Amyloid pathology but notAPOEε4 status is permissive for tau-related hippocampal dysfunction

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-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.

Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease

“…Recent findings from the DELCODE cohort, focusing on Aβ and tau interactions on hippocampal novelty responses in individuals without dementia, suggest that Aβ pathology is permissive for tau-related hippocampal dysfunction. 26 Together, these findings highlight the presence of nonlinear region-specific relationships between ADrelated pathology, fMRI activity, and memory impairment.…”

“…Associations between fMRI task-memory performance, hippocampal activity, and Aβ × tau interactions in the groups without dementia with CSF data have been examined by other studies. 24 , 26 …”

Single-value scores of memory-related brain activity reflect dissociable neuropsychological and anatomical signatures of neurocognitive aging

“…When they do show age-related deviations, this may be indicative of a more pronounced age-related impairment of the hippocampus-dependent memory system. Compatible with this, attenuated hippocampal novelty responses have been linked to lower memory performance in individuals at risk for Alzheimer’s disease (AD) 37 .…”

“…The reductionist single-value scores of age-related whole-brain fMRI activation (and deactivation) patterns described here may prove more reliable. In this context, it is of importance that in recent studies with older participants at risk for AD, researchers have often employed novelty rather than subsequent memory contrasts, owing to the lack of successfully encoded items in individuals with pronounced memory impairment 37, 38, 44 . Our observation that the novelty-related scores, particularly the FADE novelty score, show relatively strong and specific correlations with tests of hippocampus-dependent memory, support the validity of this approach.…”

“…Previous studies show that, compared to young individuals, older adults exhibited lower activations of inferior and medial temporal structures and reduced deactivations in the Default Mode Network (DMN) during novelty processing and successful long-term memory encoding (Maillet & Rajah, 2014; Soch et al, 2021a; Billette et al, 2022; E. Duzel et al, 2022).…”