Christopher W. Gregory

Sex hormones and ApoE4: beyond steroids.

The accompanying paper by Burkhardt and colleagues [2] highlights the complexity of the estrogen/Alzheimer’s disease (AD) connection. One possible explanation of these interesting results is that there is a link between particular estrogen receptor polymorphisms and apolipoprotein E (ApoE) polymorphisms. While there are conflicting reports in the literature, several studies have suggested an increased risk of AD in women with particular estrogen receptor polymorphisms [1]. There is a well established physiologic relationship between estrogen and apolipoproteins due to the fact that estrogen is a reproductive steroid hormone formed from cholesterol, the primary source of which is ApoE. Considering the importance of estrogen in regulation of reproductive function, it is easy to imagine that individuals with ApoE4 might be more fertile if they possessed a particular estrogen receptor polymorphism. Alternatively, the ApoE polymorphism dependent differential effect of estrogen on cognition might be explained by the finding that there appears to be a “critical period” during which hormone replacement therapy (HRT) must be initiated in order to have a protective effect on cognition [4]. One possible explanation for the finding that estrogen exposure had no effect on cognition in individuals possessing an ApoE4 gene relates to this “critical period” hypothesis. Since published data suggests that the possession of an ApoE4 allele is associated with an earlier onset of cognitive decline [3], it may be that the “critical period” for patients positive for ApoE4 begins before it does for ApoE4 nega-

P4-354: Luteinizing hormone: A unifying hypothesis for Alzheimer disease etiology, pathogenesis and treatment

58% of the subjects in Group 1 scored no change or improved at Week 48 compared to 38% in Group 2 (p 0.031 unadjusted; p 0.093 adjusted). Mean ADCS-ADL scores in Group 1 declined by 0.54 points at Week 48 compared with a decline of 6.85 points in Group 2 (unadjusted p 0.015; adjusted p 0.044). Leuprolide acetate was well tolerated in this study. Conclusions: Leuprolide acetate was well tolerated and had a stabilizing effect on cognitive and global functioning in women with mild to moderate AD over a 48 week period. This analysis served as the basis of design for our current Phase III pivotal studies of VP4896 (Voyager’s proprietary formulation of leuprolide acetate) as adjunctive AD therapy with AChEIs.

P1-369: Evidence of gonadotropin-induced steroidogenesis in Alzheimer’s disease

embryos, maintained in culture for 7 days in Neurobasal medium supplemented with B27 (which contains insulin). Prior to treatment B27 was withdrawn for 2 hr. Duplicate sets (n 4 per set) of neurons were then left untreated or treated with either recombinant Wnt3a at 400ng/ml, insulin at 50 nM, Dickkopf-1 (DKK-1) at 800 ng/ml, 20 mM lithium chloride all for 2 hr for RNA or 4 hr for protein. Total RNA was harvested using Triazol, analyzed on an Agilent Bioanalyser and quantified using a Nanodrop fluorospectrometer. cRNA was generated using the one-cycle kit from Affymetrix and hybridized to Rat U230v2 genomic arrays. Data was analyzed using Genespring (Silicon Genetics). For 2D separation total cell lysates were first subjected to iso-electric focusing (pH range 3-11) on an Amersham IPGPhor. Second dimension separation was performed using 10% acrylamide gels in an Amersham DaltII tank. Gels were scanned and analyzed using ImageMaster Platinum software. The most significant genes whose transcription levels increase or decrease in response to either insulin, Wnt3a or both treatments and proteins whose expression levels were found to change or which were post-transcriptionally modified by these treatments will be presented.