Amyloid pathology but not APOE ε4 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.

Keywords: Alzheimer’s disease biomarker; hippocampus; memory; mild cognitive impairment; subjective cognitive decline.

Figure 1

Correlation between CSF levels of total (toprow) and phospho (bottom row) tau (pg/ml) and recognition memory accuracy (dprime) for the novel scenes presented during task-functional MRI. Colour codes indicate healthy controls (blue), subjective complainers (SCD, red) and individuals with MCI (green). The left column shows correlations in Aβ42-negative and the right column in Aβ42-positive individuals.

Figure 2

Correlation between CSF levels of total (top row) and phospho (bottom row) tau (pg/ml) and free recall performance in the FCSRT free recall test. Colour codes indicate healthy controls (blue), subjective complainers (SCD, red) and individuals with MCI (green). The left column shows correlations in Aβ42-negative and the right column in Aβ42-positive individuals.

Figure 3

Functional MRI results. (A) The whole-brain novelty response in the full sample (healthy controls, SCD, MCI) without any covariates. (B) Results of an interaction analysis with CSF total-tau levels and amyloid status (binary variable; amyloid-positive Aβ42 < 638.7 and amyloid-negative Aβ42 ≥ 638.7) on novelty activation (covariates age, sex, MRI site, years of education, left and right hippocampal volume). Including diagnosis as an additional covariate did not change the results substantially. (C) Results of an interaction analysis with CSF phospho-tau levels and amyloid status on novelty activation. Including diagnosis as a covariate in this analysis did not change the results substantially. (D) A group-specific regression analysis in amyloid-positive individuals showing the correlation between CSF total-tau levels and medial temporal novelty responses (covariates age, sex, MRI site, years of education, left and right hippocampal volume and Aβ42 CSF levels). This finding remained stable with a slightly lower significance and cluster sizes when including diagnosis as a covariate. (E) A group-specific regression analysis in amyloid-positive individuals showing the correlation between CSF phospho-tau levels (covariates age, sex, MRI site, years of education, left and right hippocampal volume and Aβ42 CSF levels). This finding remained stable with a slightly lower significance and cluster size when including diagnosis as a covariate. (F) A group-specific regression analysis in amyloid-positive individuals (covariates age, sex, years of education, MRI site, diagnosis, Aβ42 CSF levels) showing the correlation between dprime and novelty responses.

Figure 4

Propensity score matching for phospho-tau pathology across amyloid-positive (A+) and amyloid-negative (A−) individuals. (A) A+ and A− individuals are equated for CSF levels of phospho-tau (y-axis, in pg/ml), both in those with normal (T−) and pathological (T+) phospho-tau levels. (B) Despite matched phospho-tau pathology, FCSRT free recall is reduced in A+/T+ compared to A−/T+. (C) Despite matched phospho-tau pathology, dprime is reduced in A+/T+ compared to A−/T+. Box-and-whisker plots show median (thick horizontal lines), minimum and maximum values (lower and upper end of whiskers) and outliers (circle, star). Whiskers below each box show the first quartile range and those above the fourth quartile range of data. Green bars denote amyloid-positivity and blue bars amyloid-negativity.