Synapse vulnerability and resilience underlying Alzheimer's disease

Synapse preservation is key for healthy cognitive ageing, and synapse loss represents a critical anatomical basis of cognitive dysfunction in Alzheimer's disease (AD), predicting dementia onset, severity, and progression. Synapse loss is viewed as a primary pathologic event, preceding neuronal loss and brain atrophy in AD. Synapses may, therefore, represent one of the earliest and clinically most meaningful targets of the neuropathologic processes driving AD dementia. The synapse loss in AD is highly selective and targets particularly vulnerable synapses while leaving others, termed resilient, largely unaffected. Yet, the anatomic and molecular hallmarks of the vulnerable and resilient synapse populations and their association with AD neuropathologic changes (e.g. amyloid-beta plaques and tau tangles) and memory dysfunction remain poorly understood. Characterising the selectively vulnerable and resilient synapses in AD may be key to understanding the mechanisms of cognitive preservation versus loss and enable the development of robust biomarkers and disease-modifying therapies for dementia. Copyright Crown Copyright (c) 2025 Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).