A natural experiment on the effect of herpes zoster vaccination on dementia, 2025, Eyting et al

[bobbler]

I agree it is a complicated time period for that break to be over. Free school meals came in around 1944 apparently and rationing only ended fully in 1954. So 1933 birthed would have been 11 when that came in.

Plus there is the contraceptive pill right around the same generation. 1961 for married women and then 1967. Which means those born in 1933 married and 28yrs old aren't looking at potentially having so many kids. Apparently the ave age for women to marry then was 20-24yrs old then

There is also the roll-out of HRT which apparently was in the 1990s, with peak prescribing 50-54yrs old. so would coincide too


The other issues come from things that vice versa increased men's lifespan where they might have died from something else before getting dementia. Which would mean pre- and post- isn't really comparing the same population (a bit like the drop-outs issue). Coronary heart disease has dropped by something like 70% in welsh men over the decades.

Fewer people in Wales dying from heart disease – new report | GOV.WALES

Fewer people are dying prematurely from coronary heart disease in Wales, with a 68% reduction in the death rate over the last 20 years.

www.gov.wales

intriguingly, given the cut-off was Sept 1 1933, the school leaving age was changed from 14yrs to 15yrs in 1947 - so those with a day's difference would have potentially left school at 14yrs old vs 15yrs old.

 

[bobbler]

Note that the regression they did weighed birthweeks closer to the cutoff point more heavily. That's the grey shading of the dots in the figures above. It looks like past about [edit: two years] on either side, there was very little weight given to the data points. They did this because the further apart people are in time of birth in the two groups, the more confounders you'd expect that could skew the analysis.


The main thing of interest is how suddenly the probability of dementia drops for people born directly after the cutoff. I'd expect it to be more gradual if it was due to something like the Great Depression, which didn't have a hard cutoff.

If there was confounding, which I think is possible, I think it'd be related to education. Starting school a year later is the only relevant event I know of, apart from vaccination, that was a major difference in life events between people born directly on either side of that birthdate cutoff.

Someone's comment on Pubpeer noted a potential interesting detail about the groups being in different school years:


Another thing that ChatGPT suggested to me when I was trying to get it to suggest confounders is related to school year and World War II.

It said that schooling begins at age 5 in Wales, which seems right. So children born in the weeks before September 1933 would have been 5 before September 1, 1938 and would have entered school that year. Children born in the weeks after, would have entered school a year later, at the end of 1939. Notably, World War II started September 1, 1939.

Is there a reason children first starting school immediately at the start of WWII would end up better protected from dementia than children who had already completed a year of school? I'm not sure what the connection would be.

the thing is, and I'm no expert at all, just getting a sense from what those around me have inferred, in the UK the whole 'generation thing' becomes relevant because it's often not just one policy/policies at certain ages or years but things actually following cohorts through those periods in time. A bit like it possibly being the case of hitting or missing the entire run of green traffic lights I think.

And - this is really where I'm ad-libbing a bit - there still is a divide, but back then there was quite a difference between when developments followed through from the most propserous areas and those in different parts of the UK.

Post WW2 was sort of a fast push that somewhat started evening things up a bit, but even if you talk to people who are the children of that generation they might say there were big differences between the conditions and attitudes and so on of people in eg a northern town and one in the south-east.

I don't know the possibility of that coming together in such a way it could contribute to something looking like a cliff-edge, because things like the NHS (1948), national insurance (1946)/old age pension (1948) and council housing/house building and slum clearance and other welfare policies coming in but also the impact on attitudes and policies about women being allowed to access work before and after marriage often simply due to need/these being available but also the war having meant women had previously back-filled jobs whilst men were conscripted.

SO I'm not saying this isn't down to the vaccine, just that probably looking really carefully at those smaller amount of years near the cut-off and more close to matched pairs type things might be interesting to separate out the general from the 'bundle of factors', because regression lines showing trajectory angles around a period where high numbers of developments were impacting well I don't know how much room there is for averages over those years one side or the other to 'tilt' them to cause what looks like a clean shift of '+x'

It would be interesting looking at the other countries that have similar vaccine roll-outs as/if they come out because if theirs coincide as precisely, but they likely might have slightly different coalescence of developments over time periods (or countries where there are vastly different eg north-south timings in these changes), then hopefully that helps to tease things out

 

[bobbler]

I think a big problem with these studies is that someone who gets a Shingles or RSV vaccine is not, on average, like a person who does not.

Either, the person who is vaccinated is well enough organised, capable of deciding to do something to maintain their health, making the appointment and getting themselves there. They probably regularly visit the doctor for their other health needs. In which case, they are still thinking well and are regularly seen by a doctor, and so are, at worst, some years off getting diagnosed with dementia.

And/or, the person who is vaccinated lives in a situation where someone is looking after their health needs and getting vaccinations done, and so they are also being closely monitored for signs of dementia. So again, if they had dementia, they would probably have already been diagnosed with it. I imagine in a retirement home, there is more funding for a resident with dementia, so it would be in the retirement home's interests to get the diagnosis fairly quickly.

