Oh dear: Dairy?

# # # # Dairy-based products make up a significant portion of the world’s diet and represent a fundamental component of most western cuisine. Previous research has, however, pointed towards an association between consumption of dairy and risk of Parkinson’s. New research provides further support for this connection. In today’s post, we will look at the mysterious bond between dairy intake and Parkinson’s. # # # #

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Me and Brie. Source: Wikipedia

When I turned 25, I realised that my body no longer accepted cheese.

This represented a very serious problem for me.

You see, I still really loved cheese. A bottle of red wine, a baguette and a chunk of brie – is there any better combination in life?

Heaven. Source: Healthylivingpc

My body and I had a really bad falling out about this. And yes, it got ugly. I wanted things to keep going the way they had always been, so I tried to spice things up by introducing new and exotic kinds of cheeses, which my body didn’t want to know about it. It rejected all of my efforts. And after a while, I gradually started resenting my body for not letting me be who I was.

We sought help. We tried some interventions. But sadly, nothing worked.

And then things got really bad: My body decided that it didn’t have room in my life for yogurt, milk or even ice cream anymore (not even ice cream!!!).

Basically no dairy what so ever.

There’s something’s missing in my life. Source: Morellisices

OMG! How did you survive without ice cream?

Well, I’ll tell ye – it’s been rough.

All silliness aside though, here is what I know: It is actually very common to develop a lactase deficiency as we age – lactase being the enzyme responsible for the digestion of whole milk. In fact, about 65% of the global population has a reduced ability to digest lactose after infancy (Source: NIH – more on this in a moment).

I am not lactose intolerant (one of the few tests that I actually aced in my life), but I do have trouble digesting a particular component of dairy products – which can result in discomfort… and let’s just say socially embarrassing situations (one day over a drink I’ll tell you the ‘summer afternoon cheese fondue story’).

If one is forced to drop a particular food group, dairy is not too bad (but if I am ever forced to give up wine, I swear I’ll go postal).

And some new Parkinson’s-related research has indicated that more of us should possibly be avoiding dairy.

What is the new research?

Earlier this year, this report was published:

Title: Dairy Intake and Parkinson’s Disease: A Mendelian Randomization Study.
Authors: Domenighetti C, Sugier PE, Ashok Kumar Sreelatha A, Schulte C, Grover S, Mohamed O, Portugal B, May P, Bobbili DR, Radivojkov-Blagojevic M, Lichtner P, Singleton AB, Hernandez DG, Edsall C, Mellick GD, Zimprich A, Pirker W, Rogaeva E, Lang AE, Koks S, Taba P, Lesage S, Brice A, Corvol JC, Chartier-Harlin MC, Mutez E, Brockmann K, Deutschländer AB, Hadjigeorgiou GM, Dardiotis E, Stefanis L, Simitsi AM, Valente EM, Petrucci S, Duga S, Straniero L, Zecchinelli A, Pezzoli G, Brighina L, Ferrarese C, Annesi G, Quattrone A, Gagliardi M, Matsuo H, Kawamura Y, Hattori N, Nishioka K, Chung SJ, Kim YJ, Kolber P, van de Warrenburg BPC, Bloem BR, Aasly J, Toft M, Pihlstrøm L, Correia Guedes L, Ferreira JJ, Bardien S, Carr J, Tolosa E, Ezquerra M, Pastor P, Diez-Fairen M, Wirdefeldt K, Pedersen NL, Ran C, Belin AC, Puschmann A, Hellberg C, Clarke CE, Morrison KE, Tan M, Krainc D, Burbulla LF, Farrer MJ, Krüger R, Gasser T, Sharma M, Elbaz A; Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (Courage-PD) Consortium.
Journal: Mov Disord. 2022 Apr;37(4):857-864.
PMID: 34997937

In this study, the researchers conducted Mendelian randomisation study to look at the association between genetically predicted dairy intake and Parkinson’s.

Ooooookay… and what does any of that mean?

Let’s start with the ‘genetically predicted dairy intake’ part.

Genetically predicted dairy intake refers to our ability to metabolise dairy products. The breaking down of dairy requires an enzyme that is produced in our guts called lactase. It is essential for the complete digestion of dairy products. Lactase breaks down lactose, which is the sugar that gives milk its sweetness.

