Can Alcohol Use or Abuse Cause or Aggravate Alzheimer's Disease?

While the MIND diet promotes moderate consumption of red wine as a preventative for Alzheimer's disease, we understand that chronic alcohol abuse can produce dementia-like symptoms.  So some (including me) wonder if chronic alcohol abuse can actually trigger the onset of Alzheimer's disease or if it can promote its progress.  I found a couple of studies that attempt to answer these questions.

This week, the journal Alzheimer's and Dementia published a study entitled "Association between alcohol consumption and Alzheimer's disease: A Mendelian randomization study."  The study looked at several different ways in which the progress of Alzheimer's disease and chronic alcohol abuse might be intertwined with each other that had (to me) some surprising results.

I wasn't willing to pay $36 to buy the article, and so I was unable to understand their methodology.  But I was able to read the synopsis.  They concluded the following:

• There was no association of alcohol consumption, alcohol dependence, or diagnosed alcohol use disorder with the occurrence of older onset (sporadic) Alzheimer's disease.  (Older onset Alzheimer's disease is the common type that becomes symptomatic at age 65 or later.)  
• The study identified an apparent protective effect of alcohol with respect to the age of onset survival for Alzheimer's disease (how long a subject lived after onset), but the researchers believed this was likely due to "survivor bias."  In other words, alcohol abuse could have eliminated part of the study population in a way that made those counted at the end of the study unrepresentative of the study population as a whole. 

Reading what I could of similar studies led me to an older study that pointed to some somewhat different conclusions.  This study was published in the journal Current Alzheimer's Research on July 25, 2017.  The study was entitled "The association between alcohol use and the progression of Alzheimer's disease," and it involved 360 early-stage Alzheimer's patients followed over 19 years.  (I'm not sure how many remained "early stage" throughout the study.)

The researchers tried to address a popular model of the disease from the time, that alcohol use and incidence of Alzheimer's disease could be depicted with a "U-shaped" curve.  In the curve, both non-drinkers and heavy drinkers experienced near-equal risk of developing the disease on their respective ends of the curve, while moderate drinkers in the middle received a protective effect.  The researchers wanted to determine if this picture might be more complicated than a simple relationship in which X amount of drinking equals Y probability of developing Alzheimer's disease.

For example, if moderate drinkers tended to drink red wine, and heavy drinkers drank beer and hard liquor, moderate drinkers would receive an unequal benefit from the resveratrol in red wine.  Resveratrol has nothing to do with alcohol content of the wine, but it appears to retard the development of Alzheimer's disease.

So what did they find?

• Cognition declined significantly faster in heavy drinkers than in moderate drinkers.  (Nothing in the paper suggested an effort to control for the cognitive effects due to alcohol abuse as differentiated from Alzheimer's disease, but I'm not sure how they would do that.) 
• They didn't find a significant difference in the rate of decline between mild-moderate drinkers and abstainers (like me).  So much for the U-shaped curve.
• All other factors being equal, subjects who consumed hard liquor declined more rapidly than those who consumed beer and/or wine.

So does drinking cause or aggravate Alzheimer's disease?  I guess it depends on who you ask.     

And another one bites the dust...

Neuroinflammation is part of the pathology of Alzheimer's disease.  The brain's immune cells -- the microglia -- participate in inflammation when they are trying to fight infection or rid the brain of debris from dead cells.  Accumulation of the debris and other unwanted substances (like beta amyloid) occurs as Alzheimer's disease progresses and is part of the disease process. 

Inflammation has a protective function, but it also causes collateral damage to other brain cells.  (We discussed this briefly on May 8, 2019 and on September 12, 2019.)  Therefore, diets thought to be good for Alzheimer's disease exclude foods that aggravate inflammation -- generally processed foods, including refined sugar and refined flour.  (We discussed this on March 2, 2019.) 

Unfortunately, non-steroidal anti-inflammatory drugs (NSIDs) may reduce inflammation in the brain (as in headaches), but they do not improve cognition for people with Alzheimer's disease.  So researchers were not terribly surprised when recent research found that the antibiotic minocycline also did not improve cognition in people with mild Alzheimer's disease.  Testing with mice and rats found that it could slow neuronal death and promote the generation of new neurons in the hippocampus, but a two year test on humans failed to show improved cognition.  The thinking was that the antibiotic (a derivative of tetracycline) reduced neuroinflammation, at least in the rats and mice.  So maybe it could disrupt the process by which inflammation was contributing to the progress of Alzheimer's disease in humans.

Especially after what happened with the NSIDs, no one seemed to be surprised at this failure.  They seemed more interested in this test as a model for testing other approved drugs that may be repurposed to fight Alzheimer's or other diseases.  

How Early Can We Observe Alzheimer's Disease Developing?

Considering that the Alzheimer's disease process begins as much as 20 years before the onset of Alzheimer's dementia, you'd think that people would want to know if it's in their future.  But not really.  Americans, especially seniors, often refuse screening tests, apparently in recognition that we have no pharmacological cure.  So what's the use?  Most have not heard that lifestyle changes can at least delay the advance of the disease, or they are unwilling to make the changes.  (They should read Beating the Dementia Monster.) 

