Several lines of evidence indicate that apolipoprotein E (apoE) plays a central role in the brains response to injury and neurodegeneration in the adult. The coordinated expression of apoE and several of its accessory proteins appears to regulate the transport and internalization of cholesterol and phospholipids during development and normal brain reinnervation in the adult. The discovery, a few years ago, that a genetic variant in the apoE gene called apoE4 strongly links to both sporadic and familial late onset Alzheimers disease (AD) has raised the possibility that a dysfunction of the lipid transport system in the brain could be central to AD pathophysiology. Pathophysiological evidence obtained in autopsyconfirmed sporadic AD cases clearly indicate that the presence of apoE4 allele in humans directly compromises cholinergic function in the adult brain and indirectly modulate the efficacy of medications designed to enhance the cholinergic activity in diseased brain. The apoE4 allele was found to significantly increase the risk of progression to dementia for persons exhibiting amnestic mild cognitive impairment (aMCI), a transitional state between the cognitive changes associated with normal aging and early AD. Furthermore, two accessory enzymes involved in cholinergic neurotransmission called butyrylcholinesterase and paraoxonase-1 were shown i) to display polymorphic variants that increase the risk of developing AD and ii) to modulate drug responsiveness in AD subjects exposed to cholinomimetic agents. This article reviews the most critical findings in this field and reassess the potent clinical value of pharmacogenomics of neurodegenerative diseases and dementia.