Source: Annualreviews

The lactase (LCT) gene provides the instructions for making lactase. There is a genetic variation called rs4988235, that lies in the DNA near the LCT gene and it is related to lactase persistence among Europeans.

Lactase persistence – or the ability of adult humans to continue digesting the lactose in milk beyond infancy – varies widely in frequency across human populations. It is a curious trait that represents an adaptation to our domestication of dairy-producing animals and the subsequent consumption of their milk.

The evolution of lactase persistence in Europe. Source: Mathii.github

Typically, the production of lactase starts declining after infancy and is very low in all adult mammals – with the notable exception of humans. In approximately 1/3 of humans, the production of lactase is maintained throughout life – this is the phenotype (observable trait) that we know of as lactase persistence and it can be used as a measure of genetically predicted dairy intake.

Ok. And what is a Mendelian randomisation study?

A Mendelian randomisation study uses the genetic variation in humans as a natural experiment to investigate the causal relations between potentially modifiable risk factors and health outcomes in observational data.

Ooooookay…. and what does any of that mean?

Mendelian randomisation studies are analytical methods that researchers employ to explore modifiable risk factors that affect population health. They use genetic variants – tiny errors in our DNA which all of us carry – as variables for those modifiable risk factors, and they explore how they may affect our health.

Previously, when researchers wanted to find any associations between one factor and a particular outcome to determine modifiable risk factors of health, they would conduct large observational studies. These often involved looking at enormous nationwide medical databases to determine if there was an association between an activity like smoking and a subsequent increased/decreased risk of developing a medical condition, such as cancer.

Source: Biofortis

Where associations were found the findings have been instrumental in determining public health measures.

But one of the major limitation of evidence from observational studies has been unmeasured confounding factors.

What are unmeasured confounding factors?

They are additional variables in a study examining a potential cause-and-effect relationship. An example of unmeasured confounding factors could be other aspects of life affected individuals partake in. The observational studies would always take into account easily measured factors like age or sex, but they would often miss (or struggle to evaluate) variables like ‘patterns of risky behaviour’.

This always left questions regarding the results of the observational studies. What unmeasured confounding variables could also explain an observed association? For example, perhaps the association between smoking and cancer can be explained by other behaviours/traits that people who smoke may share?

Everything comes back to ice cream. Source: Scribbr

This is where Mendelian randomisation tries to reduce the influence of confounding factors. A typical Mendelian randomisation study requires analysis of DNA to determine each individuals “genotype” – their genetic makeup and awareness of the various genetic variations that they carry. It then compares a risk factor with that genotype in relation to a particular outcome.

Can you give me an example?

Yes. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in the metabolism of alcohol (it degrades acetaldehyde to nontoxic acetic acid). The instructions for enzyme is coded in a region of our DNA called the ALDH2 gene.

Individuals with genetic variations in the ALDH2 gene can experience adverse symptoms when drinking alcohol and as a consequence they drink considerably less alcohol than people without these genetic variations. Researchers have used these genetic variants in the ALDH2 gene to determine the risk of hypertension in population of people by affecting alcohol drinking behaviour (those who drink less will have reduced levels of hypertension). The results of those studies “support the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension” (Source).

This video explains the basic idea behind Mendelian randomisation studies:

 

# RECAP #1:  Lactase persistence is the ability of adult humans to continue digesting the lactose in dairy products beyond infancy. It is present in approximately 1/3 of humans. Researchers can use Mendelian randomisation studies to better understand how genetic variations associated with traits like lactase persistence may be influencing other factors, like Parkinson’s. #

So what does lactase persistence or Mendelian randomisation studies have to do with Parkinson’s? Has a connection between dairy intake and Parkinson’s ever previously been reported?

Yes.

I have previously written about the enormous contribution that the ‘Honolulu Heart Study’ has made to our understanding of Parkinson’s. This longitudinal study of 8006 “non-institutionalized men of Japanese ancestry, born 1900-1919, resident on the island of Oahu” began in October 1965 and it has provided some with amazing insight to this condition by allowing us to go back and look at what variables were apparent before people were diagnosed with Parkinson’s (Click here to read that old post).

128 of the 8006 individuals enrolled in the study went on to develop Parkinson’s, and when the researchers went back and looked at the detail of their lives, they noticed something interesting about dairy intake – in particular: milk.

