Hippocampal‐retrosplenial connectivity is associated with tau pathology and memory in cognitively normal older adults

Abstract

AbstractBackgroundTau pathology is thought to spread transneuronally from medial temporal lobe (MTL) to medial parietal lobe (MPL) in cognitively normal older adults, but it is not known precisely which structures and processes are involved. We hypothesize that functional connectivity influences tau spread from hippocampus to the MPL, with consequences for cognition.MethodNinety‐seven cognitively normal older adults from the Berkeley Aging Cohort Study (76.4±6.1 years) received tau‐PET with 18F‐Flortaucipir, Aβ‐PET with 11C‐PiB, and resting state fMRI. We assessed unilateral resting state functional connectivity (FC) between retrosplenial cortex (RsC), an area of known connectivity with the MTL, and hippocampus (HC), anterolateral entorhinal cortex (alEC), and posteromedial entorhinal cortex (pmEC). We then used linear models to examine the association of FC strength (β‐weight) between RsC and the proportion of suprathreshold voxels for tau accumulation (SUVR>1.4) in MPL. Finally, we examined interactions between FC strength and tau to predict downstream tau accumulation and memory.ResultSemipartial region‐region correlations revealed RsC FC with HC in both hemispheres [Left: β=0.33, p<0.001, Right: β=0.40, p<0.001], but not with alEC or pmEC in either hemisphere (Figure 1). Adjusting for age, sex, and amyloid status, proportion of suprathreshold voxels in MPL was associated with RsC‐HC connectivity strength bilaterally [Left: β=0.153, p=0.004; Right: β=0.186, p=0.002], but not RsC‐alEC or RsC‐pmEC connectivity strength (Figure 2). In addition, proportion of suprathreshold voxels in MPL was associated with the interaction between RsC‐HC connectivity strength and hippocampal tau (pvc‐SUVR) [Left: β=0.586, p=0.008; Right: β=0.613, p=0.022] (Figure 3a). Adjusting for age, years of education, and practice effects, the interaction between RsC‐HC connectivity strength and MPL tau (left hemisphere only) was associated with spatial memory performance [β=‐12.773, p=0.002] (Figure 3b).ConclusionIn cognitively normal older adults, RsC exhibits FC with hippocampus but not alEC or pmEC, and the strength of this RsC‐HC connectivity predicts tau accumulation in the MPL, suggesting that tau pathology spreads to MPL through the hippocampus. Further, RsC‐HC connectivity modulated the relationship between MTL and MPL tau as well as between MPL tau and spatial memory, indicating that MTL‐MPL FC may influence the spread of tau and cognitive function.