Does Aß Drive Tau Spreading in Alzheimer’s Disease?

The major objective of our study is to assess whether Aß and phases of Aß-related neuronal hyperconnectivity promote tau pathology spread across connected brain regions in Alzheimer’s disease. We will assess longitudinal resting-state fMRI, amyloid- and tau-PET imaging in 55 patients with Alzheimer’s disease to test whether Aß induces neuronal hyperactivity/connectivity, thereby driving tau spreading across connected regions. Specifically, we will assess whether isolated Aß pathology in a given brain region is associated with subsequent increases in functional connectivity and whether the local convergence of tau and Aß leads to a subsequent connectivity breakdown. Lastly, we will determine whether Aß-induced hyperconnectivity triggers connectivity-mediated tau spreading.

In Alzheimer’s disease, the development of amyloid pathology is assumed to trigger the spread of tau pathology across interconnected brain regions, which is the major culprit driving neurodegeneration and cognitive decline and thus a promising target for intervention. It is, however, a major open question in AD research, how amyloid may trigger the spread of tau. Studies in Alzheimer’s disease mouse models and cell cultures have shown that amyloid triggers enhanced neuronal activity and connectivity. Again, other studies have shown that neuronal activity enhances tau spreading across connected neurons. Thus, amyloid may induce neuronal hyperconnectivity and thereby trigger the spread of tau. By combining resting-state fMRI with tau-PET in AD patients, we found previously that tau spreads across connected brain regions in AD patients. However, these previous studies did not address whether tau spreading across connected brain regions is specifically enhanced by amyloid-induced hyperconnectivity in AD patients. In the current study, we use cutting-edge neuroimaging protocols in AD patients, to study whether early amyloid deposition is associated with neuronal hyperactivity, thereby triggering tau spread. This study will be essential to identify neuronal activity as a potential treatment target for intervention in AD.

Our study will assess whether brain connectivity mechanistically links Aß and the spreading of tau pathology in Alzheimer’s disease patients. The study is motivated by pre-clinical findings, showing that Aß is a potent modulator of neuronal activity, which in turn drives tau spreading. To address the role of Aß and connectivity in tau spreading, we employ a cutting-edge longitudinal neuroimaging protocol in Alzheimer’s disease patients, including precision mapping of patient-level connectivity as well as 2nd generation PI2620 tau-PET and amyloid-PET.

The results of the proposed study will be essential for assessing the role of connectivity as a mechanistic link between amyloid and tau, which may render brain connectivity as a potential target for attenuating tau spread, i.e. the key driver of neurodegeneration and cognitive decline in AD. In addition, pathomechanistic tau spreading models may be used in the future for predicting patient-specific pathobiological and clinical trajectories which an be essential for precision medicine.