Androgens, ApoE, and Alzheimer's Disease
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This discussion was produced in collaboration with SAGE KE.
Jacob Raber led this live discussion on 7 May 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
Andrea LeBlanc — Posted 29 April 2004
This discussion is based on Dr. Raber's recent review for SAGE KE of
the same title (Sci. Aging Knowl. Environ., Vol. 2004, Issue 11, pp.
re2, 17 March 2004). Note: Alzheimer Research Forum members can access the
Increasing evidence indicates that there are reductions in estrogen and
androgen levels in aged men and women. These hormonal reductions might
be risk factors for cognitive impairments and the development of
Alzheimer's disease (AD). Aged people show improved cognition after
treatments with sex steroids. Therefore, ongoing clinical AD trials
have been designed to evaluate the potential benefits of estrogen
therapy in women and testosterone therapy in men. Apolipoprotein E
(apoE) plays an important role in the metabolism and redistribution of
lipoproteins and cholesterol. The three major human apoE isoforms,
apoE2, apoE3, and apoE4, differ in their effects on AD risk and
pathology. Here I review various mechanisms proposed to mediate the
differential effects of apoE isoforms on brain function and highlight
the potential contribution of detrimental isoform-dependent effects of
apoE on androgen- and androgen receptor (AR)-mediated pathways. I also
discuss potential interactions of androgens with other AD-related
Q&A with Andrea Leblanc and the Alzheimer Research Forum
Q: Estrogen-replacement therapy failed in the Women's Health Study. How could your findings be made clinically useful? Do you envision a better next-generation approach?
A: I think that we can use two approaches to counter the negative effects of hormones. First, using physiological concentrations of hormones (nM range) is sufficient for neuroprotection, as we have shown with primary human neurons. I am not sure if all the clinical trials used higher
levels but if so, then maybe smaller doses would
be sufficient for the beneficial neuroprotective
effect while eliminating the side effects.
Second, once we know how hormones induce
neuroprotection, we will be able to develop drugs
that do not have the side effects due to the
multiple actions of the hormones. For example,
anything that increases Hsp70 may prove to be an
excellent lead compound to prevent intracellular
Q: Do you see a way to activate estrogen/testosterone receptors on neurons in a sufficiently specific way to achieve a therapeutic effect short of flooding the whole body with estrogen or testosterone?
A: Peptidomimetics can be established
against one specific action in other receptors
with multiple functions. This way the receptor
can be stimulated to have only one of its
multiple responses. Maybe this approach could be
aplied to estrogen/testosterone receptors.
Q: ApoE binds Aβ and is also being studied with regard to its effect on Aβ clearance and deposition. Do you see any connection between this work and yours?
A: ApoE is secreted and will be involved in
extracellular Aβclearance but not intracellular
Aβ. Unless Apo E can alter metabolism of APP to
reduce the amount of intracellular Aβ production,
I do not see a connection with our work.
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