Synapse vulnerability and resilience across the clinical spectrum of dementias

Preservation of synapses is crucial for healthy cognitive ageing, and synapse loss is one of the closest anatomical correlates of cognitive decline in Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia. In these conditions, some synapses seem particularly vulnerable to degeneration whereas others are resilient and remain preserved. Evidence has highlighted that vulnerability and resilience are intrinsically distinct phenomena linked to specific brain structural and/or functional signatures, yet the key features of vulnerable and resilient synapses in the dementias remain incompletely understood. Defining the characteristics of vulnerable and resilient synapses in each form of dementia could offer novel insight into the mechanisms of synapse preservation and of synapse loss that underlies cognitive decline, thereby facilitating the discovery of targeted biomarkers and disease-modifying therapies. In this Review, we consider the concepts of synapse vulnerability and resilience, and provide an overview of our current understanding of the associations between synaptic protein changes, neuropathology and cognitive decline. We also consider how understanding of the underlying mechanisms could identify novel strategies to mitigate the cognitive dysfunction associated with dementias.