Challenges in Studying Synapses in Alzheimer's Disease.

Developing therapies for Alzheimer's disease (AD) is a pressing need. A key feature of AD is synapse loss. ApoE4, amyloid-β (Aβ)-peptides, phospho-tau, and neuroinflammation are thought to induce AD pathogenesis, but their molecular mechanisms are incompletely understood. Free Aβ-peptides whose levels decrease in AD are synaptogenic, whereas aggregating Aβ-peptides that accumulate in AD are synaptotoxic. It is unclear whether AD is driven primarily by the loss of free Aβ, the increase of aggregated Aβ, or both, nor do we know how ApoE4 affects synapses. Therefore, understanding the molecular pathways mediating synapse loss in AD is a priority in developing new therapies. ANN NEUROL 2026;100:683-694.