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
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
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Chatter – by Dr. Ethan Kross
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This book is about much more than just one’s internal monologue. It does tackle that, but also the many non-verbal rabbit-holes that our brains can easily disappear into.
The author is an experimental psychologist, and brings his professional knowledge and experience to bear on this problem—citing many studies, including his own studies from his own lab, in which he undertook to answer precisely the implicit questions of “How can I…” in terms of tackling these matters, from root anxiety (for example) to end-state executive dysfunction (for example).
The writing style isn’t dense science though, and is very approachable for all.
The greatest value in this book lies in its prescriptive element, that is to say, its advice, especially in the category of evidence-based things we can do to improve matters for ourselves; beyond generic things like “mindfulness-based stress reduction” to much more specific things like “observe yourself in the 3rd person for a moment” and “take a break to imagine looking back on this later” and “interrupt yourself with a brief manual task”. With these sorts of interventions and more, we can shift the voice in our head from critic to coach.
Bottom line: if you would like your brain to let you get on with the things you actually want to do instead of constantly sidetracking you, this is the book for you.
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The Vagus Nerve’s Power for Weight Loss
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Dr. Arun Dhir is a university lecturer, a gastrointestinal surgeon, an author, and a yoga and meditation instructor, and he has this to say:
Gut feelings
The vagus nerve is the 10th cranial nerve, also known as “vagus” (“the wanderer”), because it travels from the brain to many other body parts, including the ears, throat, heart, respiratory system, gut, pancreas, liver, and reproductive system. It’s no surprise then, that it plays a key role in brain-gut communication and metabolism regulation.
The vagus nerve is part of the parasympathetic nervous system, responsible for rest, digestion, and counteracting the stress response. Most signals through the vagus nerve travel from the gut to the brain, though there is communication in both directions.
You may be beginning to see how this works and its implications for weight management: the vagus nerve senses metabolites from the liver, pancreas, and small intestine, and regulates insulin production by stimulating beta cells in the pancreas, which is important for avoiding/managing insulin resistance and metabolic syndrome in general.
Dr. Dhir cites a study in which vagus nerve stimulation (originally used for treating epilepsy and depression) was shown to cause unintentional weight loss (6-11%) in patients, revealing a link to weight management. Of course, that is quite a specific sample, so more research is needed to say for sure, but because the principle is very sound and the mechanism of action is clear, it’s not being viewed as a controversial conclusion.
As for how get these benefits, here are seven ways:
- Cold water on the face: submerge your face in cold water in the morning while holding water in your mouth, or cover your face with a cold wet washcloth (while holding your breath please; no need to waterboard yourself!), which activates the “mammalian dive response” in which your body activates the parasympathetic nervous system in order to remain calm and thus survive for longer underwater
- Alternate hot and cold showers: switch between hot and cold water during showers for 10-second intervals; this creates eustress and activates the process of hormesis, improving your overall stress management and reducing any chronic stress response you may otherwise have going on
- Humming and gargling: the vibrations in the throat stimulate the nearby vagus nerve
- Deep breathing (pranayama): yoga breathing exercises, especially combined with somatic exercises such as the sun salutation, can stimulate the vagus nerve
- Intermittent fasting: helps recalibrate the metabolism and indirectly improves vagus nerve function
- Massage and acupressure: stimulates lymphatic channels and the vagus nerve
- Long walks in nature (“forest bathing”): helps trigger relaxation in general
For more on all of this, enjoy:
Click Here If The Embedded Video Doesn’t Load Automatically!
Want to learn more?
You might also like to read:
The Vagus Nerve (And How You Can Make Use Of It)
Take care!
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Zucchini vs Okra – Which is Healthier?
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Our Verdict
When comparing zucchini to okra, we picked the okra.
Why?
Looking at the macros first, okra has nearly 2x the protein and more than 3x the fiber (for about 2x the carbs).
In terms of vitamins, things are also quite one-sided; zucchini has a little more vitamin B2, while okra has a lot more of vitamins A, B1, B3, B5, B6, B9, C, E, K, and choline.
Nor does the mineral situation make any compelling counterargument; zucchini is higher only in sodium, while okra has a lot more calcium, copper, iron, magnesium, manganese, phosphorus, potassium*, selenium, and zinc.
*Actually it’s only a little more potassium. But the rest are with big margins of difference.
Both of these on-the-cusp-of-being-pungent vegetables have beneficial antioxidant polyphenols (especially various forms of quercetin), but okra has more.
In short: enjoy both, of course, but there’s a clear winner here and it’s okra.
Want to learn more?
You might like to read:
Enjoy Bitter/Astringent/Pungent Foods For Your Heart & Brain
Take care!
