Most of the data linking Estrogen to AD is correlative. In general, Women are twice as likely to get AD than men. For a long time, this was attributed simply to the fact that women tend to live longer than men (Remember, Age is the greatest risk factor for AD). However, studies which controlled for age showed women as more likely to get AD.
The big question, of course, is Why? The obvious place to look was with the sex hormones. The hypothesis which emerged was that estrogen levels plummet in women after menopause and that this reduction in estrogen would account for the increased risk of women for AD.
Evidence to support this hypothesis includes the finding that estrogen levels to not change significantly over course of men's lives. Women with AD were less likely to have been on estrogen replacement therapy.
(The reference in your post seems to have called this into question.I was under the impression that this finding was widely accepted. I only read the abstract, but it seems to me that the authors merely searched MedLine for studies associating estrogen replacement therapy to the incidence of AD. They then try to lump all the numbers from each individual study into one large sample pool. I am a bit wary of conclusions drawn from such a study....I would wait for subsequent studies to form an opinion on the effect of estrogen replacement on AD).
The regions of the brain which are most vulnerable to AD also express estrogen receptors and the enzyme Aromatase (converts testosterone into estrogen in men).
Furthermore, estrogen has been shown to modulate APP processing in cell culture. Specifically, Cells process APP non-amyloidogenically upon treatment with estrogen. (If I remember right, it was about a two-fold effect). The mechanism by which this occurs is unknown. It is worth mentioning that activation of PKC causes a fairly dramatic shift towards the non-amyloidogenic processing of APP. Estrogen has been known to work via PKC in various other pathways. I do not know if experiments have been done to determine if Estrogen works through PKC to effect APP. (I should note that these studies were done in non-neuronal cells for technical reasons).
Other people (Bruce McEwen at Rockefeller University comes to mind) have tied estrogen to synapse formation in the Hippocampus. Others have tried to tie estrogen into acetylcholine production via NGF.
My own take on all this.....well i think the estrogen story seems to gain momentum when researchers run out of ideas on other things to do.
I think it is on firmer ground than Sibia's Acetylcholine story with AD, but there are clearly more promising avenues of research in AD.
Frank
Also, Keep in mind that Billions upon Billions of women go post-menopauasal without getting AD... ie....Estrogen clearly is not a major cause of AD |
