Table 2 Summary of the association of APOE4 with greater neuroinflammation

Cultures (microglia, astrocytes, or mixed cultures) and inflammatory response by genotype

Vitek et al. [28]

Microglia derived from ApoE4-TR mice demonstrated increased NO production, increased Nos2 mRNA levels, and greater TNFα, IL6, IL12 levels compared to microglia from ApoE3-TR mice.

Colton et al. [29]

Significantly more NO was produced in primary microglia and macrophages from ApoE4-TR mice compared to ApoE3-TR mice.

Guo et al. [30]

The addition of exogenous ApoE4 induced greater IL1β than ApoE3 in rat mixed glial cells.

Chen et al. [31]

ApoE4, but not ApoE3, stimulated secretion of PGE2 and IL-1β in rat primary microglia.

Shi et al. [32]

Higher TNFα, IL1β, and IL1α levels were observed in primary microglia from ApoE4-TR mice stimulated with LPS than ApoE2 and ApoE3.

Tai et al. [33]

Greater astrogliosis and microgliosis, higher levels of IL1β in APOE4-FAD mice compared with APOE_-FAD mice.

Zhu et al. [34]

Higher levels of microglia/macrophage, astrocytes, and invading T-cells after LPS injection in ApoE4-TR mice than ApoE3-TR mice. ApoE4-TR mice also displayed greater and more prolonged increases of cytokines (IL1β, IL6, TNFα) than ApoE2-TR and ApoE3-TR mice.

Ophir et al. [35]

The expression of inflammation-related genes (NF-κB response elements) following intracerebroventricular injection of LPS was significantly higher and more prolonged in ApoE4-TR than in ApoE3-TR mice.

Both human and mouse models

Gale et al. [36]

ApoE4-TR mice displayed enhanced plasma cytokines after systemic LPS injection compared with ApoE3 counterparts. After intravenous LPS administration, APOE3/E4 patients had higher plasma TNF-α levels than APOE3/E3 patients.

Human brain studies of inflammation and oxidative stress studies by APOE genotype

Montine at al [37]

Pyramidal neuron cytoplasm was immunoreactive for 4-hydroxy-2-nonenal (HNE) in 4 of 4 APOE4 homozygotes, 2 of 3 APOE3/E4 heterozygotes, and none of 3 APOE3 homozygotes

Ramassamy et al. [20]

In hippocampal homogenates from AD brains, APOE4 carriers had greater levels of thiobarbituric acid-reactive substances (TBARS), lower catalase activities, and increased or decreased glutathione peroxidase and glutathione than tissues from patients homozygous for the APOE3 allele (n = 10 per group).

Egensperger et al. [38]

The number of activated microglia and the tissue area occupied by these cells increased significantly with the APOE4 gene dose (n = 20).

Minett et al. [39]

APOE4 allele was significantly related to greater expression of CD68, HLA-DR, and CD64 in microglia (n = 299).

Friedberg et al. [40]

Cellular density of microglial marker-Iba1 was positively associated with tau pathology in APOE4 carrier participants only (n = 154).

Systemic inflammation and dementia risk by genotype

Tao et al. [19]

Participants with APOE4 and elevated plasma C reactive protein (CRP) levels had a shortened latency for the onset of AD (n = 2562).