Hey everybody, it's Mikki here. You're listening to Mini-Mikkipedia on a Monday.

I hope you had a great weekend. And in fact, last week, cracking week, as they all are,

I got a text in a WhatsApp group that I'm part of just with a couple of my very smart friends.

And one of them put a link to an article that was in the NZ Herald. And the headline reading,

popular supplements could harm the aging brain. And I'm like, oh yeah, that's interesting. I

wonder what's going on here. And she had a note in there saying, is this just healthy user bias

that people who are concerned with their brain health might already have a small amount of

sort of cognitive decline. They start taking supplements and then this sort of reverse

association relationship occurs. And I'm like, I'd actually love to dig a little bit deeper

into the article, see what it's saying. And then where are they even getting their information

from? So the article itself was originally a Washington Post article that was published

last week as well. And it was one article discussing vitamin D, omega-3 and glucosamine.

However, these come from three different recent studies. So it wasn't just one study.

And the caveat to all of this that I'm about to go into,

that even though the original article acknowledges that the findings are preliminary,

mostly observational, sometimes contradictory, and does not establish that these supplements

cause cognitive decline. The thing with the headline is it's such clickbait for so many people

who won't really read the finer details and will just look at some of the commentary that

article provided. And of course, I will put the article in the show notes for you to have a look

at yourself.

Because as per usual, that headline asks a much stronger question than the evidence can currently

answer. But humans being humans, we're going to think that it already has. So before getting into

the individual supplements and studies, just sort of clarify what I mean by observational study

versus a randomized controlled trial, which is the gold standard in this type of research when

we're looking at one particular intervention.

So an observational study is, as the name suggests, the researchers observe what people

already do. So people taking a supplement can differ from non-users of supplements in dozens

of ways. And this is something called the healthy user bias, like people who are interested in

taking supplements are probably also interested in being active, in monitoring their drinking,

and not smoking, and watching their sleep, and all of those sorts of things, which,

of course, researchers can statistically adjust in their analyses of whatever results they find.

But you cannot adjust away that healthy user lifestyle. And you also can't adjust away for

things that aren't measured. So there'll be maybe these other underlying factors related to

supplement use that we aren't even aware of. So we don't know how to adjust them.

So this associations that are found in observational studies, as I'll go on,

to explain, they don't necessarily, or they certainly don't, suggest causation. But often

that's where our brain goes. And often that's where newspaper headlines tend to lead us.

And a really great way to think about an observational study is that they set the scene,

or they are hypothesis producing, in that the results of an association study should then be

taken into that randomized controlled environment to test the results. And that's where the

data comes from. And that's where the data comes from. And that is, in fact, a very good contrast,

that randomized controlled trial, to an observational study. So researchers randomly

assign a particular supplement or intervention to a group that there are no differences,

no indifferences between the different groups in the study. So all groups, all people within the

groups, there are sort of selection criteria for which you would be involved in a study.

And then everyone is randomized to,

a particular group. And because of that randomization process, no one is, as at that

group level, no one is different from one group to the next. And it means that these groups are

much more comparable. So if observational studies suggest harm, but a randomized controlled trial

on that particular observation wasn't able to reproduce the harm or reproduce the finding,

we have to be quite cautious about,

including that the observational research was correct. Because literally that randomized

controlled trial was designed to test the mechanism that the observational trial sort

of brought up. Anyway, and that really is, has to be an underlying theme as I go through some of what

this article was suggesting, and then actually what the studies associated with the article

actually found. So let's think about vitamin D, for example, and this is a really important

nutrient.

Some people call it a hormone, and it is involved in many, many different pathways in the body. And

of course, we talk about vitamin D a lot over here in New Zealand, particularly in winter,

because we synthesize the majority of our vitamin D from the sun. But for many months of the year,

the sun's UVB rays aren't strong enough for our body to synthesize vitamin D. And therefore,

we need to take it as a supplement. Now, in the British Medical Journal Open study in

2026, a database from the US Health and Retirement Study was used to look at vitamin D and cognitive

decline. So there were over 5,000 adults, their average age was 67 and a half years. 40% of those

users took vitamin D, and they followed these people for six years. And they assessed the

population for global cognition, memory, and executive function. And this was not a randomized

vitamin D study. It was a randomized vitamin D study. And they assessed the population for global

cognition. And they assessed the population for global cognition. And they assessed the population

for global cognition. And they assessed the population for global cognition. And so a lot

of the countries were not following the data. And they assessed the population for global

cognition. And they assessed the population for global murmurs, and calculates their average

