The association of activated microglia [
112] and complement proteins [
113] with brain AD lesions, as well the discovery that rheumatoid arthritis patients who were treated regularly with anti-inflammatory drugs are relatively spared from AD, led to the proposition that neuroinflammation plays a role in the pathogenesis of AD [
114]. This association between AD and neuroinflammation is further supported by recent genome-wide association studies that showed a marked association between AD and distinct immunity-associated genes such as
CLU and
TREM2 [
115,
116]. Importantly, neuroinflammation is more pronounced in
APOE4 carriers [
117‐
119] and in corresponding animal model studies, including co-localization of apoE with microglia in the brain [
120,
121], suggesting a role for apoE in the innate immune response in AD brain. This is corroborated by the finding that, in mice, following inflammatory stimulation,
APOE4 carriers have an enhanced and prolonged neuroinflammatory response [
47,
122‐
124]. This inflammation may be driven by the effects of apoE4 on microglial activation [
60,
125] as well as by enhancing the levels of proinflammatory cytokines [
123,
126]. Alternatively, it has been suggested that the inflammatory effects of apoE4 may be related to miRNA146a, which is the primary miRNA in the brain. This suggestion stems from the finding that the levels of miRNA146a are higher in brains of AD patients than in the corresponding mouse model. It is suggested that elevated miRNA146a levels lead to an insufficient negative feedback regulation of inflammation, resulting in chronic inflammation [
127,
128], yet the apoE isotype-specific effects remain poorly understood. However, in view of the uncertainty as to when in the course of the disease neuroinflammation is beneficial or toxic, the timing and choice of inflammatory molecule to be targeted for the treatment of AD and apoE4-related inflammation remain to be determined. Indeed, this issue may be the underlying cause for the lack of effectiveness of prospective nonsteroidal anti-inflammatory drug (NSAID) treatments [
129]. A meta-analysis of numerous studies revealed no beneficial effect of NSAIDs on cognition and overall severity of AD [
129]. Nevertheless, recent epidemiological data suggest that
APOE4 carriers are better responders to NSAID treatment [
61,
62,
89]. The mechanisms underlying this effect are not fully understood and may be related to the higher susceptibility of
APOE4 carriers to inflammation and oxidative stress [
130].
Nevertheless, it is clear that AD inflammation-related studies should be stratified according to the APOE genotype.