My whip-smart mum Ella Muir died, word by lost word, of Alzheimer’s Disease, and that’s been the driving force behind my investigation over the last five years into the latest science around prevention. This fantastic picture is of Ella living her best life with my dad Douglas at a photo booth by the Eiffel Tower in Paris. For my research, I’ve interviewed many of the major neuroscientists and menopause specialists looking into the connection between hormone loss (and replenishment) and brain health, and read a ton of science papers, a few of which are linked here.
It’s surprisingly good news, particularly for us children of Alzheimer’s and those who carry copies of the APOE4 genetic variant which can put us at risk of the disease, because we can try to take preventative action now.
I’m not a doctor, but an investigative journalist and documentary maker, and I’ve one advantage: I can hop between medical and academic silos to get the evidence and put the case to you. Often menopause specialists know little about neuroscience, and vice versa. (Caveat - we’re not talking about early-onset Alzheimer’s here, but late-onset, which seems to have a significant connection to hormonal and lifestyle choices, especially in women.)
Let me begin with some leading questions:
*Why are two thirds of Alzheimer’s patients female?
*Why are women with early menopause 35% more likely to get Alzheimer’s and dementia? (link)
*Why are women and men with low testosterone levels more likely to get Alzheimer’s?
Yes, the big hitter in this story is hormones, and we should be shouting that from the rooftops. While billions have been spent on research which failed to find a cure for Alzheimer’s in men and women, it turns out that preventative action long beforehand is a much better and cheaper idea, especially for women - because we lose our major hormones years before men do. While nutrition, sleep and exercise help, replacing missing hormones at perimenopause and menopause has been proven to be hugely protective against the risk of late-onset Alzheimer’s.
The biggest cause of death in women in the UK is Alzheimer’s and dementia, and women aren’t more likely to get Alzheimer’s in such huge numbers just because they live a couple of years longer than men. No. When the hormone estrogen diminishes in women’s brains starting in perimenopause, guess what starts to build up? Amyloid-beta plaques (red line on graph) - clumps of protein that accumulate between the nerve cells of the brain. And these nasty plaques, along with tau tangles, are a hallmark feature found in brains of people with Alzheimer’s. (More detail in my previous Substack Why Does My Brain Rewire in Midlife?)
BRAIN BIOMARKERS OVER MENOPAUSE - Dr Lisa Mosconi
The graph above is the work of Professor Lisa Mosconi, director of the Alzheimer's Prevention Program and the Women's Brain Initiative at Weill Cornell Medicine in New York. She says: ‘By using a brain imaging technique called positron emission tomography (PET), we demonstrated that the ebb in estrogen causes the loss of a key neuroprotective element in the female brain, with an aggressively higher vulnerability to brain aging and Alzheimer’s disease.’ (more)
Dr Mosconi is the author of The Menopause Brain (very readable) which discusses the mechanism of the protective effect of estrogen: the longer your exposure to estrogen, the healthier for your brain – hence the neurological danger zone of surgical or early menopause, when you’re left high and dry - unless you take hormone replacement therapy (HRT).
Estrogen doesn’t cure Alzheimer’s when it’s already present, but among other benefits it stops the conditions that often allow Alzheimer’s to thrive: inflammation and lack of sleep caused by night sweats and hot flushes. Basically, estrogen helps your brain take out the recycling and rubbish at night, and keeps those amyloid plaques at bay. Women who get more hot flushes (particularly at night) are at higher risk of Alzheimer’s disease. Hot flushes aren’t power surges - they’re power outages. Interestingly, the use of HRT had the greatest improvement on those carrying the APOE4 genetic variant.
So it’s worth paying attention and considering the safer body-identical HRT (if you can take it) as early as you can, because perimenopause is ground zero for Alzheimer’s. The ‘window of opportunity’ for the best protection is before or around menopause.
The heroine of this story, who worked on the Alzheimer’s and HRT study which had me dancing round the room when I read it back in 2021, is Professor Roberta Diaz Brinton, director of the Center for Innovation in Brain Science at the University of Arizona. Here she is:
Her research comparing almost 400,000 women in a health insurance database over ten years found that those on hormone therapy were up to 58% less likely to develop Alzheimer’s disease and other neurodegenerative diseases. More specifically, the greatest reduction was observed in women who underwent menopausal hormone therapy for six years or longer, with a 79% lower risk of developing Alzheimer’s disease. The study also reported that the type, route, and duration of hormone therapy affected the degree of risk reduction, with natural transdermal estrogen showing greater benefits compared to synthetic hormones.
Prof Brinton explained more: ‘The loss of estrogen during menopause is enough to shift the brain’s glucose metabolism [pink line on graph] by 20-25% which activates a starvation response in the brain, causing it to look for supplementary fuel. The brain can use its own white matter as fuel, leading to abnormalities and the potential development of Alzheimer’s disease.’ It’s a sort of brain cannibalism… (Check out the white matter - your communication network - going downwards on the graph above.)
There’s a big group of women out there who could massively lower their chances of fading into Alzheimer’s by keeping their estrogen, progesterone and testosterone topped up with natural, body-identical HRT which is approved by the NHS in the UK and the FDA in America. I’m one of them, and I’ll be staying on HRT for life – I know already that it’s made a profound improvement in my memory and cognition, both temporarily affected by menopause.
There are also lots of older confounding studies out there on women with dementia in their seventies who have previously used HRT - but that’s because back then most of them probably used the old-fashioned oral HRT which contains nasty synthetic progestins like medroxyprogesterone acetate (right below). You can see how different it is from the natural progesterone we now use (on the left). The brain likes to get copies of its own hormones back - not synthetics, which are the hormal equivalent of ultra-processed food.
There’s also a growing body of research on the preventative effect of testosterone against Alzheimer’s in men - and mice (here) and that low testosterone in women (it’s a female hormone too!) with the APOE4 genetic variant negatively affects cognition. This is a separate article on topping up testosterone which I’ll tackle soon.
Today’s Substack is merely a scraping of the surface of complexity of Alzheimer’s - but there’s hope in so much of what’s in the new research. There’s hope in hormones.
If you want more detail and footnotes, my book, How to Have a Magnificent Midlife Crisis (here), has a chapter on ways to help prevent Alzheimer’s and vascular dementia. If you’ve any questions or thoughts, please put them in the chat and I can also point you to useful resources.
Coming next Friday – How to Avoid Alzheimer’s (Part 2) in which I’ll discuss the effects of nutrition, sleep, exercise and other drugs on Alzheimer’s prevention.
This is fascinating of course. I am now 67 but I was diagnosed with breast cancer at 50, and took aromatase inhibitors for 5 years to nix estrogen in my body. What should people with estrogen-fed cancers do?
Is the answer not drinking?