Numerous studies have suggested that variants within the APOE promoter and intronic regions, in particular, promoter SNPs rs449647 (-491A/T) and rs405509 (−219T/G), independently of or synergistically with APOE ε4 modulate AD risk [59,60,61,62], although other studies were unable to replicate these findings [63,64,65,66,67,68]. This evidence concerns the gene APOE and Alzheimer disease.