Genetically modified mouse expressing human APOE4 and mouse Trem2 p.R47H and methods of use thereof

A mouse whose genome comprises:

• (a) a genetically modified endogenous apolipoprotein E (apoE) allele comprising a nucleic acid encoding a humanized apolipoprotein E4 APOE4 protein (APOE4p), wherein the nucleic acid encoding the humanized APOE4p comprises exon 1 of the mouse ApoE4 gene, and exons 2-4 of the human APOE4 gene;
• and (b) a genetically modified endogenous allele comprising a nucleic acid encoding a mouse triggering receptor expressed on myeloid cells 2 (TREM2) protein modified to include a R47H substitution (TREM2p) relative to mouse wild type TREM2, wherein the mouse is homozygous for the modified apoE allele encoding the human APOE4p and is homozygous for the modified apoE allele encoding the mouse TREM2p, and the mouse exhibits one or more signs of non-familial late-onset Alzheimer's disease associated with expression of the human APOE4p and the mouse TREM2p.