Alzheimer’s Sex Differences May Not Be What They Appear

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Alzheimer’s Sex Differences May Not Be What They Appear

Women get Alzheimer’s at nearly twice the rate than men do, and deteriorate more rapidly after onset, too.

So… Why?

There are many potential things to look at, but four stand out for quick analysis:

  • Chromosomes: women usually have XX chromosomes, to men’s usual XY. There are outliers to both groups, people with non-standard combinations of chromosomes, but not commonly enough to throw out the stats.
  • Hormones: women usually have high estrogen and low testosterone, compared to men. Again there are outliers and this is a huge oversimplification that doesn’t even look at other sex hormones, but broadly speaking (which sounds vague, but is actually what is represented in epidemiological studies), it will be so.
  • Anatomy: humans have some obvious sexual dimorphism (again, there are outliers, but again, not enough to throw out the stats); this seems least likely to be relevant (Alzheimer’s is probably not stored in the breasts, for examples), though average body composition (per muscle:fat ratio) could admittedly be a factor.
  • Social/lifestyle: once again, #NotAllWomen etc, but broadly speaking, women and men often tend towards different social roles in some ways, and as we know, of course lifestyle can play a part in disease pathogenesis.

As a quick aside before we continue, if you’re curious about those outliers, then a wiki-walk into the fascinating world of intersex conditions, for example, could start here. But by and large, this won’t affect most people.

So… Which parts matter?

Back in 2018, Dr. Maria Teresa Ferretti et al. kicked up some rocks in this regard, looking not just at genes (as much research has focussed on) or amyloid-β (again, well-studied) but also at phenotypes and metabolic and social factors—bearing in mind that all three of those are heavily influenced by hormones. Noting, for example, that (we’ll quote directly here):

  • Men and women with Alzheimer disease (AD) exhibit different cognitive and psychiatric symptoms, and women show faster cognitive decline after diagnosis of mild cognitive impairment (MCI) or AD dementia.
  • Brain atrophy rates and patterns differ along the AD continuum between the sexes; in MCI, brain atrophy is faster in women than in men.
  • The prevalence and effects of cerebrovascular, metabolic and socio-economic risk factors for AD are different between men and women.

See: Sex differences in Alzheimer disease—the gateway to precision medicine

So, have scientists controlled for each of those factors?

Mostly not! But they have found clues, anyway, while noting the limitations of the previous way of conducting studies. For example:

❝Women are more likely to develop Alzheimer’s disease and experience faster cognitive decline compared to their male counterparts. These sex differences should be accounted for when designing medications and conducting clinical trials❞

~ Dr. Feixiong Cheng

Read: Research finds sex differences in immune response and metabolism drive Alzheimer’s disease

Did you spot the clue?

It was “differences in immune response and metabolism”. These things are both influenced by (not outright regulated by, but strongly influenced by) sex hormones.

❝As [hormonal] sex influences both the immune system and metabolic process, our study aimed to identify how all of these individual factors influence one another to contribute to Alzheimer’s disease❞

~ Dr. Justin Lathia

Ignoring for a moment progesterone’s role in metabolism, estrogen is an immunostimulant and testosterone is an immunosuppressant. These thus both also have an effect in inflammation, which yes, includes neuroinflammation.

But wait a minute, shouldn’t that mean that women are more protected, not less?

It should! Except… Alzheimer’s is an age-related disease, and in the age-bracket that generally gets Alzheimer’s (again, there are outliers), menopause has been done and dusted for quite a while.

Which means, and this is critical: post-menopausal women not on HRT are essentially left without the immune boost usually directed by estrogen, while men of the same age will be ticking over with their physiology that (unlike that of the aforementioned women) was already adapted to function with negligible estrogen.

Specifically:

❝The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women❞

~ Dr. Rasha Saleh

Source: Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women

Critical idea to take away from all this:

Alzheimer’s research is going to be misleading if it doesn’t take into account sex differences, and not just that, but also specifically age-relevant sex differences—because that can flip the narrative. If we don’t take age into account, we could be left thinking estrogen is to blame, when in fact, it appears to be the opposite.

In the meantime, if you’re a woman of a certain age, you might talk with a doctor about whether HRT could be beneficial for you, if you haven’t already:

❝Women at genetic risk for AD (carrying at least one APOE e4 allele) seem to be particularly benefiting from MHT❞

(MHT = Menopausal Hormone Therapy; also commonly called HRT, which is the umbrella term for Hormone Replacement Therapies in general)

~ Dr. Herman Depypere

Source study: Menopause hormone therapy significantly alters pathophysiological biomarkers of Alzheimer’s disease

Pop-sci press release version: HRT could ward off Alzheimer’s among at-risk women

Take care!

