APOE and Alzheimer disease: Conversely, in both AD patients and AD animal models, apoE4 protein levels are lower in the central nervous system (CNS) compared to the other apoE isoforms [19–23], and decreased cerebrospinal fluid (CSF) apoE levels are associated with reduced CSF Aβ42 and worse clinical outcome, whereas increased CSF apoE has been suggested to be a protective response to injury in AD [24, 25].