APOE and Alzheimer disease: As proof-of-concept, we investigated some of the major genetic risk factors for AD, hypothesizing that they would modulate microglia according to their role in AD risk, that is, APOE2/2 should increase protective and/or decrease damaging responses, whereas APOE4/4 and TREM2 mutations should increase damaging or reduce protective responses1, to the extent that their pathological effect is restricted to microglia.