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!

Impairment to cognitive function is often comorbid with Parkinson’s disease. That is to say: it’s not a symptom of Parkinson’s, but it often occurs in the same people. This may seem natural: after all, both are strongly associated with aging.

However, recent (last month, at time of writing) research has brought to light a very specific way in which medication for Parkinson’s may impair the ability to make sound decisions.

Obviously, this is a big deal, because it can affect healthcare decisions, financial decisions, and more—greatly impacting quality of life.

See also: Age-related differences in financial decision-making and social influence

(in which older people were found more likely to be influenced by the impulsive financial preferences of others than their younger counterparts, when other factors are controlled for)

As for how this pans out when it comes to Parkinson’s meds…

Pramipexole (PPX)

This drug can, due to an overlap in molecular shape, mimic dopamine in the brains of people who don’t have enough—such as those with Parkinson’s disease. This (as you might expect) helps alleviate Parkinson’s symptoms.

However, researchers found that mice treated with PPX and given a touch-screen based gambling game picked the high-risk, high reward option much more often. In the hopes of winning strawberry milkshake (the reward), they got themselves subjected to a lot of blindingly-bright flashing lights (the risk, to which untreated mice were much more averse, as this is very stressful for a mouse).

You may be wondering: did the mice have Parkinson’s?

The answer: kind of; they had been subjected to injections with 6-hydroxydopamine, which damages dopamine-producing neurons similarly to Parkinson’s.

This result was somewhat surprising, because one would expect that a mouse whose depleted dopamine was being mimicked by a stand-in (thus, doing much of the job of dopamine) would be less swayed by the allure of gambling (a high-dopamine activity), since gambling is typically most attractive to those who are desperate to find a crumb of dopamine somewhere.

They did find out why this happened, by the way, the PPX hyperactivated the external globus pallidus (also called GPe, and notwithstanding the name, this is located deep inside the brain). Chemically inhibiting this area of the brain reduced the risk-taking activity of the mice.

This has important implications for Parkinson’s patients, because:

• on an individual level, it means this is a side effect of PPX to be aware of
• on a research-and-development level, it means drugs need to be developed that specifically target the GPe, to avoid/mitigate this side effect.

You can read the study in full here:

Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson’s Disease

Don’t want to get Parkinson’s in the first place?

While nothing is a magic bullet, there are things that can greatly increase or decrease Parkinson’s risk. Here’s a big one, as found recently (last week, at the time of writing):

Air Pollution and Parkinson’s Disease in a Population-Based Study

Also: knowing about its onset sooner rather than later is scary, but beneficial. So, with that in mind…

Recognize The Early Symptoms Of Parkinson’s Disease

Finally, because Parkinson’s disease is theorized to be caused by a dysfunction of alpha-synuclein clearance (much like the dysfunction of beta-amyloid clearance, in the case of Alzheimer’s disease), this means that having a healthy glymphatic system (glial cells doing the same clean-up job as the lymphatic system, but in the brain) is critical:

How To Clean Your Brain (Glymphatic Health Primer)

Take care!