UC Berkeley

Alzheimer’s disease (AD) is characterized by pathological aggregates of amyloid-β and tau proteins, which begin to develop decades before the onset of clinical symptoms. Tau pathology within the medial temporal lobe is nearly universal in aging, and is proposed to spread to other cortical regions through trans-synaptic and activity-driven mechanisms in the transition from normal aging to AD. Both tau and Aβ pathology can now be measured in vivo with positron emission tomography (PET) and targeted radiotracers. In this dissertation, we investigate whether the development of tau pathology, measured within a sample of cognitively normal older adults using tau-PET, is related to measures of neural activity and connectivity. In Chapter 1, we demonstrate that the relationship between tau pathology and glucose metabolism, a measure of synaptic activity, is dependent on the level of AD pathology. In older adults with low levels of tau and Aβ pathology, tau is associated with increased glucose metabolism, while in older adults with high levels of tau and Aβ pathology, tau is related to hypometabolism in temporoparietal regions that are the signature of AD. In Chapter 2, we establish that functional connectivity of the anterolateral entorhinal cortex, the first cortical region to accumulate tau pathology, predicts the spatial extent and level of tau deposition in aging. This functional connectivity strength interacts with Aβ, suggesting Aβ facilitates the trans-synaptic spread of tau out of the anterolateral entorhinal cortex and to connected cortical targets. In Chapter 3, we find that tau pathology in entorhinal cortex is related to hyperactivity during repetition suppression, an implicit form of memory processing. This hyperactivity leads to an inability to deactivate to repeated stimuli, producing deficits in repetition suppression activation. Finally, in Chapter 4, we provide the first preliminary evidence that patterns of activation and functional connectivity are predictive of longitudinally measured tau accumulation in aging. Group-level patterns of hyperactivity and functional connectivity of the anterolateral entorhinal cortex predict tau accumulation in temporal and limbic regions, while increased activation and hyperactivity in entorhinal cortex and hippocampus predict within-subject tau accumulation in entorhinal cortex. Together, our results support a bidirectional model in which neural activity and connectivity initially guide the development and spread of tau pathology. High levels of tau pathology, potentiated by Aβ, then lead to neural dysfunction. Further, our findings highlight the role of the anterolateral entorhinal cortex as an epicenter of age-related pathology, as tau spread out of this region reflects the transition from normal aging to AD. Future work should continue to investigate these processes longitudinally in samples spanning the disease spectrum.