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  • Why Has Nobody Told Me This Before? – by Dr. Julie Smith

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    Superficially, this can be called a “self-help” book, but that undersells it rather. It’s a professionally-written (as in, by a professional psychologist) handbook full of resources. Its goal? Optimizing your mental health to help you stay resilient no matter what life throws your way.

    While the marketing of this book is heavily centered around Dr. Smith’s Internet Celebrity™ status, a lot of her motivation for writing it seems to be precisely so that she can delve deeper into the ideas that her social media “bites” don’t allow room for.

    Many authors of this genre pad their chapters with examples; there are no lengthy story-telling asides here, and her style doesn’t need them. She knows her field well, and knows well how to communicate the ideas that may benefit the reader.

    The main “meat” of the book? Tips, tricks, guides, resources, systems, flowcharts, mental frameworks, and “if all else fails, do this” guidance. The style of the book is clear and simple, with very readable content that she keeps free from jargon without “dumbing down” or patronizing the reader.

    All in all, a fine set of tools for anyone’s “getting through life” toolbox.

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  • Fasting Cancer – by Dr. Valter Longo

    10almonds is reader-supported. We may, at no cost to you, receive a portion of sales if you purchase a product through a link in this article.

    We’ve previously reviewed Dr. Longo’s “The Longevity Diet”, and whereas that one was about eating, this one is (superficially, at least) about not eating. Nor is this any kind of dissonance, because, in fact, it’s important to do both!

    That said, he discusses not just fasting per se, but also the use of a personalized fast-mimicking diet, to accomplish the same goal of not overloading the metabolism—as overloading the metabolism results in metabolic disease, and cancer is, ultimately, a metabolic disease of immune dysfunction with genetic disorder*—which makes for quite a deadly trifecta.

    *not in the sense of “hereditary”, though certainly genes can influence cancer risk, but rather, in the sense of “your gene-copying process becomes disordered”.

    The first three chapters (after the introduction, which we’ll comment on shortly) are devoted to explaining the principles at hand:

    1. Fasting cancer while feeding patients
    2. Genes, aging, and cancer
    3. Fasting, nutrition, and physical activity in cancer prevention

    In those chapters, he details a lot of the science for exactly how and why it is possible to “feed the patient and starve the cancer” at the same time.

    After that, the rest of the book—another nine chapters, not counting appendices etc—are given over to fasting and nutrition in the context of nine main types of cancer, one chapter per type. These are not hyperspecific, though, and are rather categorizations, such as “blood cancers”, and “gynecological cancers” and so forth. It’s comprehensive, and while it could be argued that it may mean chapters feel irrelevant to some people (à la “I have never smoked and have no pressing concern about my lung cancer risk” etc), the reality is that it’s good to know how to avoid them all, because if nothing else, it’d be super embarrassing to get a cancer you “thought you couldn’t get”. So, it’s honestly worth the time to read each chapter.

    In the category of criticism, he did open the introduction with a handful of anecdotes to defend the consumption of (well-established group 1 carcinogens) red meat and alcohol as “secondary concerns that might not be such a big deal”, even discussing how surprised his colleagues in the field are that he has this view. Suffice it to say, it’s contrary to the overwhelming body of evidence, and reads suspiciously like a man who simply doesn’t want to give up his steak and wine despite his own longevity diet forswearing them.

    The style is self-indulgently autobiographical and very complimentary, and (in this reviewer’s opinion) it can be tedious to wade through that to get to the science, but at the end of the day, his self-accolades might be needless fluff, but they don’t actually remove anything from the science in question.

    Bottom line: as you can see, there are good and bad things to say about this book, but the information contained in the good makes it well worth reading through the stylistically questionable to get it.

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  • Does This New Machine Cure Depression?

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    Let us first talk briefly about the slightly older tech that this may replace, transcranial magnetic stimulation (TMS).

    TMS involves electromagnetic fields to stimulate the left half of the brain and inhibit the right half of the brain. It sounds like something from the late 19th century—“cure your melancholy with the mystical power of magnetism”—but the thing is, it works:

    Regulatory Clearance and Approval of Therapeutic Protocols of Transcranial Magnetic Stimulation for Psychiatric Disorders

    The main barriers to its use are that the machine itself is expensive, and it has to be done in a clinic by a trained clinician. Which, if it were treating one’s heart, say, would not be so much of an issue, but when treating depression, there is a problem that depressed people are not the most likely to commit to (and follow through with) going somewhere probably out-of-town regularly to get a treatment, when merely getting out of the door was already a challenge and motivation is thin on the ground to start with.

