Alzheimer's disease; biomarkers; diffusion tensor imaging; entorhinal cortex; locus coeruleus; magnetic resonance imaging; microstructural integrity; neurite orientation dispersion and density imaging; preclinical; tau; white matter; tau Proteins; Glial Fibrillary Acidic Protein; Biomarkers; MAPT protein, human; Humans; Male; Female; Aged; Biomarkers/blood; Middle Aged; Diffusion Magnetic Resonance Imaging; Neural Pathways/diagnostic imaging; Neural Pathways/pathology; tau Proteins/blood; Locus Coeruleus/diagnostic imaging; Locus Coeruleus/pathology; Glial Fibrillary Acidic Protein/blood; Entorhinal Cortex/diagnostic imaging; Entorhinal Cortex/pathology; Alzheimer Disease/blood; Alzheimer Disease/pathology; Neural Pathways; Epidemiology; Health Policy; Developmental Neuroscience; Neurology (clinical); Geriatrics and Gerontology; Cellular and Molecular Neuroscience; Psychiatry and Mental Health
Abstract :
[en] INTRODUCTION: Pretangle tau inclusions from the locus coeruleus (LC) are hypothesized to propagate to the entorhinal cortex (EC) via neuron-to-neuron transmission along its projections. The lower integrity of the LC-EC pathway accompanying Alzheimer's disease (AD) pathology is supported by post mortem studies, but in vivo evidence remains limited.
METHODS: We associated diffusion-weighted 7T magnetic resonance imaging (MRI) metrics of microstructural integrity within the LC-EC tract to plasma AD-related biomarkers in a cohort of 47 cognitively unimpaired adults.
RESULTS: Worse overall and local LC-EC integrity, indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), was related to elevated concentrations of plasma phosphorylated tau 181 (p-tau181), p-tau217, and glial fibrillary acidic protein (GFAP). A higher orientation dispersion index (ODI) within the LC-EC tract was linked to elevated plasma p-tau181 and p-tau231 levels.
DISCUSSION: The lower integrity of the LC-EC pathway may serve as a key indicator of the earliest AD-related pathophysiological processes to improve detection of at-risk individuals.
HIGHLIGHTS: Standard DTI model metrics in the LC- EC tract are linked to elevated plasma p-tau and GFAP. A higher ODI in the voxels containing the LC-EC tract is related to elevated plasma p-tau. LC-EC integrity links to AD-related biomarkers show topographic specificity. Lower LC-EC integrity may be a key indicator of the earliest AD-related pathology.
Disciplines :
Neurology Radiology, nuclear medicine & imaging Neurosciences & behavior
Author, co-author :
Patsyuk, Yuliya; Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Centre Limburg, Maastricht University, Maastricht, Netherlands
Van Egroo, Maxime; Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Centre Limburg, Maastricht University, Maastricht, Netherlands ; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Beckers, Elise ; Université de Liège - ULiège > GIGA ; Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Centre Limburg, Maastricht University, Maastricht, Netherlands
Koops, Elouise A; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Ashton, Nicholas J; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden ; Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway ; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, UK ; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK
Janelidze, Shorena; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
Blennow, Kaj; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden ; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Hansson, Oskar; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
Zetterberg, Henrik; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden ; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK ; UK Dementia Research Institute at UCL, London, UK ; Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China ; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA ; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
Poser, Benedikt A; Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands ; Maastricht Brain Imaging Centre, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
Jacobs, Heidi I L; Faculty of Health, Medicine and Life Sciences, Mental Health and Neuroscience Research Institute, Alzheimer Centre Limburg, Maastricht University, Maastricht, Netherlands ; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Language :
English
Title :
Locus coeruleus-entorhinal cortex tract integrity is linked to plasma tau and glial fibrillary acidic protein.
