = "13",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "612",
}