APOE and Alzheimer disease: In the CNS, TREM2 can interact with a range of ligands, but it is mostly known as a receptor for lipid substrates.210 For example, APOE, ApoJ/CLU, Galectin-3, lipidated Aβ as well as lipids exposed on the surface of apoptotic cells can bind with TREM2 and activate it.211 In addition, in vitro study found that nucleotides released from damaged cells may also bind with TREM2.212 For AD patients without TREM2 variations, TREM2 signaling still plays crucial role in the progression of disease.