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Apolipoprotein E (ApoE) is a secreted lipoprotein involved in cholesterol metabolism, and the ε4 allele of ApoE is the strongest known genetic risk factor for late-onset Alzheimer’s disease. Multiple mechanisms have been suggested to underlie ApoE’s effect on AD risk, including effects on Aβ aggregation and clearance, systemic inflammation leading to vascular pathology, and neuroinflammation (see Parhizkar and Holtzman, 2022 for review).

Early studies pointed toward astrocytes as the main source of ApoE in non-Alzheimer’s brains (Boyles et al., 1985; Diedrich et al., 1991; Lafarga et al., 1994). However, in the brains of individuals with Alzheimer’s disease, ApoE expression is downregulated in astrocytes and upregulated in microglia (Grubman et al., 2019; Mathys et al., 2019). Elevated expression of ApoE is also seen in microglia in mouse models of amyloidosis and is one of the earliest transcriptional changes in the microglial transition from a homeostatic to a disease-associated phenotype (Keren-Shaul et al., 2017; Krasemann et al., 2017; Zhou et al., 2020).

The amino acid sequence of mouse ApoE is 70 percent homologous to that of the human protein. While the human protein has three major alleles—ε2, ε3, and ε4—that differ in the use of arginine or cysteine at positions 112 and 158, murine ApoE has one allele, which matches ε4 at the equivalent positions (Rajavashisth et al., 1985).