Title: Consumption of milk and calcium in midlife and the future risk of Parkinson disease
Authors: Park M, Ross GW, Petrovitch H, White LR, Masaki KH, Nelson JS, Tanner CM, Curb JD, Blanchette PL, Abbott RD.
Journal: Neurology. 2005 Mar 22;64(6):1047-51.
PMID: 15781824

The researcher found that the incidence of Parkinson’s increased with milk intake. In fact, it jumped from 6.9/10,000 person-years in men who consumed no milk to 14.9/10,000 person-years in men who consumed >16 oz/day (approx. 1/2 a litre; p = 0.017). This result suggested that drinking a large cup of milk per day doubled your chances of developing Parkinson’s. The researchers noted that this effect was independent of calcium intake. Calcium (from both dairy and nondairy sources) inferred no increase/decrease in the risk of developing Parkinson’s.

The effect was specific to milk.

Has anyone replicated this finding?

Unfortunately, yes. Two independent groups have found similar results:

Title: Consumption of dairy products and risk of Parkinson’s disease.
Authors: Chen H, O’Reilly E, McCullough ML, Rodriguez C, Schwarzschild MA, Calle EE, Thun MJ, Ascherio A.
Journal: Am J Epidemiol. 2007 May 1;165(9):998-1006.
PMID: 17272289               (This article is OPEN ACCESS if you would like to read it)

These researchers looked at the subjects (57,689 men and 73,175 women) enrolled in the American Cancer Society’s Cancer Prevention Study II Nutrition Cohort, and found a total of 250 men and 138 women with Parkinson’s. Dairy product consumption was positively associated with risk of Parkinson’s, 1.8 times that of normal in men and 1.3 times in women. When the dairy products were divided into milk, cheese, yogurt and ice cream, only milk remained significantly associated with an increased risk of developing Parkinson’s. 

That was the first independent study, and this was the second:

Title: Dietary and lifestyle variables in relation to incidence of Parkinson’s disease in Greece.
Authors: Kyrozis A, Ghika A, Stathopoulos P, Vassilopoulos D, Trichopoulos D, Trichopoulou A.
Journal: Eur J Epidemiol. 2013 Jan;28(1):67-77.
PMID: 23377703

In this third study, the researchers conducted a population-based prospective cohort study involving 26,173 participants in the EPIC-Greece cohort. After analysing their data the investigators also found a strong positive association between the consumption of milk and Parkinson’s. And like the previous study, there was no association with cheese or yoghurt. The effect was again specific to milk.

So what is there something in particular in milk causing this effect?

That is the assumption, but we are not clear on what it is exactly. There is some evidence, however, hinting that certain contaminants.

For example in 2016, this study was published:

Title: Midlife milk consumption and substantia nigra neuron density at death
Authors: Abbott RD, Ross GW, Petrovitch H, Masaki KH, Launer LJ, Nelson JS, White LR, Tanner CM.
Journal: Neurology. 2016 Feb 9;86(6):512-9.
PMID: 26658906

In this study, the researchers looked at the milk intake data for 449 men in the Honolulu Heart Study (which were collected from 1965 to 1968), and then conducted postmortem examinations of their brains (between 1992 to 2004). The researchers found that subjects who drank more than 2 cups of milk per day during their midlife years had approximately 40% fewer dopamine neurons (in certain areas of a region called the substantia nigra where the dopamine neurons live).

But here is the interesting twist in the story:

None of these 449 subjects were diagnosed with Parkinson’s.

These were all neurologically normal/healthy individuals.

Plus this particular effect was only observed among the milk drinking, non-smokers. The milk drinking smokers did not have this cell loss (smoking is associated with a reduced risk of developing Parkinson’s – click here for more on this).

The researchers then took the study a step further. They noticed that the cell loss effect was also associated with the presence of heptachlor epoxide in the brain.

What is heptac..whatever?

Heptachlor is an organochlorine compound that was used as an insecticide. Pesticides and insecticides have long been associated with increased risk of Parkinson’s (Click here to read that post). Heptachlor epoxide is created when heptachlor mixes with oxygen.

In this study, of the 116 brains analysed, heptachlor epoxide was found in 90% of the non-smokers who drank the most milk, but only 63% of those subjects who drank no milk. This lead the researchers to speculate as to whether contamination of milk by heptachlor epoxide could have caused the cell loss. We should point out here that this particular part of the analysis was rather speculative. The sample size for the non-smoking, high milk consumption group was very small: only 12 individuals.

