The Role of Synaptic Loss in Early Alzheimer’s Disease: A Systematic Review

Background: Synaptic loss is increasingly recognized as the best neuropathological correlate of cognitive decline in Alzheimer’s disease (AD), often appearing before widespread neuron death.

Objective: To systematically review evidence for the timing, mechanisms, measurement, and clinical implications of synaptic loss in early AD (preclinical and prodromal/MCI stages).

Methods: We searched PubMed/MEDLINE, Web of Science, and Scopus through August 26, 2025 using terms spanning Alzheimer’s, synapse, spine, SV2A PET, neurogranin, GAP-43, SNAP-25, NPTX2, complement, TREM2, and microglia. We included human studies (post-mortem, fluid biomarkers, in vivo imaging), translational animal work clarifying mechanisms, and interventional trials reporting synaptic or network endpoints.

Results: Classic quantitative neuropathology shows cortical and hippocampal synapse loss correlates more strongly with cognition than plaques or tangles. Mechanistically, soluble Aβ oligomers, dendritic mislocalization of tau, and glial complement pathways converge to drive synapse elimination. Emerging CSF/plasma synaptic proteins (neurogranin, GAP-43, SNAP-25, NPTX2) and SV2A-PET enable in-vivo tracking of synaptic density; these changes appear early and relate to decline. Network hyperexcitability is a functional readout of synaptic dysfunction and is modifiable in MCI.

Conclusions: Early synaptic injury is central to pathogenesis and a promising therapeutic endpoint. Longitudinal multimodal frameworks (SV2A-PET + fluid synaptic panel + neurophysiology) should stratify trials and monitor synaptoprotective therapies, including complement modulation and circuit-level interventions.