Understanding the impact of late-onset Alzheimer’s disease mutations in CD2AP on synapses

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline and is the leading cause of dementia worldwide. While early-onset AD is most often driven by rare autosomal-dominant mutations in genes such as APP, PSEN1 and PSEN2, late-onset AD (LOAD) arises from a complex interaction between genetic risk factors and environmental influences. How these risk genes contribute to disease progression remains poorly understood. Although AD research has historically focused on amyloid-beta (Aβ) and tau pathology, increasing evidence indicates that synaptic dysfunction is a central and early driver of cognitive decline in LOAD. One of the strongest genetic risk factors for LOAD is the CD2-associated protein (CD2AP), yet its function in the brain and its contribution to synaptic failure remain largely unexplored. Our previous work showed that loss of CD2AP alters endosomal trafficking and enhances Aβ production, suggesting that CD2AP links genetic risk to classical AD pathology. Here, we extend this view by showing that CD2AP also plays a crucial role in maintaining the structure and function of synaptic connections. When CD2AP levels are reduced, neurons lose many of their synapses, becoming smaller and weaker, and overall network activity declines. In contrast, higher levels of CD2AP support stronger and more stable connections between neurons. We further examined a disease-associated variant of CD2AP and found that it disrupts the normal architecture of synapses, leading to abnormal and poorly functioning contacts between brain cells. These findings suggest that some genetic forms of Alzheimer’s directly interfere with the mechanisms that allow synapses to form, stabilize and remodel. Importantly, the synaptic defects caused by altered CD2AP were not reversed by blocking beta-amyloid, indicating that this pathway can drive synaptic damage independently of the classical hallmarks of AD. Because learning and memory depend on the ability of synapses to change their shape and strength, our results identify CD2AP as a key regulator of brain plasticity. By influencing both the internal structure of synapses and the movement of neurotransmitter receptors, CD2AP helps determine whether neuronal connections are strengthened or lost over time. Disruption of this system may therefore contribute to the progressive breakdown of neural circuits and cognitive decline in late-onset Alzheimer’s disease.