Tau pathology mediates the effects of amyloid on neocortical tau propagation and neurodegeneration among individuals without dementia

Abstract Amyloid is associated with greater tau pathology and is thought to facilitate tau propagation from medial temporal lobe (MTL) to the neocortex, where tau is closely associated with local neurodegeneration. We used causal mediation analysis to quantify the involvement of amyloid and tau in tau propagation and neurodegeneration, as measured by cerebral blood flow, glucose metabolism, and volume, in two longitudinal samples of individuals without dementia. Greater entorhinal tau was associated with greater inferior temporal tau. This association was stronger among amyloid+ individuals, suggesting that amyloid facilitates tau propagation from MTL to neocortex. Entorhinal tau mediated up to 50% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with colocalized neurodegeneration, including lower cerebral blood flow, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on neurodegeneration via tau, implying that tau is the primary driver of neurodegeneration. Our findings suggest targeting amyloid or MTL tau might slow down neocortical spread of tau, but a combination therapy may yield better outcomes.