TREM2 and Alzheimer disease: The PI3K/Akt pathway, upregulated by TREM2, may regulate the activity and subcellular localization of FoxO3a, thereby reducing the expression levels of pro-inflammatory cytokines.259 Moreover, TREM2 has been reported to bind with high affinity to C1q (the initiator of the classical complement pathway) to effectively inhibit the classical complement pathway, protecting synapses from abnormal phagocytosis and loss in AD.260