Zhu et al. found that postmortem human brain tissues of ApoE4 carriers had a lower level of phosphoinositol biphosphate (PIP2) compared with those of ApoE3 counterparts at early stages of AD, and similar results were also found in primary neurons expressing ApoE4 alleles and in the brains of ApoE4 knock-in mice. Here, APOE is linked to Alzheimer disease.