More recently, however, the association has been found to be more modest and unclear than initially thought:

Title: Intake of dairy foods and risk of Parkinson disease.
Authors: Hughes KC, Gao X, Kim IY, Wang M, Weisskopf MG, Schwarzschild MA, Ascherio A.
Journal: Neurology. 2017 Jul 4;89(1):46-52.
PMID: 28596209                  (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers used data from two large prospective cohort studies (the Nurses’ Health Study, which involves 80,736 participants, and the Health Professionals Follow-up Study, involving 48,610 people). These two studies have a total of 26 and 24 years of follow-up, respectively.

The results indicate that total dairy intake was not significantly associated with a higher risk of Parkinson’s in these cohorts, but curiously intake of low-fat dairy foods was. And this effect appears to have been driven by skim and low-fat milk. The association in this study was the same for men and women.

Another recent study of 81,915 Swedish adults reported a weak association between milk intake and increased risk of Parkinson’s:

Title: Milk and Fermented Milk Intake and Parkinson’s Disease: Cohort Study.
Authors: Olsson E, Byberg L, Höijer J, Kilander L, Larsson SC.
Journal: Nutrients. 2020 Sep 10;12(9):2763.
PMID: 32927800                    (This report is OPEN ACCESS if you would like to read it)

In this study, the results did not support any dose-response relationship, but milk intake was associated with increased risk of Parkinson’s. Interestingly, fermented milk was not associated with any increased risk.

These slightly mixed results led to researchers considering the potential problem of the unmeasured confounding factors we discussed above.

And that resulted in some of them conducting a Mendelian randomization study.

# # RECAP #2:  Milk intake has been associated with a modest increase in risk of developing Parkinson’s. While this pattern has been consistent, some of the details of results (such as gender differences) have varied somewhat between studies making it difficult to determine the nature of the mechanisms behind this association. # #

So what did they find with the Mendelian randomization study?

So, this is the report that I initially mentioned above:

Title: Dairy Intake and Parkinson’s Disease: A Mendelian Randomization Study.
Authors: Domenighetti C, Sugier PE, Ashok Kumar Sreelatha A, Schulte C, Grover S, Mohamed O, Portugal B, May P, Bobbili DR, Radivojkov-Blagojevic M, Lichtner P, Singleton AB, Hernandez DG, Edsall C, Mellick GD, Zimprich A, Pirker W, Rogaeva E, Lang AE, Koks S, Taba P, Lesage S, Brice A, Corvol JC, Chartier-Harlin MC, Mutez E, Brockmann K, Deutschländer AB, Hadjigeorgiou GM, Dardiotis E, Stefanis L, Simitsi AM, Valente EM, Petrucci S, Duga S, Straniero L, Zecchinelli A, Pezzoli G, Brighina L, Ferrarese C, Annesi G, Quattrone A, Gagliardi M, Matsuo H, Kawamura Y, Hattori N, Nishioka K, Chung SJ, Kim YJ, Kolber P, van de Warrenburg BPC, Bloem BR, Aasly J, Toft M, Pihlstrøm L, Correia Guedes L, Ferreira JJ, Bardien S, Carr J, Tolosa E, Ezquerra M, Pastor P, Diez-Fairen M, Wirdefeldt K, Pedersen NL, Ran C, Belin AC, Puschmann A, Hellberg C, Clarke CE, Morrison KE, Tan M, Krainc D, Burbulla LF, Farrer MJ, Krüger R, Gasser T, Sharma M, Elbaz A; Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (Courage-PD) Consortium.
Journal: Mov Disord. 2022 Apr;37(4):857-864.
PMID: 34997937

In this study, the researchers used genetic data collected from the “COmprehensive Unbiased Risk factor Assessment for Genetics and Environment in Parkinson‘s Disease” (or Courage-PD) project. This was a collective of 23 studies, involving 9823 individuals with Parkinson’s and 8376 unaffected controls – all of European ancestry. Genetic variations located in the lactase gene (rs4988235) were analysed.

The investigators found that there was an association between the “genetic predisposition toward higher dairy intake and PD (odds ratio per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013)“. This means that those individuals who carried the genetic variant that results in the ability to consume milk products into adulthood (and who continued to intake dairy products) had higher odds of developing Parkinson’s.

