This is my response to a blog written by Trish Vradenburg from USAAgainstAlzheimer's.

Trish Vrandenburg recently asked why are women more likely to develop Alzheimer's disease than men.  The answer mainly lies in that post-menopausal women have higher levels of serum nitric oxide than men.

 http://link.springer.com/article/10.1007/s00404-014-3338-x

 http://www.ncbi.nlm.nih.gov/pubmed/20505437

Estrogen reduces levels of myo-inositol which is the precursor to inducible nitric oxide and superoxides which combine to form peroxynitrite--the primary oxidant in Alzheimer's disease.  In post-menopausal women, levels of inducible nitric oxide, superoxides, and peroxynitrite increase.  However, it is not simply a matter of hormone replacement therapy as estrogen activates a g protein-coupled receptor and overactivation of these receptors is one of the triggers for Alzheimer's disease.

Please take a moment to consider the following.  Through oxidation and nitration, peroxynitrite inhibits the synthesis and release of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness, inhibits the transport of glucose and limits the flow of blood in the brain which can lead to delusions, inhibits the regeneration of neurons, and contributes via caspase 3 to the death of neurons.  Where g protein-coupled receptor activity remains high (the ApoE4 gene and stress), hallucinations are possible.  Peroxynitrite scavengers not only lower peroxynitrite levels, they partially reverse oxidation and nitration--which helps improve some forms of short-term memory (object recognition, repetitive memory, recognition of places, for instance), sleep, mood, social recognition, and alertness.  Some peroxynitrite scavengers such as ferulic acid by binding to myo-inositol also helps to reduce pyschological and behavioral problems.  Thus, peroxynitrite scavengers such as eugenol in various essential oils (Jimbo, 2009), ferulic acid, syringic acid, vanillin, p-coumaric acid, and maltol in Korean red ginseng and heat processed ginseng  (Heo 2011 and 2012) and THC at low levels and cannabidiol have helped in the treatment of Alzheimer's disease (Shelef, 2016, Cheng 2014).

Estrogen seems to be preventative in regard to AD. Pathology tends to increase after menopause (as I recall reading in the research), but estrogen replacement therapy doesn't seem to help. Here is another connection. Perhaps this also connects to nitric oxide or peroxynitrite.

 27-Hydroxycholesterol in Human Physiology through the Modulation of Estrogen Receptor Function

"we discovered that 27HC binds to ER and acts as an endogenous inhibitor of ER action in the vasculature. It turned out that the effects by 27HC are tissue-specific, thus 27HC is the first identified endogenous selective estrogen receptor modulator, or SERM. The serum 27HC levels correlate well with cholesterol levels and also rise progressively with age. We have been investigating the pathophysiologic implications of the findings on the oxysterol in vitro and in vivo. We hope to develop a new therapeutic approach towards modulating 27HC levels to treat cholesterol- and/or estrogen receptor-mediated diseases such as cardiovascular diseases, bone weakening called osteoporosis, cancer and metabolic diseases."

I am going to look more into the possible estrogen connections to Alzheimer's disease, but here are two: one positive and the other with age and oxidative stress negative.

The researchers found that women who had been treated with tamoxifen had lower levels of myo-inositol in the brain than the untreated women. Women who took estrogen also had lower levels of the chemical.

Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C

Here are a couple of other reasons why women are more likely to get Alzheimer's disease than men.

"Levothyroxine acts upon a G-protein-coupled transmembrane receptor."  Now for a person taking levothyroxine and who has the ApoE4 gene it is a double whammy because not only is levothyroxine increasing g protein signalling via a g protein-coupled receptor but ApoE4 is increasing (via LRP1)  g protein signalling independent of that receptor.

Now if someone takes Fosamax or some of the other biphosphonate osteoporosis drugs to counteract the effects of levothyroxine then yet another problem arises.

The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFkappaB pathway in osteosarcoma cells.

The present findings demonstrate that alendronate inhibited the PI3K-Akt-NFkappaB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.

So not only do postmenopausal women have high levels of myo-inositol (due to declining estrogen levels) and ultimately higher levels of peroxynitrite than most men and pre-menopausal women, they are also at greater risk for Alzheimer's disease because certain drugs for hypothyroidism and osteoporosis are increasing peroxynitrite levels even more.