Should the ApoE genotype be a covariate for clinical trials in Alzheimer disease 英文参考文献.docVIP

Farlow Alzheimer’s Research Therapy 2010,2:15 /content/2/3/15 COMMENTARY Should the ApoE genotype be a covariate for clinical trials in Alzheimer disease? Martin R Farlow* up signi? cantly with gene dos ese associations hold Abstract true for both sporadic and familial forms of the illness. Pathologically, inheritance of the E4 genotype has been associated with greater total amyloid deposition in the brain, both in cortical plaques and in the vessels, and increased neuro? brillary tangles [1,2]. In mild cognitive impairment (MCI) or very-early-stage AD, the E4 genotype is asso ciated with greater de? cits on the New York Paragraph Recall test, Auditory-Verbal Learning Test, and Buschke test at baseline. On magnetic reso- nance imaging, there are increases in both hippocampal atrophy and global atrophy at baseline [3], and on posi- tron emission tomo graphy using FDG (? uorine-18- ? uorodeoxy glucose), there are greater de? cits in glucose metabolism in the posterior parietal and parahippo- campal regions. In MCI subjects with the E4 genotype, cerebrospinal ? uid analyses typically have shown decreased levels of the protein amyloid beta (Aβ) 1-42 and increased levels of Tau and pTau [4]. Should the apolipoprotein E (ApoE) genotype be a covariate for clinical trials in Alzheimer disease (AD)? ApoE is a transport protein for lipids, amyloid-beta proteins, and the di?erent phenotypes di?erentially a?ect amyloid-beta deposition, neuro?brillary tangle formation, and microglial activation. The ApoE genotype has not a?ected e?cacy in short symptomatic AD trials. ApoE4 has been associated with greater e?cacy in at least two mild cognitive impairment studies. Vasogenic edema was more frequent in ApoE4 AD patients treated with a monoclonal antibody to amyloid beta. Since there is evidence that the ApoE genotype may di?erentially a?ect disease mechanisms, e?cacy, and adver