Cholesterol and the cholesterol oxide 24S-hydroxycholesterol (24S-HC) are highly enriched in the human CNS. Clinical, genetic, neurochemical and epidemiological evidence continue to support dysfunctional cholesterol metabolism as an important contributing factor driving the development and/or progression of Alzheimer's disease (AD) neuropathology. Cholesterol overabundance in the brain plasma membrane lipid- raft domains, appears to be fundamental to the generation of the more neurotoxic forms of amyloid-β (Aβ) peptide from β-amyloid holoprotein precursor. 24S-HC may have a pivotal role in promoting altered inflammatory signaling, apoptotic genetic responses and AD-type change. In clinical studies, cholesterol-lowering statins, nonsteroidal anti-inflammatory drugs, cholesterol absorption/transport inhibitors and related modulators of cholesterol trafficking have demonstrated some pharmacological benefit for the treatment of AD, but overall their efficacy at slowing the cognitive decline and the progression of AD remains controversial and open to question.