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How To Rebuild Your Neurons’ Myelin Sheaths
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PS: We Love You
Phosphatidylserine, or “PS” for short, is a phospholipid found in the brain. In other words, a kind of fatty compound that is such stuff as our brains are made of.
In particular, it’s required for healthy nerve cell membranes and myelin (the protective sheath that neurons live in—basically, myelin sheaths do for neurons what telomere caps do for DNA).
For an overview that’s more comprehensive than we have room for here, check out:
Phosphatidylserine and the human brain
Many people take it as a supplement.
Does taking it as a supplement work?
This is a valid question, as a lot of supplements can’t be absorbed well, and/or can’t pass the blood-brain barrier. But, as the above-linked study notes:
❝Exogenous PS (300-800 mg/d) is absorbed efficiently in humans, crosses the blood-brain barrier, and safely slows, halts, or reverses biochemical alterations and structural deterioration in nerve cells. It supports human cognitive functions, including the formation of short-term memory, the consolidation of long-term memory, the ability to create new memories, the ability to retrieve memories, the ability to learn and recall information, the ability to focus attention and concentrate, the ability to reason and solve problems, language skills, and the ability to communicate. It also supports locomotor functions, especially rapid reactions and reflexes.❞
(“Exogenous” means “coming from outside of the body”, as opposed to “endogenous”, meaning “made inside the body”. Effectively, in this context “exogenous” means “taken as a supplement”.)
Why do people take it?
The health claims for phosphatidylserine fall into two main categories:
- Neuroprotection (helping your brain to avoid age-related decline in the long term)
- Cognitive enhancement (helping your brain work better in the short term)
What does the science say?
There’s a lot of science that’s been done on the neuroprotective properties of PS, and there are thousands of studies we could draw from here. The upshot is that regular phosphatidylserine supplementation (most often 300mg/day, but studies are also found for 100–500mg/day) is strongly associated with a reduction in cognitive decline over the course of 12 weeks (a common study duration). Here are a some spotlight studies showing this:
- Effects of phosphatidylserine in Alzheimer’s disease
- Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type
- Effect of Phosphatidylserine on Cerebral Glucose Metabolism in Alzheimer’s Disease
- The effect of soybean-derived phosphatidylserine on cognitive performance in elderly with subjective memory complaints
Note: PS can be derived from various sources, with the two most common forms being bovine (i.e., from cow brains) or soy-derived.
There is no established difference in the efficacy of these.
There have been some concerns raised about the risk of CJD (the human form of BSE, as in “mad cow disease”) from consuming brain matter from cows, but studies have not found any evidence of this actually happening.
There is also some evidence that phosphatidyserine significantly boosts cognitive performance, even in young people with no extant cognitive decline, for example:
(as the title suggests, they did also test for its effect on mood and endocrine response, but found it made no difference to those, just the cognitive function—which enjoyed a boost before exercise, as well as after it, meaning that the boost wasn’t dependent on the exercise)
PS for cognitive enhancement in the young and healthy is not nearly so well-explored as its use as a later-life guard against age-related cognitive decline. However, just because the studies in younger people are dwarfed in number by the studies in older people, doesn’t detract from the validity of the studies in younger people.
Basically: its use in older people has been studied the most, but all available evidence points to it being beneficial to brain health at all ages.
Where can we get it?
We don’t sell it (or anything else), but for your convenience, here’s an example product on Amazon.
Enjoy!
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The Dopamine Precursor And More
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What Is This Supplement “NALT”?
N-Acetyl L-Tyrosine (NALT) is a form of tyrosine, an amino acid that the body uses to build other things. What other things, you ask?
Well, like most amino acids, it can be used to make proteins. But most importantly and excitingly, the body uses it to make a collection of neurotransmitters—including dopamine and norepinephrine!
- Dopamine you’ll probably remember as “the reward chemical” or perhaps “the motivation molecule”
- Norepinephrine, also called noradrenaline, is what powers us up when we need a burst of energy.
Both of these things tend to get depleted under stressful conditions, and sometimes the body can need a bit of help replenishing them.
What does the science say?
This is Research Review Monday, after all, so let’s review some research! We’re going to dive into what we think is a very illustrative study:
A 2015 team of researchers wanted to know whether tyrosine (in the form of NALT) could be used as a cognitive enhancer to give a boost in adverse situations (times of stress, for example).
They noted:
❝The potential of using tyrosine supplementation to treat clinical disorders seems limited and its benefits are likely determined by the presence and extent of impaired neurotransmitter function and synthesis.❞
More on this later, but first, the positive that they also found:
❝In contrast, tyrosine does seem to effectively enhance cognitive performance, particularly in short-term stressful and/or cognitively demanding situations. We conclude that tyrosine is an effective enhancer of cognition, but only when neurotransmitter function is intact and dopamine and/or norepinephrine is temporarily depleted❞
That “but only”, is actually good too, by the way!
