However, when cholesterol concentration decreases in the cytofacial leaflet and increases in the exofacial layer, which is typical of aging or AD and ApoE4-knock-in mouse synaptosomes (Wood et al., 1984, 1990, 2002; Igbavboa et al., 1996; Hayashi et al., 2002; Yanagisawa, 2005), the peptide loses the α-helicity and extrudes its reactive N-terminus into the extracellular space, which can lead to deleterious aggregation. Here, APOE is linked to Alzheimer disease.