Apolipoprotein E represents a potent gene-based therapeutic target for the treatment of sporadic Alzheimer's disease.

Alzheimer’s disease (AD) is associated with neuronal loss, ynaptic damage, deposition of -amyloid, and loss of cholinrgic activity in susceptible brain regions. These three neuroathologic markers of AD are markedly modulated by the resence of the apolipoprotein e4 (APOE e4) allele in sporadic D subjects. The APOE e4 allele is also a well-known risk actor for sporadic late-onset AD. Patients born with two E4 lleles were shown to exhibit (1) an earlier age of onset, (2) igher amyloid plaque counts [1–3], (3) cerebrovascular amyoid deposition [2], and (4) marked reductions in choline cetyltransferase [4–7], nicotinic, and nerve growth factor reeptor [5] density compared with non-e4 allele subjects. Recent clinical evidence clearly indicates that the APOE olymorphism significantly affects the rate of conversion from ild cognitive impairment (MCI) to probable AD [8]. It conomitantly affects the decline in cognitive performance of MCI ubjects in an APOE e4 allele dose-dependent manner on ognitive performance (according to the Alzheimer’s Disase Assessment Scale, cognitive subscale [ADAS-cog]) in -to-4 year follow-up studies with donepezil, rivastigmine, nd galantamine [8–10]. Moreover, it was shown that hereas reductions of hippocampal and entorhinal cortex olumes appear to act as predictors of conversion from MCI o AD, they do so only in APOE e4 carriers [10,11]. When one examines the effect of the APOE e4 allele on ate of conversion to AD, rate of decline, synaptic remodling, pathologic accumulation of amyloid, and even on xtent of cholinergic drug response in sporadic AD subjects, t is tempting to postulate that specific pharmacologic maipulations designed to counter the impact of APOE e4 on he physiology of the adult central nervous system (CNS) re bound to provide beneficial relief to both “genetically at