Publication date :
2025
Journal title :
Alzheimer's and Dementia: the Journal of the Alzheimer's Association
UK DRI - UK Dementia Research Institute EU - European Union Stiftelsen för Gamla Tjänarinnor CAF - Cure Alzheimer’s Fund KAW - Knut och Alice Wallenbergs Stiftelse Hjärnfonden ADDF - Alzheimer's Drug Discovery Foundation Sverige Vetenskapsrådet European Union. Marie Skłodowska-Curie Actions BrightFocus Foundation Alzheimer's Association Alzheimer Nederland
Funding text :
Yuliya Patsyuk (Conceptualization, Methodology, Formal analysis, Visualization, Writing \u2013 original draft, Writing \u2013 review and editing), Maxime Van Egroo (Conceptualization, Methodology, Supervision, Writing \u2013 original draft, Writing \u2013 review and editing), Elise Beckers (Methodology, Writing \u2013 review and editing), Elouise A. Koops (Methodology, Writing \u2013 review and editing), Nicholas J. Ashton (Methodology, Writing \u2013 review and editing), Shorena Janelidze (Methodology, Writing \u2013 review and editing), Kaj Blennow (Methodology, Writing \u2013 review and editing), Oskar Hansson (Methodology, Writing \u2013 review and editing), Henrik Zetterberg (Methodology, Writing \u2013 review and editing), Benedikt A. Poser (Writing \u2013 review and editing), and Heidi I. L. Jacobs (Conceptualization, Funding acquisition, Project administration, Supervision, Writing \u2013 original draft, Writing \u2013 review and editing). This work was supported by Alzheimer Nederland (WE.03\u20102019\u201002, Heidi I. L. Jacobs), Alzheimer's Association (AARG\u201022\u2010920434, Heidi I. L. Jacobs) and the BrightFocus Foundation (A20211016F, Maxime Van Egroo). Maxime Van Egroo is supported by European Union's Marie Sk\u0142odowska\u2010Curie Actions (101109451\u2010ADEEPSLEEP). Kaj Blennow is supported by the Swedish Research Council (2017\u221200915), the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB\u2010201809\u20102016615), the Swedish Alzheimer Foundation (AF\u2010930351, AF\u2010939721, and AF\u2010968270), Hj\u00E4rnfonden, Sweden (FO2017\u20100243 and ALZ2022\u20100006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF\u2010agreement (ALFGBG\u2010715986 and ALFGBG\u2010965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019\u2010466\u2010236), the National Institute of Health (NIH), USA, (grant 1R01AG068398\u201001), and the Alzheimer's Association 2021 Zenith Award (ZEN\u201021\u2010848495). Oskar Hansson is supported by the Swedish Research Council (2016\u201300906), the Knut and Alice Wallenberg foundation (2017\u20130383), the Marianne and Marcus Wallenberg Foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Foundation (AF\u2010939932), the Swedish Brain Foundation (FO2021\u20130293), Parkinson Foundation of Sweden (1280/20), the Cure Alzheimer's Fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Sk\u00E5ne University Hospital Foundation (2020\u2010O000028), Regionalt Forskningsst\u00F6d (2020\u20130314), and the Swedish federal government under an ALF agreement (2018\u2010Projekt0279). Henrik Zetterberg is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (2023\u221200356; 2022\u221201018, and 2019\u201302397), the European Union's Horizon Europe Research and Innovation Programme under grant agreement no. 101053962, Swedish State Support for Clinical Research (ALFGBG\u201071320), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809\u20132016862), the AD Strategic Fund and the Alzheimer's Association (ADSF\u201021\u2010831376\u2010C, ADSF\u201021\u2010831381\u2010C, ADSF\u201021\u2010831377\u2010C, and ADSF\u201024\u20101284328\u2010C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling\u2010Persson Family Foundation, Stiftelsen f\u00F6r Gamla Tj\u00E4narinnor, Hj\u00E4rnfonden, Sweden (FO2022\u20100270), the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sk\u0142odowska\u2010Curie grant agreement no. 860197 (MIRIADE), the European Union Joint Programme\u2014Neurodegenerative Disease Research (JPND2021\u201000694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI\u20101003). Elouise A. Koops is supported by an Alzheimer's Association Research Fellowship (23AARF\u20101026796). Benedikt A. Poser is supported by H2020 FET\u2010Open AROMA grant agreement no. 88587. Heidi I. L. Jacobs is supported by NIH grants R01AG062559, R01AG06806, R01AG082006, and R21AG074220.
Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009;10(3):211–223. doi:10.1038/nrn2573
Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70(11):960–969. doi:10.1097/NEN.0b013e318232a379
Hary AT, Chadha S, Mercaldo N, et al. Locus coeruleus tau validates and informs high-resolution MRI in aging and at earliest Alzheimer's pathology stages. Acta Neuropathol Commun. 2025;13(1):44. doi:10.1186/s40478-025-01957-6
Stratmann K, Heinsen H, Korf HW, et al. Precortical phase of Alzheimer's disease (AD)-related tau cytoskeletal pathology. Brain Pathol. 2016;26(3):371–386. doi:10.1111/bpa.12289
Braak H, Del Tredici K. Alzheimer's pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol. 2011;121(5):589–595. doi:10.1007/s00401-011-0825-z
Gilvesy A, Husen E, Magloczky Z, et al. Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging. Acta Neuropathol. 2022;144(4):651–676. doi:10.1007/s00401-022-02477-6
Chu WT, Wang W-E, Zaborszky L, et al. Association of cognitive impairment with free water in the nucleus basalis of meynert and locus coeruleus to transentorhinal cortex tract. Neurology. 2022;98(7):e700–e710. doi:10.1212/WNL.0000000000013206
Quattrini G, Pini L, Boscolo Galazzo I, et al. Microstructural alterations in the locus coeruleus-entorhinal cortex pathway in Alzheimer's disease and frontotemporal dementia. Alzheimers Dement (Amst). 2024;16(1):e12513. doi:10.1002/dad2.12513
Sun W, Tang Y, Qiao Y, et al. A probabilistic atlas of locus coeruleus pathways to transentorhinal cortex for connectome imaging in Alzheimer's disease. NeuroImage. 2020;223:117301. doi:10.1016/j.neuroimage.2020.117301
Aiello M, Marizzoni M, Borrelli P, et al. Microstructural assessment of the locus coeruleus–entorhinal cortex pathway and association with ATN markers in cognitive impairment. Alzheimers Dement. 2025;21(4):e70126. doi:10.1002/alz.70126
Engels-Domínguez N, Koops EA, Prokopiou PC, et al. State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer's disease: challenges and opportunities. Neurosci Biobehav Rev. 2023;144:104998. doi:10.1016/j.neubiorev.2022.104998
Priovoulos N, Jacobs HIL, Ivanov D, Uludağ K, Verhey FRJ, Poser BA. High-resolution in vivo imaging of human locus coeruleus by magnetization transfer MRI at 3T and 7T. NeuroImage. 2018;168:427–436. doi:10.1016/j.neuroimage.2017.07.045
Zhang H, Schneider T, Wheeler-Kingshott CA, Alexander DC. NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. NeuroImage. 2012;61(4):1000–1016. doi:10.1016/j.neuroimage.2012.03.072
Beckers E, Egroo MV, Ashton NJ, et al. Microstructural associations between locus coeruleus, cortical, and subcortical regions are modulated by astrocyte reactivity: a 7T MRI adult lifespan study. Cereb Cortex. 2024;34(6):bhae261. doi:10.1093/cercor/bhae261
Van Egroo M, van Hooren RWE, Jacobs HIL. Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer's disease plasma biomarkers: a 7T MRI study. Alzheimers Res Ther. 2021;13(1):159. doi:10.1186/s13195-021-00902-8
Van Egroo M, Riphagen JM, Ashton NJ, et al. Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau. Mol Psychiatry. 2023;2023:1–11. doi:10.1038/s41380-023-02041-y. Published online April 5.