People simply reported whether they took vitamin D or not, which is how they came up with the number

of people that actually took vitamin D. And what they found across that six years was that

vitamin D users had a statistically faster decline in global cognition and executive function. Memory

decline was not statistically significantly different. So the association appeared primarily

in people who started with what the researchers classified as adequate vitamin D status,

rather than those that were deficient or insufficient so let's have a look at what

they actually found so global cognition was 0.052 points a year lower in vitamin d users

and executive function was 0.021 points per year lower and to put that effect size into context

the global cognition scale went up to 27 so the excess decline associated with supplement use

across those six years was essentially 0.31 points so 0.31 out of a 27 point scale so whilst

it was statistically significant can you really tell me that one third of a point across 27 points

is clinically important i don't know i would probably argue not

you

and you've got to remember that sometimes a real strength of a study is the fact that they are

looking at thousands of participants right so that is you know obviously a strength however

the reverse is actually true as well is that when you get large databases like that you can detect

very small differences and they can be statistically significant even if they're

not clinically important and i think that's a really worthwhile thing to sort of bear in mind

there were some big limitations to the study so they did not know the actual

actual value of the study and they didn't know the actual value of the study and they didn't

know it to a great extent also because of the fact that they were normally taking vitamin d

dose in sufficient detail so you could have been taking 400 international units or iu you could be

taking 2 000 iu or 5 000 iu and all of these people were sort of lumped into that broad category of

vitamin d user you can see that it was such a vast difference between the dosing and also of course

as with a lot of nutrition supplement use was self-reported in addition to that vitamin d users

were already actually different from the non-users so vitamin d users were actually the ones that were

For example, their baseline global cognitive scores were slightly higher.

They were 16.3 out of that 27 versus 15.8.

So residual confounding also remains possible.

And when vitamin D users were compared specifically with people taking neither a vitamin D or

a multivitamin, the difference fell to 0.044 points per year, which was no longer statistically

significant.

So on observational level, there was a slight difference in that global cognition and that

executive functioning by 0.3 of a point across six years, but that was pretty much it.

And this was just an observational trial.

So what actually happens when we randomize vitamin D?

And I think this is a really important point and an important comparison.

There was a study called VITAL, and it randomized older adults, similar age, 60 plus, to 2,000

international units of vitamin D3 a day versus taking nothing at all.

And there was a cognitive sub-study within that that had 4,000 adults who were, as I

said, aged over 60, and they found no significant difference in cognitive decline between these

groups.

And there was no interaction with baseline vitamin D status.

So that's interesting as well.

Like in the previous observational study, those people taking vitamin D tended to have

an adequate status, whereas here, there was no sort of interaction with that vitamin D

status.

So the major take-home probably is that there isn't good evidence that taking vitamin D

when you already have adequate vitamin D stores prevents cognitive decline.

And this new...

This new observational study, as highlighted by this newspaper report, it also doesn't

establish that ordinary vitamin D supplementation causes cognitive decline.

Yet that is sort of the message that's pervading that article.

So the take-home for me that I think all of us should be thinking about is we need to

correct a deficiency, we should aim for adequacy, and also don't automatically assume that pushing

a nutrient higher and higher creates benefit.

But if you are taking vitamin D, you don't really need to be worried about that.

You don't need to be worried about your cognitive function.

Now, this one really surprised me, the next supplement that they looked at, and that was

omega-3 or fish oil.

So there was a 2026 paper in the Journal of Prevention of Alzheimer's Disease, and they

used the data from the Alzheimer's Disease Neuroimaging Initiative, or ADNI.

And so that's an important context because this wasn't just a random sample of healthy

older people.

ADNI specifically follows people across that cognitive system.

So we're looking at cognitively normal, subjective memory concerns, mild cognitive

impairment, right through to Alzheimer's disease.

And researchers compared 273 omega-3 users with 546 matched non-users, and they followed

them for around or a medium of about five years.

And what they found was that omega-3 use was associated with faster decline across three

cognitive systems.

And these are all indexes or questionnaires looking at cognitive function, MMSE, ADAS,

COG-13, and CDR-SB.

And they found that in the MMSE, or mini mental state examination, that declined by an additional

0.266 points per year amongst omega-3 users.

The ADAS, COG-13, or Alzheimer's Disease Assessment Scale.

That worsened by 0.823 points per year.

And the CDR-SB, or Clinical Dementia Rating Sum of Boxes Scale, that increased by 0.205

points per year faster.

So different to vitamin D, this isn't just some sort of numerical difference.

There is a signal here, and it is worth investigating.

But it is still...

An observational signal.

And I think that's really important to remember.

This is still just observing individuals.

And what they were able to do was use an imaging technology to examine the metabolic activity

of the brain.

And so what they used was something called FDG PET, P-E-T.

And I'm probably going to get this wrong, but I'll give it a go.