    Thus, antidepressant medications are more often the go-to for cost-effectiveness and adherence. Of course, some will work better than others for different people, and some may not work at all in the case of what is generally called “treatment-resistant depression”:

    Antidepressants: Personalization Is Key!

    Transcranial stimulation… At home?

    Move over transcranial magnetic stimulation; it’s time for transcranial direct-current stimulation (tDCS).

    First, what it’s not: electroconvulsive therapy (ECT). Rather, it uses a very low current.

    What it is: a small and portable headset (as opposed to the big machine to go sit in for TMS) that one can use at home. Here’s an example product on Amazon, though there are more stylish versions around, this is the same basic technology.

    In a recent study, 45% of those who received treatment with this device experienced remission in 10 weeks, significantly beating placebo (bearing in mind that placebo effect is strongest when it comes to invisible ailments such as depression).

    See also: How To Leverage Placebo Effect For Yourself ← this explains more about how the placebo effect works, to the extent that it can even be an adjuvant tool to augment “real” therapies

    And as for the study, here it is:

    Home-based transcranial direct current stimulation treatment for major depressive disorder: a fully remote phase 2 randomized sham-controlled trial

    …which rather cuts through the “depressed people don’t make it to the clinic consistently, if at all” problem. Of course, it still requires adherence to its use at home, for example three 30-minute sessions per week, but honestly, “lie/sit still” is likely within the abilities of the majority of depressed people. However…

    Important note: you remember we said “in 10 weeks”? That may be critical, because shorter studies (e.g. 6 weeks) have previously returned without such glowing results:

    Home-Use Transcranial Direct Current Stimulation for the Treatment of a Major Depressive Episode

    This means that if you get this tech for yourself or a loved one, it’ll be necessary to persist for likely 10 weeks, certainly more than 6 weeks, and not abandon it after a few sessions when it hasn’t been life-changing yet. And that may be more of a challenge for a depressed person, so likely an “accountability buddy” of some kind is in order (partner, close friend, etc) to help ensure adherence and generally bug you/them into doing it consistently.

    And then, of course, you/they might still be in the 55% of people for whom it didn’t work. And that does suck, but random antidepressant medications (i.e., not personalized) don’t fare much better, statistically.

    Want something else against depression meanwhile?

    Here are some strategies that not only can significantly help, but also are tailored to be actually doable while depressed:

    The Mental Health First-Aid You’ll Hopefully Never Need ← written by your writer who has previously suffered extensively from depression and knows what it is like

    Take care!

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    We previously reviewed Dr. Boss’s excellent book “Loss, Trauma, and Resilience: Therapeutic Work With Ambiguous Loss”, which partially overlaps in ideas with this one. In that case, it was about grief when a loved one is “gone, but are they really?”, which can include missing persons, people killed in ways that weren’t 100% confirmed (e.g. no body to bury), and in contrast, people who are present in body but not entirely present mentally: perhaps in a coma, for example. It also includes people are for other reasons not entirely present in the way they used to be, which includes dementia. And that latter case is what this book focuses on.

    In the case of dementia, we cannot, of course, simply focus on ourselves. Well, not if we care about the person with dementia, anyway. Much like with the other kinds of ambiguous loss, we cannot fully come to terms with things while on the cusp of presence and absence, and we cannot, as such, “give up” on our loved one.

    What then, of hope? The author makes the case for—in absence of any kind of closure—making our peace with the situation as it is, making our peace with the uncertainty of things. And that means not only “at any moment could come a more clearly complete loss”, but also on the flipside at least a faint candle of hope, that we should not grasp with both hands (that is not how to treat a candle, literally or metaphorically), but rather, hold gently, and enjoy its gentle light.

    Dr. Boss also covers more practical considerations; family rituals, celebrations, gatherings, and the idea of “the good-enough relationship”. Particularly helpfully, she gives her “seven guidelines for the journey”, which even if one decides against adopting them all, are definitely all good things to at least have considered.

    The style is much more tailored to the lay reader than the other book of hers that we reviewed, which was intended more for clinicians, but useful also for those of us who have been hit by such kinds of grief. In this case, however, her intention is first and foremost for the family of a person who has dementia—there are still footnotes throughout though, for those who still want to read scientific papers that support the various ideas discussed in the book.

    Bottom line: if a loved one has dementia or that seems a likely possibility for you, this book can help a lot!

