Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease

Abstract

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Figure 1

Seed-based LFC connectivity pattern. Surface renderings of significant LFC-connectivity in the DIAN and DELCODE sample at a voxel threshold of α < 0.001, family-wise error corrected at the cluster level at α < 0.05. The LFC-region of interest that was used for seed-based functional connectivity analyses is superimposed as a blue sphere on the left hemisphere.

Figure 2

Interaction gLFC-connectivity × Alzheimer’s disease severity on cognition. Scatterplots of the interaction gLFC-connectivity × Alzheimer’s disease severity on cognitive performance in the ADAD (DIAN) and sporadic Alzheimer’s disease (DELCODE) sample. For DIAN, the estimated years from symptom onset (EYO) are plotted against the MMSE score (A) and the delayed free recall score of the logical memory scale (B). For DELCODE, CSF-tau levels are plotted against MMSE (C) and logical memory delayed free recall (D). For illustrational purposes, groups of high and low gLFC-connectivity (defined via median split) are plotted separately, statistical interactions were calculated using continuous measures. Dashed lines indicate 95% confidence intervals. P-values of the interaction terms are displayed for each graph. Aβ = amyloid-β.

Figure 3

Cognitive and biomarker changes. Cognitive and biomarker changes as a function of Alzheimer’s disease severity. MMSE is plotted separately for individuals with high versus low gLFC-connectivity (as defined via median split). For the DIAN sample (A) we plotted the standardized difference between mutation carriers (MC) and non-mutation carriers (NC) against the EYO based on the polynomial linear mixed models that best fit each marker. The plot suggests that high gLFC-connectivity is associated with a delay of cognitive decline towards a later timepoint with more progressed levels of Alzheimer’s disease pathology. For the DELCODE sample (B) we plotted the standardized difference between CSF-amyloid-β+ and CSF-amyloid-β− subjects against CSF-tau levels. Congruent with the DIAN sample, the plot suggests that cognitive decline is shifted to a later time point in individuals with high levels of gLFC-connectivity.