The largest genetic risk for late-onset Alzheimer's disease (AD) resides at the 
apolipoprotein E gene (APOE) locus, which has three common alleles (ɛ2, ɛ3, ɛ4) 
that encode three isoforms (apoE2, apoE3, apoE4). The very strong association of 
the APOE ɛ4 allele with AD risk and its role in the accumulation of amyloid β in 
brains of people and animal models solidify the biological relevance of apoE 
isoforms but do not provide mechanistic insight. The innate immune response is 
consistently observed in AD and is a likely contributor to neuronal injury and 
response to injury. Here we review emerging data showing that apoE isoform 
regulation of multiple facets of the innate immune response in the brain may 
alter AD not only through amyloid β-dependent mechanisms, but also through 
other, amyloid β-independent mechanisms.