You do not want too much dopamine (that could cause addiction and/or psychosis) or too much norepinephrine (that could cause hypertension and/or heart attacks). You want just the right amount!
So it’s good that NALT says “hey, if you need some more, it’s here, if not, no worries, I’m not going to overload you with this”.
Read the study: Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands
About that limitation…
Remember they said that it seemed unlikely to help in treating clinical disorders with impaired neurotransmitter function and/or synthesis?
Imagine that you employ a chef in a restaurant, and they can’t keep up with the demand, and consequently some of the diners aren’t getting fed. Can you fix this by supplying the chef with more ingredients?
Well, yes, if and only if the problem is “the chef wasn’t given enough ingredients”. If the problem is that the oven (or the chef’s wrist) is broken, more ingredients aren’t going to help at all—something different is needed in those cases.
So it is with, for example, many cases of depression.
See for example: Tyrosine for depression: a double-blind trial
About blood pressure…
You may be wondering, “if NALT is a precursor of norepinephrine, a vasoconstrictor, will this increase my blood pressure adversely?”
Well, check with your doctor as your own situation may vary, but under normal circumstances, no. The effect of NALT is adaptogenic, meaning that it can help keep its relevant neurotransmitters at healthy levels—not too low or high.
See what we mean, for example in this study where it actually helped keep blood pressure down while improving cognitive performance under stress:
Effect of tyrosine on cognitive function and blood pressure under stress
Bottom line:
For most people, NALT is a safe and helpful way to help keep healthy levels of dopamine and norepinephrine during times of stress, giving cognitive benefits along the way.
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Clean Needles Save Lives. In Some States, They Might Not Be Legal.
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Kim Botteicher hardly thinks of herself as a criminal.
On the main floor of a former Catholic church in Bolivar, Pennsylvania, Botteicher runs a flower shop and cafe.
In the former church’s basement, she also operates a nonprofit organization focused on helping people caught up in the drug epidemic get back on their feet.
The nonprofit, FAVOR ~ Western PA, sits in a rural pocket of the Allegheny Mountains east of Pittsburgh. Her organization’s home county of Westmoreland has seen roughly 100 or more drug overdose deaths each year for the past several years, the majority involving fentanyl.
Thousands more residents in the region have been touched by the scourge of addiction, which is where Botteicher comes in.
She helps people find housing, jobs, and health care, and works with families by running support groups and explaining that substance use disorder is a disease, not a moral failing.
But she has also talked publicly about how she has made sterile syringes available to people who use drugs.
“When that person comes in the door,” she said, “if they are covered with abscesses because they have been using needles that are dirty, or they’ve been sharing needles — maybe they’ve got hep C — we see that as, ‘OK, this is our first step.’”
Studies have identified public health benefits associated with syringe exchange services. The Centers for Disease Control and Prevention says these programs reduce HIV and hepatitis C infections, and that new users of the programs are more likely to enter drug treatment and more likely to stop using drugs than nonparticipants.
This harm-reduction strategy is supported by leading health groups, such as the American Medical Association, the World Health Organization, and the International AIDS Society.
But providing clean syringes could put Botteicher in legal danger. Under Pennsylvania law, it’s a misdemeanor to distribute drug paraphernalia. The state’s definition includes hypodermic syringes, needles, and other objects used for injecting banned drugs. Pennsylvania is one of 12 states that do not implicitly or explicitly authorize syringe services programs through statute or regulation, according to a 2023 analysis. A few of those states, but not Pennsylvania, either don’t have a state drug paraphernalia law or don’t include syringes in it.
Those working on the front lines of the opioid epidemic, like Botteicher, say a reexamination of Pennsylvania’s law is long overdue.
There’s an urgency to the issue as well: Billions of dollars have begun flowing into Pennsylvania and other states from legal settlements with companies over their role in the opioid epidemic, and syringe services are among the eligible interventions that could be supported by that money.
The opioid settlements reached between drug companies and distributors and a coalition of state attorneys general included a list of recommendations for spending the money. Expanding syringe services is listed as one of the core strategies.
But in Pennsylvania, where 5,158 people died from a drug overdose in 2022, the state’s drug paraphernalia law stands in the way.
Concerns over Botteicher’s work with syringe services recently led Westmoreland County officials to cancel an allocation of $150,000 in opioid settlement funds they had previously approved for her organization. County Commissioner Douglas Chew defended the decision by saying the county “is very risk averse.”
Botteicher said her organization had planned to use the money to hire additional recovery specialists, not on syringes. Supporters of syringe services point to the cancellation of funding as evidence of the need to change state law, especially given the recommendations of settlement documents.