Contrast that with someone who doesn't get the vaccine. Someone in the first stages of dementia and living on their own will be struggling to hold everything together, and probably won't be thinking about discretionary activities such as getting a vaccine. If the unvaccinated person is living with a spouse or a child who isn't able to arrange for the vaccine or doesn't believe in vaccines, then they probably aren't getting to the doctor often either, and may not be being closely monitored for signs of dementia.


If a person who is vaccinated has any signs of dementia, they probably will have already been diagnosed with it already. So, for them, the chance of being diagnosed in those next 18 months is only the chance of a new onset that moves very swiftly.

Whereas, a person who is not vaccinated may already have quite significant signs of dementia but be undiagnosed. So, for them, the chance of being diagnosed in those next 18 months is the chance of an onset in quite a lot of years prior as well as the next 18 months.

That last bit of those already diagnosed with dementia by the time they get said vaccine is another thing to note and check - simply because if I've read right this is 2013 when the vaccine was introduced and 1933 birth date would be 80yrs old and I'm just going from school and myth but the biggest risk for it is age

I'm intrigued to note that looking for a definitive stat there doesn't seem to be complete agreement even though the charities are banding around eg 1 in 6 by 80yrs old and then that might increase to 1 in 3 by 85yrs depending on which source is being looked at.

It would be particularly interesting to better understand these figures and which are the best available for what dates because I'm assuming the vaccine will now be continuing on with good uptake (is it still being given at the same age? etc) and something like this underlines what we already know about how important good prior categorisation and data can be for potentially picking up on things that make a difference and then (hopefully if this is correct) optimising when it is best given for maximum impact etc. if so

I was about to copy out the para that @forestglip has above as it sounds pretty convincing that the group did their homework on checking there wasn't something obvious by changing the data around and so on, so they've done what they can but then in the discussion note:

Our quasi-experimental approach reduces the probability of confounding compared with more standard associational analyses. Moreover, we have provided evidence from a series of analyses against any of the possible remaining sources of bias being a likely explanation of our findings.

Nonetheless, it is possible (even if statistically unlikely) that our findings are due to chance. Confirmation of our findings in other populations, settings and data sources is therefore critical.

Importantly, we have successfully confirmed our findings using country-wide death certificate data from England and Wales10. Specifically, because England rolled out the zoster vaccine in an almost identical way to Wales44, we were able to use the same quasi-experimental approach as in our electronic health record data from Wales to determine the effect of eligibility for zoster vaccination based on one’s date of birth on deaths for which the underlying cause was recorded as being dementia.

We found that, over a nine-year follow-up period, approximately 1 in 20 such deaths were averted from being eligible for zoster vaccination. This study constitutes an important confirmation of our results because it analysed a different population (England’s population accounts for approximately 95% of England’s and Wales’s combined population45), type of data (death certificates as opposed to electronic health records) and outcome (deaths due to dementia).

reference 10: https://www.medrxiv.org/content/10.1101/2023.09.08.23295225v1 which I guess might be already on this thread - it's Michealik et al (2023)

reference 44: https://www.gov.uk/government/publi...-quarter-1-of-the-financial-year-2022-to-2023

reference 45: https://www.ons.gov.uk/peoplepopula...imatesenglandandwales/census2021unroundeddata


Do we have other countries who might have any similar data?

 

[bobbler]

The change in risk in females looks quite compelling. It's interesting that there was no change in risk in males.

Scrabbling for an alternative explanation, there is the fact that the people on the 'no vaccination' side were born and may have had their earliest years more affected by the Great Depression and the industrial decline in Wales before it. (The study is on data from Wales. The study looked at people born up to 3 years either side of the Sep 2033 date.



It seems likely that many of the babies in those early 1930s had a tough start to life. I suppose it's conceivable that the girl babies might have been a bit more deprived than the boy babies?

AI says:




I think things were still tough in Wales after 1933. But, perhaps the earlier years were more dislocating and people adapted over time. Scarlet fever most affects children aged 2 to 10 years old, so maybe that scarlet fever epidemic in Wales in 1933 affected the people born before Sep 1933 and that set people up for earlier dementia? Maybe the decline in industries in Wales actually reduced levels of environmental pollution over time, maybe having less coal dust in the home environment or not having a father exposed to the toxins and lack of sun of coal mining was a pre-natal advantage?

I don't think my alternative theories are rock solid, far from it. But, I think there are enough questions there that this study isn't the last word on the idea of the shingles vaccine being protective against dementia. (I haven't looked at the other papers.)

I wonder how the researchers chose that 'three years before - three years after' time frame. Perhaps it was a nice coincidence that the timing gave the most compelling result?

OK this is interesting

. First, we cannot exclude the possibility of substantial reductions in new dementia diagnoses from zoster vaccination among men, especially given the lower incidence of dementia in older age among men than women in our data and, therefore, our wider confidence intervals for analyses among men.