Fluorodeoxyglucose positron emission topography.

That was actually easier than I thought.

So fluorodeoxyglucose PET.

And essentially what they do is they inject a radioactive glucose-like tracer.

They see how much glucose that the different brain regions actually take up.

And lower uptake can indicate lower metabolic activity.

And researchers found greater FDG hypometabolism in Alzheimer's vulnerable brain regions among

those omega-3 users.

So that is really interesting.

And they said...

So they thought, looking, using another statistical analysis, that this could explain anywhere

between 19 and 41% of the relationships that we found in those scales that I just walked

you through.

Now, they didn't find any amyloid or tau or gray matter atrophy, which could explain that

association.

And that's worth mentioning because these are conditions which are definitely associated

with that sort of progression to Alzheimer's.

But I guess the thing is...

Even with the FDG PET results, is that this just measures glucose metabolism.

It does not directly measure neuronal death, mitochondrial damage, lipid peroxidation,

DHA oxidation, DHA is a type of an omega-3, and synaptic destruction.

So it is worth noting that as well.

And I guess some of the sort of key criticisms and objections to the study that I've seen

online since it's come...

Since it was published is...

Well, the biggest one is that the omega-3 intake wasn't randomized.

So the matching was principally around factors such as age, sex, APOE4, genetic sort of presence,

and also, of course, diagnosis.

So this wasn't a randomized controlled trial.

Again, it was just an associative trial looking at people that were already in that age,

And so even when you match participants according to different age and sex,

and even diagnosis, you can't account perfectly for things like

why somebody started taking a fish oil, their overall diet health,

their health consciousness, cardiovascular disease, supplement use in general,

any sort of other cognitive concerns, socioeconomic factors, exercise wasn't accounted for,

overall metabolic...

Health and their ability to utilize glucose, and other unmeasured differences.

And when I said that, you know, the study has been sort of challenged by other scientists,

there were letters that were published subsequently raising concerns about exposure classification.

You know, how long had they been taking the fish oil?

Residual confounding from other factors.

The fact that the FDG hypometabolism was interpreted as synaptic dysfunction,

not adequately accounting for omega-3 status, or the formulation of the omega-3,

how much EPA, how much DHA that these omega-3s are contained.

And also, this is super important, the inconsistency with previous evidence

showing that omega-3 was beneficial for the brain.

And then when we compare it to a randomized trial, again vital,

vital actually randomized older adults to receive one gram of marine omega-3,

omega-3 a day, that provided 460 milligrams of EPA, 380 milligrams of DHA.

And that was versus a placebo.

And they had more than 4,200 older adults included in their cognitive analyses.

This was for around two to three years, and they found no significant difference in cognitive

decline.

And interestingly, they found no benefit from taking the omega-3 with cognitive change.

And in fact, vital found that fish oil really didn't change.

It didn't change cognition.

So it did not demonstrate that it improved cognition, but importantly, it does not demonstrate

substantial cognitive harm suggested by that observational ADNI study.

And that is a big distinction.

So if you have, I guess, these two studies sitting together, and you're wondering where

the sort of strength of evidence is, it has to be in that randomized control trial where

they gave them set doses of omega-3s.

Rather than what we see in observational studies.

We know that omega-3 is so helpful for inflammation, cardiovascular disease, improving lipid profiles,

vascular function, endothelial function, blood pressure, so much.

And having dietary omega-3 rich foods, salmon, mackerel, sardines, other fatty fish, super

important.

Or taking a supplement also can be super beneficial.

And I certainly take an omega-3 supplement.

Pillar performance.

Not that it's an ad, but that's what I take.

What I think we know right now is that taking an omega-3 supplement purely because you think

it will prevent dementia, that's just not that strongly supported right now.

But one observational analysis is nowhere near enough to tell someone taking fish oil

that it's damaging their brain.

And one last supplement that they looked at in the article was glucosamine.

And in fact, I am very familiar with glucosamine.

It was sort of all the rage maybe 15 to 20 years ago in relation to joint health and

helping sort of lubricate in and around the joints, knee osteoarthritis, hip osteoarthritis,

along with chondroitin.

Now this one, in this particular study, which appeared in Nature Metabolism 2026, looked

at glucosamine and its role in Alzheimer's disease.

And so this wasn't an observational supplement study, actually.

The reason it wasn't an observational supplement study, actually, is that it was a study that

looked at glucosamine and its role in Alzheimer's disease.

And the researchers, elegantly really, they combined post-mortem human brains, Alzheimer's

mouse models, experimental manipulation of glycosylation, and human electronic health

records to look at all of these different mechanisms and the impact of glucosamine on

that hyperglycosylation process that may drive Alzheimer's disease.

