Treatment with 17β-estradiol in postmenopausal women is associated with lower PiB-PET retention

Abstract

Treatments to reduce the amyloid plaque burden in the aging, cognitively normal population may prevent or delay the development of dementia. Pittsburgh compound B (PiB) binds to amyloid plaque and provides a surrogate for amyloid β pathology using PET. PiB-PET retention is a frequent finding in the aging, cognitively normal population. We investigated whether the treatment of postmenopausal women with menopausal hormone therapy (MHT) would have an association with amyloid burden measured by PiB-PET. Participants were recruited from the Kronos Early Estrogen Prevention Study (KEEPS), which was a randomized, placebo controlled trial to evaluate cardiovascular effects of MHT in recently menopausal women. PiB imaging was performed on a subgroup of subjects about 7 years after initiating 4 years of MHT where women within 6-36 months of their last menses had been randomized to either oral conjugated equine estrogen (CEE), Premarin, 0.45mg/day (N=17); or transdermal 17β-estradiol (TE), Climara, 50μg/day (N=21) (each with progesterone 200mg/day for 12 days/month) or placebo pills and patch (N=30). Participants had full clinical and neuropsychometric assessments. PiB images from each group were compared after treatment using a global SUVr measurement as a continuous measure. Positive PiB-PET scans were seen in 3(18%), 1(5%) and 1(3%) with median(range) SUVr's of 1.27 (1.19, 1.76), 1.25 (1.12, 1.75), 1.28 (1.20, 1.44) in the CEE, TE, and placebo groups respectively. A trend for reduced PiB retention was seen in the TE group vs. placebo (p=0.08). Among women who were APOE 4+ (N=18), we observed differences in PiB retention between CEE vs. TE (p=0.049) and TE vs. placebo (p=0.055) groups. No significant differences were observed in APOE 4- participants (n=40). (Figure). Boxplots of PiB ratios by treatment status. For ε4 positive only (right box), the p-values between 3 groups are as follows; CEE vs. Estradiol = 0.049, CEE vs. Placebo = 0.25 and Estradiol vs. Placebo = 0.055. The box on left has all subjects with e4 positives in red. The middle box has e4 negative subjects only. P-values are from Kruskal-Wallis and Wilcoxon rank sum tests. PiB cutoff for positivity at 1.4 is shown by a red-hashed line. These preliminary findings in a small number of women suggest an active role of TE for reducing amyloid brain deposition in postmenopausal women when treated for 4 years, shortly after menopause. These data may provide the rationale for a clinical trial to further investigate these findings in a larger population. These findings would support the observation that 17β-estradiol reduces the release of Aβ peptides in preclinical models. This interaction seems to be most pronounced in APOE 4+ women.