The molecular mechanism underlying pathological aggregation of Aβ in an AD brain remains to be determined. In the case of familial AD, the generation of responsible genes is likely to enhance Aβ aggregation via increased generation of Aβ. However, no evidence of altered Aβ generation in sporadic AD, a major form of the disease, has been provided. Thus, it is reasonable to assume that Aβ aggregation in sporadic AD may be induced by an as yet unknown post-translational modification of Aβ and/or by an altered clearance mechanism. On this subject, we previously hypothesized that Aβ starts to be aggregated in the brain via its binding to a glycolipid molecule, GM1 ganglioside (Yanagisawa et al., 1995). Based on the unique molecular characteristics of the GM1 ganglioside-bound Aβ (GM1-Aβ), including its extremely high aggregation potential and altered immunoreactivity, we consider that Aβ adopts an altered conformation via binding to GM1 and accelerates aggregation of soluble Aβ by acting as a seed (Yanagisawa et al., 1995; Yanagisawa and Ihara, 1998). Recently, we attempted to clarify the molecular mechanism underlying generation of GM1-Aβ and found that the binding of Aβ to GM1 was markedly accelerated in a cholesterol-rich environment (Kakio et al., 2001). Furthermore, our study also suggested that cholesterol-dependent formation of GM1-Aβ is due to the formation of a GM1 “cluster” in membranes rich in cholesterol, and that soluble Aβ recognizes the GM1 “cluster” as a chemical receptor and binds to it (Kakio et al., 2001). Previously, it was reported that Aβ initially accumulated in the fractions with a lipid composition similar to that of lipid rafts in an animal model of AD (Sawamura et al., 2000). Furthermore, cholesterol-associated aggregation of Aβ was also observed in cultured cells, mimicking impaired cholesterol trafficking in Niemann-Pick type C disease (NPC), a genetic disorder of cholesterol trafficking (Yamazaki et al., 2001). Taken together with the results of previous in vitro studies (Mizuno et al., 1999; Yip et al., 2001), it is highly likely that membrane lipids, including cholesterol and ganglioside, are highly involved in the aggregation of soluble Aβ in AD brains.