Left frontal connectivity attenuates the adverse effect of entorhinal tau pathology on memory.

Objective: To investigate whether higher global left frontal cortex (gLFC) connectivity, a putative neural substrate of cognitive reserve, attenuates the effect of entorhinal tau PET levels on episodic memory in older adults.

Methods: Cross-sectional F-AV-1451 PET (to assess tau pathology), F-AV-45 or F-BAY94-9172 PET (to assess β-amyloid [Aβ]), and resting-state fMRI were obtained in 125 elderly participants from the Alzheimer's Neuroimaging Initiative, including 82 cognitively normal participants (amyloid PET-positive [Aβ+], n = 27) and 43 patients with amnestic mild cognitive impairment (Aβ+ = 15). Resting-state fMRI gLFC connectivity was computed for each participant as the average functional connectivity between the left frontal cortex (LFC) (seed) and each remaining voxel in the gray matter. As a measure of tau pathology, we assessed the mean tau PET uptake in the entorhinal cortex. In linear mixed-effects regression analysis, we tested the interaction term gLFC connectivity × entorhinal tau PET on delayed free recall performance. In addition, we assessed whether higher connectivity of the whole frontoparietal control network (FPCN), of which the LFC is a major hub, is associated with reserve.

Results: Higher entorhinal tau PET was strongly associated with poorer delayed free recall performance (β/SE = -0.49/0.07, < 0.001). A significant gLFC connectivity × entorhinal tau PET interaction was found (β/SE = 0.19/0.06, = 0.003), such that at higher levels of gLFC connectivity, the decrease in memory score per unit of entorhinal tau PET was attenuated. The FPCN connectivity × tau interaction was also significant (β/SE = 0.10/0.04, = 0.012).

Conclusion: Both gLFC and FPCN connectivity are associated with higher resilience against the adverse effect of early-stage entorhinal tau pathology on memory performance.