Marques JP, Kober T, Krueger G, van der Zwaag W, Van de Moortele PF, Gruetter R. MP2RAGE, a self-bias-field corrected sequence for improved segmentation and T1-mapping at high field. NeuroImage. 2010;49(2):1271–1281. doi:10.1016/j.neuroimage.2009.10.002
Fischl B. FreeSurfer. NeuroImage. 2012;62(2):774–781. doi:10.1016/j.neuroimage.2012.01.021
Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis: I. Segmentation and surface reconstruction. NeuroImage. 1999;9(2):179-194. doi:10.1006/nimg.1998.0395
Jenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. NeuroImage. 2012;62(2):782–790. doi:10.1016/j.neuroimage.2011.09.015
Desikan RS, Ségonne F, Fischl B, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage. 2006;31(3):968–980. doi:10.1016/j.neuroimage.2006.01.021
Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol. 2021;141(5):709–724. doi:10.1007/s00401-021-02275-6
Janelidze S, Berron D, Smith R, et al. Associations of plasma phospho-tau217 levels with tau positron emission tomography in early Alzheimer disease. JAMA Neurol. 2021;78(2):149–156. doi:10.1001/jamaneurol.2020.4201
Braak H, Del Tredici K. The preclinical phase of the pathological process underlying sporadic Alzheimer's disease. Brain. 2015;138(10):2814–2833. doi:10.1093/brain/awv236
Bueichekú E, Diez I, Kim CM, et al. Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition. Nat Aging. 2024;4(5):625–637. doi:10.1038/s43587-024-00626-y
Ehrenberg AJ, Nguy AK, Theofilas P, et al. Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease. Neuropathol Appl Neurobiol. 2017;43(5):393–408. doi:10.1111/nan.12387
Iba M, McBride JD, Guo JL, Zhang B, Trojanowski JQ, Lee VMY. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections. Acta Neuropathol. 2015;130(3):349–362. doi:10.1007/s00401-015-1458-4
Ghosh A, Torraville SE, Mukherjee B, et al. An experimental model of Braak's pretangle proposal for the origin of Alzheimer's disease: the role of locus coeruleus in early symptom development. Alzheimers Res Ther. 2019;11(1):59. doi:10.1186/s13195-019-0511-2
Lantero Rodriguez J, Karikari TK, Suárez-Calvet M, et al. Plasma p-tau181 accurately predicts Alzheimer's disease pathology at least 8 years prior to postmortem and improves the clinical characterization of cognitive decline. Acta Neuropathol. 2020;140(3):267–278. doi:10.1007/s00401-020-02195-x
Lehmann S, Schraen-Maschke S, Vidal JS, et al. Plasma phosphorylated-tau181 predicts amyloid status and conversion to dementia stage dependent on renal function. J Neurol Neurosurg Psychiatry. 2023;94(6):411–419. doi:10.1136/jnnp-2022-330540
Milà-Alomà M, Ashton NJ, Shekari M, et al. Publisher Correction: plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease. Nat Med. 2022;28(9):1965–1965. doi:10.1038/s41591-022-02037-1
Bayoumy S, Verberk IMW, den Dulk B, et al. Clinical and analytical comparison of six Simoa assays for plasma p-tau isoforms p-tau181, p-tau217, and p-tau231. Alzheimers Res Ther. 2021;13(1):198. doi:10.1186/s13195-021-00939-9
Mattsson-Carlgren N, Janelidze S, Palmqvist S, et al. Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease. Brain. 2020;143(11):3234–3241. doi:10.1093/brain/awaa286
Ercan-Herbst E, Ehrig J, Schöndorf DC, et al. A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early-stage Alzheimer's disease brain. Acta Neuropathol Commun. 2019;7:192. doi:10.1186/s40478-019-0823-2
Solders SK, Galinsky VL, Clark AL, et al. Diffusion MRI tractography of the locus coeruleus-transentorhinal cortex connections using GO-ESP. Magn Reson Med. 2022;87(4):1816–1831. doi:10.1002/mrm.29088
Jacobs HIL, Hedden T, Schultz AP, et al. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci. 2018;21(3):424–431. doi:10.1038/s41593-018-0070-z
Bozzali M, Falini A, Franceschi M, et al. White matter damage in Alzheimer's disease assessed in vivo using diffusion tensor magnetic resonance imaging. J Neurol Neurosurg Psychiatry. 2002;72(6):742–746. doi:10.1136/jnnp.72.6.742
