Hogervorst Eva, Smith A David
Oxford Project To Investigate Memory and Ageing, University Department of Pharmacology, Radcliffe Infirmary, Oxford, United Kingdom.
Neuro Endocrinol Lett. 2002 Apr;23(2):155-60.
In vitro and in vivo animal studies suggest that sex steroids, such as estrogens and testosterone, could protect the brain. However, estrogen replacement therapy (ERT) for Alzheimer's disease (AD) in women has not been successful. We hypothesised that the lack of effect of ERT might be related to an interaction between estrogens and some other factor(s) associated with AD.
DESIGN, SETTING AND METHODS: We analysed total estrogen (TE) and testosterone (TT) levels in women diagnosed with AD and controls of the Oxford Project To Investigate Memory and Ageing. Because estradiol (TE2) after the menopause is largely derived from estrone (TE1), we computed the ratio TE2/(TE1+TE2) and a total steroid index (TT+TE2+TE1).
Women with AD (n=66) had significantly higher levels of TE2 (27+/-13 vs. 21+/-13) and a higher TE2/(TE1+TE2) ratio. Stepwise logistic regression analyses showed that the TE2/(TE1+TE2) ratio was the main sex steroid predictor for AD (O.R.=1.06, 95% C.I.=1.01-1.11, p<0.01). Multiple regression analyses revealed that dementia severity was associated with an interaction between the TE2/(TE1+TE2) ratio and serum folate (B=4.59 (SE=1.48), beta=1.22, 95% C.I.=1.62-7.56, p<0.005). None of the other potential mediators of this association (body mass index, sex hormone binding globulin, homocysteine levels, ApoE genotype, smoking, diabetes, blood pressure) was significant.
A high ratio of estradiol to total estrogens is associated with AD but, in subjects with a high ratio, the dementia severity was lower in those with high serum folate levels.
If this association is causal, then supplementation with folic acid might be considered in future studies on ERT in AD.
体外和体内动物研究表明，雌激素和睾酮等性类固醇可能对大脑有保护作用。然而，女性阿尔茨海默病（AD）的雌激素替代疗法（ERT）并未取得成功。我们推测ERT缺乏效果可能与雌激素和某些其他与AD相关的因素之间的相互作用有关。
设计、研究地点和方法：我们分析了牛津记忆与衰老研究项目中被诊断为AD的女性和对照组的总雌激素（TE）和睾酮（TT）水平。由于绝经后的雌二醇（TE2）主要来源于雌酮（TE1），我们计算了TE2/（TE1+TE2）的比值和总类固醇指数（TT+TE2+TE1）。
AD女性（n=66）的TE2水平显著更高（27±13对21±13），且TE2/（TE1+TE2）比值更高。逐步逻辑回归分析表明，TE2/（TE1+TE2）比值是AD的主要性类固醇预测指标（比值比=1.06，95%置信区间=1.01-1.11，p<0.01）。多元回归分析显示，痴呆严重程度与TE2/（TE1+TE2）比值和血清叶酸之间的相互作用有关（B=4.59（标准误=1.48），β=1.22，95%置信区间=1.62-7.56，p<0.005）。这种关联的其他潜在介导因素（体重指数、性激素结合球蛋白、同型半胱氨酸水平、载脂蛋白E基因型、吸烟、糖尿病、血压）均无显著意义。
雌二醇与总雌激素的高比值与AD相关，但在该比值较高的受试者中，血清叶酸水平高者的痴呆严重程度较低。
如果这种关联是因果关系，那么在未来AD的ERT研究中可能会考虑补充叶酸。
