Estrogen, Hormone Replacement Therapy, and Alzheimer's Disease

Lane Simonian

Early menopause and late hormone replacement therapy may both increase the risk for Alzheimer's disease, which may at first seem counterintuitive

https://www.healthline.com/health-news/alzheimers-disease-how-early-menopause-and-delayed-hormone-therapy-treatment-may-impact-risk#3

For awhile estrogen helps reduce myo-inositol levels which can be a factor in Alzheimer's disease. High glucose levels, high blood pressure due to high sodium levels, and Down syndrome all increase myo-inositol levels in the brain. Women who go through early menopause lack the estrogen levels needed to reduce myo-inositol concentrations in the brain. Over time, myo-inositol is converted into phosphatidyinositol 4,5 biphosphate which when tied to the over-activation of various receptors such as g protein-coupled receptors increases the risk for Alzheimer's disease. Estrogen can over-activate g protein-coupled receptors. So low levels of estrogen due to early menopause or late hormone replacement therapy can both increase the risk for Alzheimer's disease.

Marta

Lane: would you share your thoughts about the mechanism of late HRT and an increased risk of AD?

In 26 years I only started HRT at the time of menopause.

Lane Simonian

Perhaps the great unanswered question is how long after the start of menopause, does hormone replacement therapy become counterproductive.

The possible mechanism of action is this, estrogen activates a g protein-coupled receptor which leads to oxidative and nitrostative stress. Oxidative and nitrostative stress may be the underlying cause of Alzheimer's disease.

One study suggestst that estrogen activation of a g protein-coupled receptor does not lead to damage to neurons, but I am not sure if this conclusion is correct when high levels of estrogen are involved (link not working, but here is the title and conclusion).

G protein-coupled estrogen receptor activates cell type-specific signaling pathways in cortical cultures: relevance to the selective loss of astrocytes

"In this study, we also demonstrate that selective activation of GPER induced astrocyte apoptosis via the phospholipase C pathway and subsequent intracellular calcium rise, whereas in neurons, this effect was not observed. Taken together, this evidence supports a direct impact of GPER activity on the viability of astrocytes, which seems to be associated with the regulation of different signaling pathways in astrocytes and neurons.

Figure 3 potentially connects late hormone replacement therapy with Alzheimer's disease. MGluR (metabotropic glutamate receptor which is a g-protein coupled receptor), PLC is phospholipase C, Ca+2 is intracellular calcium rise, and ONOO- is the nitro-oxidant peroxynitrite.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362409/

Lane Simonian

Maybe I should not blame it all on late hormone replacement therapy. I am a big believer in tipping points. A factor by itself may not lead to a disease, but when combined with another risk factor or factors it can.