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000164071 0247_ $$2doi$$a10.1093/brain/awab405
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000164071 037__ $$aDZNE-2022-00734
000164071 041__ $$aEnglish
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000164071 1001_ $$0P:(DE-2719)2000005$$aDüzel, Emrah$$b0$$eFirst author$$udzne
000164071 245__ $$aAmyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction.
000164071 260__ $$aOxford$$bOxford Univ. Press$$c2022
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000164071 520__ $$aWe 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-β42 (Aβ42) 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 Aβ42 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 Aβ42 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.
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000164071 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
000164071 650_7 $$2Other$$aAlzheimer’s disease biomarker
000164071 650_7 $$2Other$$ahippocampus
000164071 650_7 $$2Other$$amemory
000164071 650_7 $$2Other$$amild cognitive impairment
000164071 650_7 $$2Other$$asubjective cognitive decline
000164071 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000164071 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000164071 650_2 $$2MeSH$$aAmyloidogenic Proteins
000164071 650_2 $$2MeSH$$aAmyloidosis
000164071 650_2 $$2MeSH$$aApolipoproteins E: genetics
000164071 650_2 $$2MeSH$$aBiomarkers
000164071 650_2 $$2MeSH$$aCognitive Dysfunction: diagnosis
000164071 650_2 $$2MeSH$$aCognitive Dysfunction: genetics
000164071 650_2 $$2MeSH$$aCross-Sectional Studies
000164071 650_2 $$2MeSH$$aHippocampus: metabolism
000164071 650_2 $$2MeSH$$aHumans
000164071 650_2 $$2MeSH$$atau Proteins: metabolism
000164071 693__ $$0EXP:(DE-2719)DELCODE-20140101$$5EXP:(DE-2719)DELCODE-20140101$$eLongitudinal Cognitive Impairment and Dementia Study$$x0
000164071 7001_ $$0P:(DE-2719)2814076$$aZiegler, Gabriel$$b1$$udzne
000164071 7001_ $$0P:(DE-2719)2812972$$aBerron, David$$b2$$udzne
000164071 7001_ $$0P:(DE-2719)2811815$$aMaaß, Anne$$b3$$udzne
000164071 7001_ $$0P:(DE-2719)9001467$$aSchütze, Hartmut$$b4$$udzne
000164071 7001_ $$0P:(DE-2719)2810750$$aCardenas-Blanco, Arturo$$b5$$udzne
000164071 7001_ $$0P:(DE-2719)2811614$$aGlanz, Wenzel$$b6$$udzne
000164071 7001_ $$0P:(DE-2719)9000443$$aMetzger, Coraline$$b7$$udzne
000164071 7001_ $$0P:(DE-2719)2811611$$aDobisch, Laura$$b8$$udzne
000164071 7001_ $$0P:(DE-2719)2812134$$aReuter, Martin$$b9$$udzne
000164071 7001_ $$0P:(DE-2719)2811324$$aSpottke, Annika$$b10$$udzne
000164071 7001_ $$0P:(DE-2719)2810593$$aBrosseron, Frederic$$b11$$udzne
000164071 7001_ $$0P:(DE-2719)2811326$$aFliessbach, Klaus$$b12$$udzne
000164071 7001_ $$0P:(DE-2719)2000008$$aHeneka, Michael T$$b13$$udzne
000164071 7001_ $$0P:(DE-2719)2000055$$aLaske, Christoph$$b14$$udzne
000164071 7001_ $$0P:(DE-2719)2811024$$aPeters, Oliver$$b15$$udzne
000164071 7001_ $$0P:(DE-2719)2811122$$aPriller, Josef$$b16$$udzne
000164071 7001_ $$0P:(DE-2719)2812446$$aSpruth, Eike Jakob$$b17$$udzne
000164071 7001_ $$0P:(DE-2719)2812825$$aRamirez, Alfredo$$b18$$udzne
000164071 7001_ $$0P:(DE-2719)2810706$$aSpeck, Oliver$$b19$$udzne
000164071 7001_ $$0P:(DE-2719)2812035$$aSchneider, Anja$$b20$$udzne
000164071 7001_ $$0P:(DE-2719)2000026$$aTeipel, Stefan$$b21$$udzne
000164071 7001_ $$0P:(DE-2719)2810394$$aKilimann, Ingo$$b22$$udzne
000164071 7001_ $$0P:(DE-2719)2811317$$aWiltfang, Jens$$b23$$udzne
000164071 7001_ $$0P:(DE-2719)2814326$$aSchott, Björn$$b24$$udzne
000164071 7001_ $$0P:(DE-2719)9000703$$aPreis, Lukas$$b25$$udzne
000164071 7001_ $$0P:(DE-2719)9001704$$aGref, Daria$$b26$$udzne
000164071 7001_ $$aMaier, Franziska$$b27
000164071 7001_ $$0P:(DE-2719)9001516$$aMunk, Matthias H$$b28$$udzne
000164071 7001_ $$0P:(DE-2719)2812341$$aRoy, Nina$$b29$$udzne
000164071 7001_ $$0P:(DE-HGF)0$$aBallarini, Tomasso$$b30
000164071 7001_ $$0P:(DE-2719)2812398$$aYakupov, Renat$$b31$$udzne
000164071 7001_ $$aHaynes, John Dylan$$b32
000164071 7001_ $$aDechent, Peter$$b33
000164071 7001_ $$aScheffler, Klaus$$b34
000164071 7001_ $$0P:(DE-2719)2000057$$aWagner, Michael$$b35$$udzne
000164071 7001_ $$0P:(DE-2719)2000032$$aJessen, Frank$$b36$$eLast author$$udzne
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