Kantarci K, Murray ME, Schwarz CG, et al. White-matter integrity on DTI and the pathologic staging of Alzheimer's disease. Neurobiol Aging. 2017;56:172–179. doi:10.1016/j.neurobiolaging.2017.04.024
Medina D, DeToledo-Morrell L, Urresta F, et al. White matter changes in mild cognitive impairment and AD: a diffusion tensor imaging study. Neurobiol Aging. 2006;27(5):663–672. doi:10.1016/j.neurobiolaging.2005.03.026
Wen Q, Mustafi SM, Li J, et al. White matter alterations in early-stage Alzheimer's disease: a tract-specific study. Alzheimers Dement (Amst). 2019;11:576–587. doi:10.1016/j.dadm.2019.06.003
Zhang Y, Schuff N, Jahng GH, et al. Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology. 2007;68(1):13–19. doi:10.1212/01.wnl.0000250326.77323.01
Araque Caballero MÁ, Suárez-Calvet M, Duering M, et al. White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease. Brain J Neurol. 2018;141(10):3065–3080. doi:10.1093/brain/awy229
Nabizadeh F, Pourhamzeh M, Khani S, et al. Plasma phosphorylated-tau181 levels reflect white matter microstructural changes across Alzheimer's disease progression. Metab Brain Dis. 2022;37(3):761–771. doi:10.1007/s11011-022-00908-7
Fu X, Shrestha S, Sun M, et al. Microstructural white matter alterations in mild cognitive impairment and Alzheimer's disease. Clin Neuroradiol. 2020;30(3):569–579. doi:10.1007/s00062-019-00805-0
Wearn A, Tremblay SA, Tardif CL, et al. Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status. Nat Commun. 2024;15(1):4706. doi:10.1038/s41467-024-48490-z
Braun D, Madrigal JLM, Feinstein DL. Noradrenergic regulation of glial activation: molecular mechanisms and therapeutic implications. Curr Neuropharmacol. 2014;12(4):342–352. doi:10.2174/1570159X12666140828220938
Finnell JE, Moffitt CM, Hesser LA, et al. The contribution of the locus coeruleus-norepinephrine system in the emergence of defeat-induced inflammatory priming. Brain Behav Immun. 2019;79:102–113. doi:10.1016/j.bbi.2019.01.021
Heneka MT, Nadrigny F, Regen T, et al. Locus coeruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A. 2010;107(13):6058–6063. doi:10.1073/pnas.0909586107
Heneka MT, Ramanathan M, Jacobs AH, et al. Locus coeruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci Off J Soc Neurosci. 2006;26(5):1343–1354. doi:10.1523/JNEUROSCI.4236-05.2006
Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE. GFAP mRNA increases with age in rat and human brain. Neurobiol Aging. 1993;14(5):421–429. doi:10.1016/0197-4580(93)90100-p
Porchet R, Probst A, Bouras C, Dráberová E, Dráber P, Riederer BM. Analysis of glial acidic fibrillary protein in the human entorhinal cortex during aging and in Alzheimer's disease. Proteomics. 2003;3(8):1476–1485. doi:10.1002/pmic.200300456
Pillai EK, Franze K. Mechanics in the nervous system: from development to disease. Neuron. 2024;112(3):342–361. doi:10.1016/j.neuron.2023.10.005
Theofilas P, Ehrenberg AJ, Dunlop S, et al. Locus coeruleus volume and cell population changes during Alzheimer's disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2017;13(3):236–246. doi:10.1016/j.jalz.2016.06.2362
Olajide OJ, Suvanto ME, Chapman CA. Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer's disease. Biol Open. 2021;10(1):bio056796. doi:10.1242/bio.056796
Hara M, Hirokawa K, Kamei S, Uchihara T. Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology. Acta Neuropathol. 2013;125(4):565–579. doi:10.1007/s00401-013-1097-6
Uematsu M, Nakamura A, Ebashi M, Hirokawa K, Takahashi R, Uchihara T. Brainstem tau pathology in Alzheimer's disease is characterized by increase of three repeat tau and independent of amyloid β. Acta Neuropathol Commun. 2018;6(1):1. doi:10.1186/s40478-017-0501-1
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259. doi:10.1007/BF00308809
Thal DR, Rüb U, Orantes M, Braak H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791–1800. doi:10.1212/wnl.58.12.1791