I haven't got far in looking this up and aware that the overall term dementia includes ALzheimers, vascular dementia and other types. But the gist I'm getting from googling seems to suggest the lifetime incidence is much higher for women, but when you look at chances of having it by age then that's not the same

I'm just going by one paper so far: https://pmc.ncbi.nlm.nih.gov/articles/PMC5286729/ which is from 2016 and not picked out for any reason other than finding it first, so highly aware this is a point in time thing as thinking might have changed a lot on any of the subsets mentioned in it

Depending on the subtype of dementia, the ratio of male to female prevalence differs. For example, females are at greater risk of developing Alzheimer disease dementia, whereas males are at greater risk of developing vascular dementia.

Alzheimer disease (AD) is the most common form of dementia, comprising up to 80% of cases; however, not all studies distinguish AD from all-cause dementia.

The estimated prevalence of all-cause dementia varies from 4.7% in Central Europe to 8.7% in North Africa/Middle East, with North America falling between at 6.4%.

That's missing out quite a bit of the world there.

Several epidemiologic studies show that neurodegeneration and clinical symptoms occur more rapidly for females once a diagnosis is suspected. 36, 38-40 Researchers have hypothesized that this is due to longer female life expectancy or sociocultural detection bias 34; however, there is support that faster progression is due to neurobiological vulnerability in postmenopausal females.1, 36

Though progression of the disease may be more rapid among elderly women, studies conducted in the United States and United Kingdom suggest that males with AD have a shorter survival time.41, 42

Women are often diagnosed earlier in the course of illness than men, which could confound determination of postdiagnosis longevity. However, data from a recent systematic review focusing on mortality in AD and all-cause dementia support findings of a shorter life span among males, regardless of age at diagnosis.43

The below para in full is interesting but I was wary of copying too much hence the chopping the middle out to just leave snippets.

The importance of considering SABV and gender with other risk factors for dementia such as apolipoprotein E (APOE) genotype, alcohol use, and depression, has become increasingly apparent. The APOE gene encodes a protein that transports cholesterol in the bloodstream.

Carriers of the ε4 variant are predisposed to high cholesterol and AD. When examined at autopsy, a greater portion of individuals diagnosed with AD were found to have one or two copies of the APOE ε4 allele.2 Female allele carriers were twice as likely as noncarriers to have dementia, and allele status predicted progression from MCI to AD in both sexes.45 ...

.... Finally, several sex and APOE genotype interactions have been described for effectiveness of treatments used to slow progression of cognitive decline in AD. Treatment with intranasal insulin showed a positive impact on cognition in male APOE ε4 carriers versus noncarriers, whereas their female APOE ε4-negative female counterparts experienced worsening cognition during insulin treatment.48

 

[Mij]

I think I posted a study here that suggests the vaccines can also reverse dementia for some.

 

[Mij]

The Munro Report: June 23, 2026

Alasdair Munro:
"Cutting through the noise on child health, vaccines, and medical evidence. By a working NHS paediatrician and researcher."

The truth about the shingles vaccine and dementia

Ground breaking intervention or senseless hype?

Summary
"The initial hype over an enormous risk reduction in dementia from receiving the shingles vaccine has not held up in the largest independent replication study to date. The hypothesis is not dead (although it is on life support), but it’s hard to see how a trial is currently the answer. The lesson is not that the vaccine is useless, nor that natural experiments are bad, but that an unbelievable result deserves the same hard scrutiny whether or not it tells us what we hoped to hear. Science Communicators must give due effort to appraising the research that they cite, not simply repeating the headlines. At present it is not good enough.

So the truth: does the shingles vaccine prevent dementia? Probably not - although I would love it to be proven so".

 

[forestglip]

The Munro Report: June 23, 2026

Alasdair Munro:
"Cutting through the noise on child health, vaccines, and medical evidence. By a working NHS paediatrician and researcher."

The truth about the shingles vaccine and dementia

Ground breaking intervention or senseless hype?

Snippets

As Vinay Prasad has noted, where survival curves have been presented (showing differences in how many cases occur over time) the effect seems to occur implausibly early following vaccination.

Speaking to the differences in these findings, a point made in the lecture was that the type of method deployed to these study (regression discontinuity design, for those who are interested), enables the researcher a huge degree of freedom in making analytical decisions.

My friend, the venerable George Davey Smith and colleagues did the next obvious thing and ran the identical design in a far larger population, which was presented at a guest lecture on June 17th. England used the same vaccine, the same date, the same cut-off, so an almost identical natural experiment exists, across 6.3 million people (roughly twenty times the Welsh sample).

As one would expect from this group, the study is persuasive. First they confirmed that eligibility produced a clear drop in recorded shingles. This is proof the design works (and the vaccine, which is excellent, does its actual job). Then they looked at dementia, and found….nothing.