TY  - JOUR
AU  - Düzel, Emrah
AU  - Ziegler, Gabriel
AU  - Berron, David
AU  - Maaß, Anne
AU  - Schütze, Hartmut
AU  - Cardenas-Blanco, Arturo
AU  - Glanz, Wenzel
AU  - Metzger, Coraline
AU  - Dobisch, Laura
AU  - Reuter, Martin
AU  - Spottke, Annika
AU  - Brosseron, Frederic
AU  - Fliessbach, Klaus
AU  - Heneka, Michael T
AU  - Laske, Christoph
AU  - Peters, Oliver
AU  - Priller, Josef
AU  - Spruth, Eike Jakob
AU  - Ramirez, Alfredo
AU  - Speck, Oliver
AU  - Schneider, Anja
AU  - Teipel, Stefan
AU  - Kilimann, Ingo
AU  - Wiltfang, Jens
AU  - Schott, Björn
AU  - Preis, Lukas
AU  - Gref, Daria
AU  - Maier, Franziska
AU  - Munk, Matthias H
AU  - Roy, Nina
AU  - Ballarini, Tomasso
AU  - Yakupov, Renat
AU  - Haynes, John Dylan
AU  - Dechent, Peter
AU  - Scheffler, Klaus
AU  - Wagner, Michael
AU  - Jessen, Frank
TI  - Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction.
JO  - Brain
VL  - 145
IS  - 4
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2022-00734
SP  - 1473-1485
PY  - 2022
N1  - (CC BY-NC)
AB  - 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-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.
KW  - Alzheimer Disease: pathology
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloidogenic Proteins
KW  - Amyloidosis
KW  - Apolipoproteins E: genetics
KW  - Biomarkers
KW  - Cognitive Dysfunction: diagnosis
KW  - Cognitive Dysfunction: genetics
KW  - Cross-Sectional Studies
KW  - Hippocampus: metabolism
KW  - Humans
KW  - tau Proteins: metabolism
KW  - Alzheimer’s disease biomarker (Other)
KW  - hippocampus (Other)
KW  - memory (Other)
KW  - mild cognitive impairment (Other)
KW  - subjective cognitive decline (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9128811
C6  - pmid:35352105
DO  - DOI:10.1093/brain/awab405
UR  - https://pub.dzne.de/record/164071
ER  -