APOE and Alzheimer disease: In conclusion, we have proved the existence of a joint signaling pathway between TREM2 and ApoE, the proteins encoded by the two strongest genetic risk factors for AD, and found that the human ApoE isoforms ε2, ε3, and ε4 are all agonists to human and murine TREM2, albeit with reduced potency to murine TREM2.