So glycosylation, what even is it?

Glycols attach carbohydrate structures called glycans to proteins and other molecules.

And that's just like normal biology.

Researchers have found that excess glycan production, hyperglycosylation, has been found

in Alzheimer's brains.

And when researchers reduced glycan synthesis in Alzheimer's mice, cognitive performance

improved.

And when they gave glucosamine, cognitive impairment worsened.

So this is looking at that preclinical diagnosis.

This is a preclinical trial in mice showing that glucosamine worsened cognitive impairment.

But what happens in humans?

So researchers then looked at electronic health records.

They had a sample of 24,000 or over 24,000 people with Alzheimer's-related dementias.

And they had 41,000, close to 42,000 people with mild cognitive impairment.

And they followed these people up, or they had records for them for approximately five

years.

And they found that the glycosamine use was associated with approximately 25% greater

progression from mild cognitive impairment to Alzheimer's-related dementia.

And among people who already had Alzheimer's or a related dementia, there was an increased

mortality risk by 25%.

That sounds certainly concerning, right?

But I guess I think the real thing I want you to remember is that you don't want to

extrapolate it to everybody taking glucosamine.

The human component is still the real thing.

So that's the first thing.

The second thing I want you to remember is that you don't want to extrapolate it to

the retrospective observational data.

So it does not prove glucosamine caused dementia progression.

And critically, the signal was particularly relevant to people who may already have existing

mild cognitive impairment or established neurodegenerative disease.

So if you are one of these healthy 50-year-old people who's taking glucosamine for your

knee, there's no evidence to suggest that glucosamine is increasing your risk of Alzheimer's

disease.

So to sort of tie all this together, what was that herald?

Well, what was that herald article really telling us?

We've got three studies, but they're not showing the same thing.

With the vitamin D, we saw observational association with a very small excess decline that was

found, but there is good randomized controlled evidence that it does not demonstrate harm.

And then with omega-3, there was this interesting observational signal of a faster cognitive

decline and that hypometabolism of glucose in the brain, but that directly conflicts

with a randomized control.

And with glucosamine, this was probably the most interesting signal because there is experimental

biology supporting it, plus observational human evidence, but there is still insufficient

evidence to conclude that glucosamine causes dementia in humans.

And really, I mean, supplements are biologically active.

And this is much broader than just these three supplements, this just means that even though

they're not inert and more isn't always better.

And I guess it's also important to again, state that one observational study showing

harm doesn't suddenly turn an established supplement into a toxin.

You always want to ask who was studied, were they deficient in that particular nutrient?

How old were they?

Did they already have cognitive impairment in this case?

What dose was used?

Was supplementation actually measured properly?

Was the exposure of the supplement actually measured properly?

Was the exposure of the supplement actually measured properly?

Was the exposure randomized?

How long were they exposed?

How big was the effect?

Does the finding here agree with the randomized control trials, which really are gold standard

when we're thinking about these one supplement studies?

Is there a plausible mechanism with which this could even be an issue?

And has the study been replicated?

And that is how you interpret the study rather than the headline that the Herald is giving

you.

So vitamin D, you do want to supplement to correct or prevent deficiency where appropriate.

And it is appropriate here in New Zealand, particularly during winter.

There is not convincing evidence that higher vitamin D protects cognition once you're replete,

but neither is there persuasive evidence from these data that usual supplementation damages

the brain.

And with omega-3, fish and seafood remain excellent foods.

Obviously.

Omega-3 supplementation hasn't convincingly prevented cognitive decline in randomized

controlled trials, but current evidence also doesn't justify telling people that fish or

vegetable oil is neurotoxic.

And for what it's worth, it is one of my go-to supplements for a range of different reasons.

And glucosamine, this is particularly interesting.

If you are an individual with mild cognitive impairment or established dementia, you do

want to watch this one.

And I think what we have to wait for is replication of study findings.

And ideally you'd have some intervention data here as well.

So there's mini Mikkipedia for you.

If you saw that article last week and were a little bit panicked by what it told you,

hopefully this just alleviates some of your fears.

And if you didn't see it, I've got the link in the show notes for you as well.

Yeah.

Keen to hear your thoughts.

Hit me up on Instagram threads or X at Mikki Williden Facebook at Mikki Williden nutrition

or head to my website, Mikki Williden.com.

I've got this recipe portal with over a thousand recipes.

It's 12 bucks a month.

I'm constantly adding to it and they are macro friendly.

They are carb appropriate.

They are higher protein.

They are higher fat.

Some of them in the early days, there's something for everyone there.

If you want some quick, easy, tasty meals to add to your repertoire.

All right, guys, you have the best week.

See you later.