Functional networks underlying the association between tau pathology and memory

Abstract

AbstractBackgroundTau pathology is associated with impaired episodic memory (EM) in both aging and Alzheimer’s disease (AD), but the mechanisms by which tau and memory are linked remain unclear. We hypothesized that strength of an EM‐defined functional brain network would mediate the relationship between tau and memory performance.MethodResting state fMRI was collected in 120 cognitively normal older adults from the Berkeley Aging Cohort Study (77.6 ± 6.4 years, 57.5% female), with a subset of 94 individuals receiving tau‐PET with 18F‐Flortaucipir and Aβ‐PET with 11C‐PiB. Functional connectivity (FC) for each ROI‐ROI pair of a 246‐region whole brain atlas was computed, yielding 30,000+ unique connections. LASSO regression of each of these values against an EM composite measure was used to select a sparse subset of connections related to greater EM performance. Overall strength of this network was computed as the sum of FC values for all selected ROI‐ROI pairs. Linear regression and causal mediation analyses were used to assess relationships between network strength and AD pathology.ResultThe EM‐defined network of 51 ROI‐ROI connections comprised limbic, temporal, and frontal regions (Figure 1). Adjusting for age and sex, reduced overall network strength was associated with an interaction between greater global Aβ and tau, both in an inferomedial temporal cortex meta‐ROI (b=‐26.97,p=.013; Figure 2a), and entorhinal cortex (b=‐14.01, p=.034; Figure 2b). For control analyses using an executive function‐defined network, overall network strength was not related to an Aβ‐tau interaction in the meta‐ROI (b=‐9.894, p=.415) or entorhinal cortex (b=‐6.206, p=.403; Figure 2c‐d). Causal mediation analysis revealed the effect of meta‐ROI tau on EM performance was mediated by the overall strength of the EM‐defined network (b=‐0.802, p=.017; Figure 3a), but not the executive function‐defined control network (b=‐0.098, p=.424; Figure 3b).ConclusionUsing LASSO regression to select a sparse subset of functional connections related to EM in older adults, we found that reduced strength of this network was associated with the coincidence of greater tau and Aβ pathology. Alterations in behaviorally‐defined networks thus are reflective of AD pathology and appear to be a key factor in understanding its link to cognitive function.