The longitudinal progression of synaptic density loss and its relationship with reactive astrogliosis and tau accumulation in Alzheimer’s disease.

Alzheimer’s disease (AD) is characterized by amyloid-beta (Ab) plaques, tau neurofibrillary tangles, synapse loss and neurodegeneration. However, the exact interplay between Ab and tau pathology and how their combination leads to synapse loss and neurodegeneration remains unclear. It is thought that Ab facilitates the trans-synaptic spread of tau across brain networks. Subsequently, tau is believed to cause the downstream synapse loss that will eventually lead to neurodegeneration. Study 1 includes an extension of an ongoing longitudinal study including synaptic density and tau PET/MR in patients with prodromal AD. This will unravel the long-term relationship between tau and synaptic density and will reveal if toxic levels of pathology are sufficient to create a continuous loss of synaptic density. The presence of tau pathology in synapses is thought to cause an increased synapse elimination by microglia and astrocytes. Study 2 investigates ultrahigh resolution synaptic density PET in association with reactive astrogliosis, tau, memory and blood-based biomarkers in patients across the AD spectrum. This will elucidate the multimodal in vivo relationship between synaptic density and reactive astrogliosis and how it is influenced by tau pathology. Moreover, the ultrahigh resolution will clarify the association between synaptic density and episodic memory loss as to further validate synaptic density PET as a biomarker for clinical disease progression.