While this finding is consistent with a previous study that demonstrated increased circulating cholesterol and lesion development in normal chow fed ApoE−/− mice [16], it remains unclear if aged ApoE−/− mice in the present study demonstrated an exacerbated proatherogenic response or if increased plaque size and severity is a consequence of either higher circulating cholesterol with advancing age or the prolonged exposure to hyperlipidemia that would have existed even before initiation of AD in the middle-aged and older mice. Here, APOE is linked to Alzheimer disease.