Complement proteins tag unwanted synapses for elimination during development. In AD, this developmental pruning program reactivates pathologically stripping healthy adult connections as if they were debris.

The Mechanism:

Developmental Legacy: C1q tags weak synapses for microglial phagocytosis during critical periods. Normally, C1q expression silences in adulthood.

Reactivation: In AD, amyloid and tau reactivate C1q expression in neurons particularly in hippocampus and cortex. C1q decorates synaptic surfaces.

Microglial Recognition: C1q-bound synapses activate microglial CR3 receptors. Microglia engulf and digest tagged synapses entirely healthy, functionally normal connections.

Selective Vulnerability: Excitatory synapses on spines are preferentially targeted. Inhibitory synapses partially spared creating excitation/inhibition imbalance.

Irreversible Loss: Once phagocytosed, synapses cannot regenerate quickly. Circuit disruption correlates with cognitive decline independent of plaque load.

Early Marker: C1q appears in mouse models before plaque formation synaptic loss begins early.

Therapeutic Implications:

C1q inhibitors (ANX-M1) blocking synaptic tagging

CR3 antagonists preventing microglial engulfment

Complement cascade blockers (eculizumab) repurposed

Don't eat me signal enhancers (CD47) protecting synapses

This reframes AD as mistaken pruning immune system eating vital connections.