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Estrogen and Cognition Current Topics in Menopause 107
plaques and neuritic tangles. What causes AD is still not known, but many risk
factors for AD show overlap with those for accelerated cognitive aging and vascular
morbidity, such as smoking, diabetes mellitus, high body mass index, high blood
pressure and high blood lipid levels. Other factors may exert protective effects, such
as high levels of education and possibly sex steroids, such as estrogens.
ESTROGENS AND THE BRAIN: BIOLOGICAL PLAUSIBILITY AND
OBSERVATIONAL TRIALS
There is a plethora of evidence from animal and cell culture studies to suggest that
estrogen should be able to protect the brain against AD and other forms of
dementia [1]. Animal and cell culture studies have shown that estrogens can
enhance acetylcholine synthesis [2] (a neurotransmitter markedly reduced in AD);
have anti-oxidant, anti-inflammatory and anti-apoptotic properties [3]; facilitate
neurotrophin expression [4]; and reduce accumulation of β-amyloid protein (the
protein that accumulates in plaques in the brains of patients with AD) [5]. Of the
estrogens, estradiol is the most potent estrogen [6].
However, after menopause, estrone is the more dominant estrogen [6]. Estrogens
can affect the brain directly through estrogen receptors, but also indirectly through
their protective effects on vascular mechanisms, for instance [6].
Earlier reviews suggested that observational studies indicated a halved risk for
dementia in women who took estrogens for menopausal symptoms [6]. In the
nineties, the main evidence published seemed to suggest that estrogens should be
able to protect the aging brain and sex steroids were then hailed as potentially
very effective for prevention and treatment of AD [7].
BIAS IN OBSERVATIONAL TRIALS OF HORMONE USE AND
DEMENTIA RISK
However, it became apparent that observational data were vulnerable to several
forms of bias which were inherent to the characteristics of the participants under
investigation [8]. As stated above, dementia is characterized by severe memory
impairments [9]. It would thus be expected that women with dementia would have
more problems in recalling their use of hormones around the age of menopause.