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  • Cannellini Protein Gratin

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    A healthier twist on a classic, the protein here comes not only from the cannellini beans, but also from (at the risk of alienating French readers) a béchamel sauce that is not made using the traditional method involving flour and butter, but instead, has cashew protein as a major constituent.

    You will need

    • 3 medium potatoes, chopped (no need to peel them; you can if you want, but many of the nutrients are there and they’re not a problem for the recipe)
    • 1 can cannellini beans (also called white kidney beans)
    • 1 medium onion, chopped
    • 2 stalks celery, sliced
    • 1 carrot, chopped
    • ½ bulb garlic, minced (or more, if you like)
    • 1 jalapeño, chopped
    • 2 tbsp tomato paste
    • 1 tbsp chia seeds
    • 2 tsp black pepper, coarse ground
    • Extra virgin olive oil, for frying

    For the béchamel sauce:

    • ½ cup milk (we recommend a neutral-tasting plant milk, such as unsweetened soy, but go with your preference)
    • ⅓ cup cashews, soaked in hot water for at least 5 minutes (longer is fine) and drained
    • ¼ cup nutritional yeast
    • 1 tsp garlic powder
    • 1 tsp dried thyme

    Method

    (we suggest you read everything at least once before doing anything)

    Note: it will be a bonus if you can use a pan that is good both for going on the hob and in the oven, such as a deep cast iron skillet, or a Dutch oven. If you don’t have something like that though, it’s fine, just use a sauté pan or similar, and then transfer to an oven dish for the oven part—we’ll mention this again when we get to it.

    1) Preheat the oven to 250℉/175℃.

    2) Heat the pan, adding some oil and then the oven; fry it for about 5 minutes, stirring often.

    3) Add the potatoes, celery, carrot, garlic, and jalapeño, stirring for another 2 minutes.

    4) Add the tomato paste, along with 1 cup water, the chia seeds, and the black pepper, and cook for a further 15 minutes, stirring occasionally as necessary.

    5) Add the cannellini beans, and cook for another 15 minutes, stirring occasionally as necessary.

    6) Blend all the ingredients for the béchamel sauce, processing it until it is smooth.

    7) If you are using an oven-safe pan, pour the béchamel sauce over the bean mixture (don’t stir it; the sauce should remain on top) and transfer it to the oven. Don’t use a lid.

    If you’re not using an oven safe pan, first transfer the bean mixture to an oven dish, then pour the béchamel sauce over the bean mixture (don’t stir it; the sauce should remain on top) and put it in the oven. Don’t use a lid.

    8) Bake for about 15 minutes, or until turning golden-brown on top.

    9) Serve! It can be enjoyed on its own, or with salad and/or rice. See also, our Tasty Versatile Rice Recipe.

    Enjoy!

    Want to learn more?

    For those interested in some of the science of what we have going on today:

    Take care!

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  • Buckwheat vs Bulgur Wheat – Which is Healthier?

    10almonds is reader-supported. We may, at no cost to you, receive a portion of sales if you purchase a product through a link in this article.

    Our Verdict

    When comparing buckwheat to bulgur, we picked the buckwheat.

    Why?

    First, some things to know up front:

    • Bulgur wheat is a kind of cracked wheat product. As such, it contains wheat, and yes, gluten.
    • Buckwheat is not a wheat, nor even a grass, but a flowering plant. Buckwheat is as related to wheat as a lionfish is to a lion. It does not contain gluten.
    • Buckwheat can be purchased whole or hulled. We went with whole. If you go with hulled, the percentages of vitamins and minerals will be relatively higher, and/but this will be because you lost the fibrous husk, so they’ll be commensurately lower in fiber. If you were to go with hulled, we’d still pick it over bulgur wheat though, just for a different reason (as in that case, the vitamin and mineral contents would be more overwhelmingly in buckwheat’s favor, even though it’d have less fiber).

    Ok, now that those things are covered…

    Looking at the macronutrients, there’s not a lot between them, except that buckwheat has the much lower glycemic index (this is only the case if you got whole, not hulled—if you got hulled, the glycemic index would be about the same).

    In terms of vitamins, buckwheat has more of vitamins B2, B5, B9, E, K, and choline, while bulgur wheat technically has more vitamin A, but the numbers are tiny; a cup of bulgur wheat will give you 0.12% of the RDA. So, an easy win (functionally: 5:0) for buckwheat.

    When it comes to minerals, buckwheat has more copper, magnesium, potassium, and selenium, while bulgur wheat has more calcium and manganese. They’re equal on iron and phosphorus, making this a 4:2 win for buckwheat.

    Adding up the categories makes this a clear win for buckwheat!

    Want to learn more?

    You might like to read:

    Take care!

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