“It’s just a huge inconsistency,” said Zoe Soslow, who leads overdose prevention work in Pennsylvania for the public health organization Vital Strategies. “It’s causing a lot of confusion.”
Though sterile syringes can be purchased from pharmacies without a prescription, handing out free ones to make drug use safer is generally considered illegal — or at least in a legal gray area — in most of the state. In Pennsylvania’s two largest cities, Philadelphia and Pittsburgh, officials have used local health powers to provide legal protection to people who operate syringe services programs.
Even so, in Philadelphia, Mayor Cherelle Parker, who took office in January, has made it clear she opposes using opioid settlement money, or any city funds, to pay for the distribution of clean needles, The Philadelphia Inquirer has reported. Parker’s position signals a major shift in that city’s approach to the opioid epidemic.
On the other side of the state, opioid settlement funds have had a big effect for Prevention Point Pittsburgh, a harm reduction organization. Allegheny County reported spending or committing $325,000 in settlement money as of the end of last year to support the organization’s work with sterile syringes and other supplies for safer drug use.
“It was absolutely incredible to not have to fundraise every single dollar for the supplies that go out,” said Prevention Point’s executive director, Aaron Arnold. “It takes a lot of energy. It pulls away from actual delivery of services when you’re constantly having to find out, ‘Do we have enough money to even purchase the supplies that we want to distribute?’”
In parts of Pennsylvania that lack these legal protections, people sometimes operate underground syringe programs.
The Pennsylvania law banning drug paraphernalia was never intended to apply to syringe services, according to Scott Burris, director of the Center for Public Health Law Research at Temple University. But there have not been court cases in Pennsylvania to clarify the issue, and the failure of the legislature to act creates a chilling effect, he said.
Carla Sofronski, executive director of the Pennsylvania Harm Reduction Network, said she was not aware of anyone having faced criminal charges for operating syringe services in the state, but she noted the threat hangs over people who do and that they are taking a “great risk.”
In 2016, the CDC flagged three Pennsylvania counties — Cambria, Crawford, and Luzerne — among 220 counties nationwide in an assessment of communities potentially vulnerable to the rapid spread of HIV and to new or continuing high rates of hepatitis C infections among people who inject drugs.
Kate Favata, a resident of Luzerne County, said she started using heroin in her late teens and wouldn’t be alive today if it weren’t for the support and community she found at a syringe services program in Philadelphia.
“It kind of just made me feel like I was in a safe space. And I don’t really know if there was like a come-to-God moment or come-to-Jesus moment,” she said. “I just wanted better.”
Favata is now in long-term recovery and works for a medication-assisted treatment program.
At clinics in Cambria and Somerset Counties, Highlands Health provides free or low-cost medical care. Despite the legal risk, the organization has operated a syringe program for several years, while also testing patients for infectious diseases, distributing overdose reversal medication, and offering recovery options.
Rosalie Danchanko, Highlands Health’s executive director, said she hopes opioid settlement money can eventually support her organization.
“Why shouldn’t that wealth be spread around for all organizations that are working with people affected by the opioid problem?” she asked.
In February, legislation to legalize syringe services in Pennsylvania was approved by a committee and has moved forward. The administration of Gov. Josh Shapiro, a Democrat, supports the legislation. But it faces an uncertain future in the full legislature, in which Democrats have a narrow majority in the House and Republicans control the Senate.
One of the bill’s lead sponsors, state Rep. Jim Struzzi, hasn’t always supported syringe services. But the Republican from western Pennsylvania said that since his brother died from a drug overdose in 2014, he has come to better understand the nature of addiction.
In the committee vote, nearly all of Struzzi’s Republican colleagues opposed the bill. State Rep. Paul Schemel said authorizing the “very instrumentality of abuse” crossed a line for him and “would be enabling an evil.”
After the vote, Struzzi said he wanted to build more bipartisan support. He noted that some of his own skepticism about the programs eased only after he visited Prevention Point Pittsburgh and saw how workers do more than just hand out syringes. These types of programs connect people to resources — overdose reversal medication, wound care, substance use treatment — that can save lives and lead to recovery.
“A lot of these people are … desperate. They’re alone. They’re afraid. And these programs bring them into someone who cares,” Struzzi said. “And that, to me, is a step in the right direction.”
At her nonprofit in western Pennsylvania, Botteicher is hoping lawmakers take action.
“If it’s something that’s going to help someone, then why is it illegal?” she said. “It just doesn’t make any sense to me.”
This story was co-reported by WESA Public Radio and Spotlight PA, an independent, nonpartisan, and nonprofit newsroom producing investigative and public-service journalism that holds power to account and drives positive change in Pennsylvania.
KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.
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