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The
Interaction of Serum Folate and Estradiol Levels in Alzheimer’s
Disease
Eva
Hogervorst
A. David Smith
Oxford
Project To Investigate Memory and Ageing, University Department
of Pharmacology, Oxford, UNITED KINGDOM
Submitted:
March 20, 2002
Accepted: March 25, 2002
Key words:
estradiol, testosterone, estrone, SHBG, serum folate,
Alzheimer’s dementia
Abstract
OBJECTIVES:
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).
RESULTS:
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.
MAIN
FINDINGS: 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.
CONCLUSIONS: If this association is causal, then supplementation
with folic acid might be considered in future studies on ERT
in AD.
Introduction
Animal
and cell culture studies have shown there is strong biological
plausibility [1] for estrogen replacement therapy (ERT) to treat
Alzheimer’s disease (AD). However, three recent randomised controlled
trails did not show any positive effect of ERT in women with
AD [2-4]. In addition, several studies using hormone assays
of adequate sensitivity reported higher levels of estrogens
in women with AD compared to controls [5-7]. There could be
a confounding factor in AD cases which prevents them from profiting
from the potential protective effects of estrogens. In the present
study, total estradiol (TE2), estrone (TE1) and testosterone
(TT) were measured. After the menopause, only very small quantities
of E2 are derived from E1 and from androgens such as testosterone
[8]. E1 then becomes the predominant estrogen through conversion
of androgens in adipose tissue, but it has less affinity for
the estrogen receptors than E2 [8]. Because of these conversions,
we calculated a ratio TE2/(TE2+TE1) and a total steroid index
(TT+TE2+ TE1). Several potential confounds for the association
between sex steroids and AD were measured and were co-varied
in the analyses, such as body mass index (B.M.I., [8], sex hormone
binding globulin (SHBG), which determines the level of free
or bioavailable hormones and changes with age and certain disease
states [9], creatinine and albumin levels as markers for steroid
clearance, and a number of risk factors for AD which have also
been reported to interact with sex steroid levels, such as smoking
[10, 11], having at least one ApoE e4 allele [12], high levels
of serum homocysteine [13-15] and low serum folate and vitamin
B12 [16-18].
Materials
and Methods:
Clinical examination; Hormone assays; Other biochemistry; Statistics;
Results:
... ...
Demographic,
clinical characteristics and sex stroid levels
... ...
Potential mediating effects of the association between estradiol
and AD
... ...
Discussion
In
women, AD was associated with a higher TE2 level and with a
higher TE2/(TE1+TE2) ratio. This association was not mediated
through ... ...
Acknowledgments
The authors would like to thank NDDK’s National Hormone
and Pituitary Programm and Dr A.F.Parlow for providing rat LH
and FSH RIA reagents and standard preparations and murine leptin.
The work was supported in part by scientific programm No 501-2-2-25-40/99
and a grant No 4P05A 135 18 from The State Committee for Scientific
Research.
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