Duezel, Emrah, Ziegler, Gabriel, Berron, David ORCID: 0000-0003-1558-1883, Maass, Anne, Schuetze, Hartmut, Cardenas-Blanco, Arturo, Glanz, Wenzel, Metzger, Coraline, Dobisch, Laura, Reuter, Martin ORCID: 0000-0002-2665-9693, Spottke, Annika, Brosseron, Frederic, Fliessbach, Klaus, Heneka, Michael T., Laske, Christoph, Peters, Oliver ORCID: 0000-0003-0568-2998, Priller, Josef, Spruth, Eike Jakob, Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Speck, Oliver, Schneider, Anja ORCID: 0000-0001-9540-8700, Teipel, Stefan, Kilimann, Ingo, Jens, Wiltfang, Schott, Bjoern-Hendrik, Preis, Lukas ORCID: 0000-0001-7601-6410, Gref, Daria, Maier, Franziska ORCID: 0000-0002-9335-9594, Munk, Matthias H., Roy, Nina, Ballarini, Tomasso, Yakupov, Renat, Haynes, John Dylan, Dechent, Peter, Scheffler, Klaus, Wagner, Michael and Jessen, Frank (2022). Amyloid pathology but not APOE epsilon 4 status is permissive for tau-related hippocampal dysfunction. Brain, 145 (4). S. 1473 - 1486. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A-) of amyloid pathology was defined by CSF amyloid-beta(42) (A beta 42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A- individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with A beta 42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and A beta 42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A- groups. After classifying this matched sample for phospho-tau pathology (T-/T+), individuals with A+/T+ were significantly more memory-impaired than A-/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer's disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer's disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Duezel, EmrahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziegler, GabrielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berron, DavidUNSPECIFIEDorcid.org/0000-0003-1558-1883UNSPECIFIED
Maass, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuetze, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cardenas-Blanco, ArturoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glanz, WenzelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Metzger, CoralineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dobisch, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reuter, MartinUNSPECIFIEDorcid.org/0000-0002-2665-9693UNSPECIFIED
Spottke, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brosseron, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fliessbach, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heneka, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laske, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, OliverUNSPECIFIEDorcid.org/0000-0003-0568-2998UNSPECIFIED
Priller, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spruth, Eike JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Speck, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, AnjaUNSPECIFIEDorcid.org/0000-0001-9540-8700UNSPECIFIED
Teipel, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kilimann, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jens, WiltfangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schott, Bjoern-HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preis, LukasUNSPECIFIEDorcid.org/0000-0001-7601-6410UNSPECIFIED
Gref, DariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, FranziskaUNSPECIFIEDorcid.org/0000-0002-9335-9594UNSPECIFIED
Munk, Matthias H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roy, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ballarini, TomassoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yakupov, RenatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haynes, John DylanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dechent, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jessen, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-694672
DOI: 10.1093/brain/awab405
Journal or Publication Title: Brain
Volume: 145
Number: 4
Page Range: S. 1473 - 1486
Date: 2022
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MILD COGNITIVE IMPAIRMENT; ALZHEIMERS ASSOCIATION WORKGROUPS; CEREBROSPINAL-FLUID; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; ENTORHINAL CORTEX; DISEASE; BIOMARKERS; DECLINE; BETAMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69467

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