Tau pathology mediates the effects of amyloid on cerebral blood flow and propagation of tau

Abstract

AbstractBackgroundAmyloid is associated with greater tau pathology and is thought to facilitate the spread of tau from the medial temporal lobe (MTL) to the neocortex. The extent to which amyloid versus MTL tau is involved in propagating tau remains unclear. Given the potential role of cortical tau in early neurodegeneration, understanding the contributors to its spread might inform preventative strategies.MethodWe acquired 18F‐flortaucipir (FTP) PET scans to measure tau pathology in 113 non‐demented Baltimore Longitudinal Study of Aging participants. To assess if amyloid facilitates the spread of tau from the MTL to the neocortex, we investigated whether amyloid moderates the association between tau in the entorhinal cortex (EC) and the inferior temporal gyrus (ITG). To quantify the involvement of amyloid versus MTL tau in propagating tau, we investigated whether EC tau mediates the association between amyloid and ITG tau. Finally, we investigated the local relationship between ITG tau and cerebral blood flow (CBF), an indicator of neurodegeneration, quantified as the relative radiotracer delivery parameter R1 computed from dynamic Pittsburgh compound B (PiB) PET scans. We used robust linear regression for all statistical models to mitigate the influence of the few outlying tau data points on the estimates, and included age, sex, race, and education as covariates.ResultAmyloid positive (A+) participants had higher FTP‐SUVR in the EC and ITG. Higher FTP‐SUVR in the EC was associated with higher FTP‐SUVR in the ITG. This association was steeper among A+ individuals (amyloid and EC FTP‐SUVR interaction β=0.269, p=0.023). EC FTP‐SUVR mediated the association between amyloid and ITG FTP‐SUVR (indirect effect=0.136, p=0.043).Higher ITG FTP‐SUVR was associated with lower PiB‐R1 (β=‐0.277, p=0.039). The direct association between amyloid and PiB‐R1 was not statistically significant (direct effect=‐0.366, p=0.192), but there was an indirect effect via ITG FTP‐SUVR (indirect effect=‐0.14, p=0.015).ConclusionOur findings suggest that both amyloid and MTL tau pathology are involved in the spread of tau into the neocortex. Tau accounted for 28% of the amyloid‐CBF relationship, indicating its role in early neuronal hypoactivity. Therapeutics may need to target both amyloid and tau early to prevent neocortical involvement.