Interestingly, the effect was stronger in men (odds ratio per one serving per day = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029) in their data set. But when they repeated their analysis in a second dataset (the IPDGC pool) the association was present in both men and women.

Has anyone else ever conducted a Mendelian randomization study on milk and PD?

Actually, yes.

This report was published last year:

Title: Genetically Predicted Milk Intake and Risk of Neurodegenerative Diseases.
Authors: Zhang Z, Wang M, Yuan S, Larsson SC, Liu X.
Journal: Nutrients. 2021 Aug 23;13(8):2893.
PMID: 34445060                (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers did not limit their analysis to just Parkinson’s – they also looked for any association between genetic predisposition toward higher dairy intake and multiple sclerosis, Alzheimer’s, & amyotrophic lateral sclerosis (ALS).

Source: PMC

Again, the lactase persistence genetic variant rs4988235 (LCT-13910 C > T) was used as the instrumental variable for milk intake, and the investigators found that genetically predicted milk intake was associated with a decreased risk of multiple sclerosis and Alzheimer’s, but with an increased risk of Parkinson’s – supporting the findings of the previous studies. No association was found for ALS.

What about for people with Parkinson’s – those already diagnosed? Is there any evidence that milk or dairy could have a negative impact on progression?

The only data that I am aware of (and I am happy to be corrected on this) dealing with this question comes from the work of Dr Laurie Mischley and colleagues at Bastyr University.

A couple of years ago, they published this report:

Title:Use of a self-rating scale of the nature and severity of symptoms in Parkinson’s Disease (PRO-PD): Correlation with quality of life and existing scales of disease severity.
Authors: Mischley LK, Lau RC, Weiss NS.
Journal: NPJ Parkinsons Dis. 2017 Jun 16;3:20.
PMID: 28649620                    (This article is OPEN ACCESS if you would like to read it)

In this comparative study, the investigators asked 58 people with Parkinson’s (who were involved in ongoing clinical trials), to fill in a questionnaire (the PRO-PD survey) about various aspects of their lives (everything from severity of their condition to dietary supplements to how far one lives from a highway). It was very thorough.

The researchers next compared the self-assessed results of that survey with the results determined in the clinical setting by clinicians. They found that the self assessed survey was highly correlated not only with patient-reported quality of life measures (such as the Parkinson’s Disease Questionaire-39), but also with clinician assessed measures (such as Hoehn & Yahr and Unified Parkinson’s disease Rating Scale (UPDRS)).

When looking at all the data, Dr Mischley and team turned their attention to the types of foods that were associated with a worsening of Parkinson’s symptoms, and they found that:

• fresh vegetables
• fresh fruit
• nuts and seeds
• fish
• olive oil
• wine
• coconut oil
• fresh herbs
• the use of spices

were all associated with significantly lower rates of disease progression (meaning a slower progression of the condition), while

• Canned fruit
• Diet soda (carbonated drinks)
• Canned vegetables
• Fried food
• Beef
• Soda (carbonated drinks)

were all associated with significantly increased rates of disease progression (that is, the condition was getting worse as a result of consuming these foods).

In addition, ice cream, yogurt and cheese were also associated with increased rates of disease progression (although this was not significant). To see the full list of foods, please click here.

This is the only data that I am aware of regarding dairy intake and progression of PD symptoms.

So what does it all mean?

I don’t miss milk. In fact, I find the smell of it off putting.

But mint chocolate chip ice cream was always my favourite.

And I do miss cheese! To make matters worse: I am married to a Frenchy!!! Every night after dinner, she likes a little cheese-on-biscuits action, and I sit there helplessly watching (it’s like Chinese water torture). I have cautioned her about the risks of high dairy intake, but she just gives me one of her naughty devilish smiles and continues enjoying her little slices of heaven.

The association between Parkinson’s and dairy intake does not appear to be a very strong. There is a clear pattern, but there are obviously other factors involved. And the Mendelian randomization study demonstrating reduced risk of multiple sclerosis and Alzheimer’s complicates the situation.

I guess it’s the old story of having a balanced diet and everything in moderation.

But heck, you only live once – with all this talk of ice cream I might just go and find some ice cream, and the socially embarrassing consequences be damned!

 

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