But we still want to know if the disease process has begun in someone, if for no other reason than we need people with pre-clinical (presymptomatic) Alzheimer's disease for drug trials and other trial interventions.  There is a growing belief that strategies, like targeting the accumulation of beta amyloid, only have hope of success if they begin very early in the disease progression.  And so we look for ways of diagnosing the disease in those very early stages.  And so we need test subjects reliably diagnosed with pre-clinical Alzheimer's disease.

I believe that within a year we will have a reliable blood test that can identify amyloid abnornalities that may signal pre-clinical Alzheimer's disease, but we are nevertheless looking for other diagnostic tools.

Last week's issue of the journal Alzheimer's and Dementia published research on using information from three existing studies that contained information connecting both cognitive test performance and accumulation of beta amyloid.  These studies included people with Alzheimer's dementia, mild cognitive impairment, and people with no evidence of cognitive impairment.

The research article was "Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD."  The researchers wanted to see how pre-clinical Alzheimer's disease could be identified by following test subjects and seeing what became of people with certain test results at different ages.

The upshot was that subjects with passing but subtly declining cognitive test scores who also showed amyloid accumulation in PET scans, were much more likely to develop mild cognitive impairment (MCI).  The MCI likely preceded Alzheimer's dementia.

What does this mean?  I will speculate.  Recall that a diagnosis of Alzheimer's disease requires both evidence of cognitive decline and biomarker evidence together.  If someone does poorly on cognitive tests, brain imaging biomarkers may also show accumulation of amyloid plaques, or an MRI may show certain patterns of brain atrophy.  It appears to me that the blood tests that are emerging may show abnormalities in amyloids in the body, but this would not be sufficient for a diagnosis.  If at the same time cognitive test scores are beginning to decline in a certain fashion, these two indicators may then be sufficient for a diagnosis.  The test scores may still be in the normal range, but this research seems to have identified a rate of decline that signals pre-clinical Alzheimer's disease.

As a footnote, I may have participated in one of the three studies supplying data for the research.  This was the Alzheimer's Disease Neuroimaging Initiative.  In February 2017 I was asked to submit to an MRI at the University of Washington, but I don't recall much about it.  They probably had me sign a bunch of papers and gave me documents describing what they were doing.  But I can't find them now, and I don't remember what they said.  The research people just told that they wanted lots of MRIs of people with MCI.  They were nice enough to send the results to my neurologist.

The same week I had another MRI in the same facility for the SNIFF study we discuss in Beating the Dementia Monster.  It might have been on the same machine.  Both images were read by the same radiologist, and the results were consistent with each other. 


 

The Incidence of Dementia Is Declining...

...but prevalence is not.  At least in industrialized countries like Denmark.

Something interesting about Denmark is their very comprehensive database for tracking health conditions of all Danish citizens from birth.  Among other uses, the data in the databases can be used as a basis for many different types of longitudinal studies.  For example, a comparison was made between immunizations and the occurrence of autism in children that encompassed every Danish child.  The study found that fewer immunized children developed autism than those not immunized, although the correlation was within the margin of error.

This week's journal, Alzheimer's and Dementia, published an interesting article in which researchers, mostly from the University of Copenhagen, delved the national database to find trends in the incidence of dementia.  What they found was consistent with what we've seen in the US -- that the incidence of dementia has been declining for several years.  What's good about this study is that the data is more reliable and comprehensive than data used in other studies, and provides a little more detail.

The second edition of Beating the Dementia Monster is still a ways off, but we will discuss this phenomenon there.

Now, when we say that the incidence of dementia has declined, that does not mean that its prevalence has declined.  Incidence corresponds to the probability that someone will develop dementia, prevalence speaks to the total number of people who have developed the syndrome.  So while people may develop dementia at a slower rate, a population that is increasingly older will have more people with dementia.

The study filled in some blanks for me.  It found that the incidence of dementia increased an average of 9% annually from 1996 to 2003.  That's pretty steep.  But in 2003 the rate of increase leveled off, and then declined 2% annually until 2015.

Why?

It is believed that people made many lifestyle changes as part of a campaign within the industrialized countries to control cardiovascular disease.  Lifestyle improvements along with drugs for control of blood pressure and cholesterol appear to be responsible for the decline.

The researchers looked at other studies in Asia and North America (notably the Framingham Heart Study), and found that they too measured declines in the incidence of dementia.  However, several noted that, while the overall incidence of dementia may have declined, the incidence of Alzheimer's disease did not.  This strongly suggests that it is vascular dementia that is being influenced by improving cardiovascular health and maybe not Alzheimer's disease.

Nevertheless, lifestyle changes with respect to physical exercise, diet, stress management, sleep, and social connection can beat back the advance of cognitive decline from Alzheimer's disease.    

Warning all Millenials -- Start Caring for Yourself Now!

If you are now in your mid-30s and you want a full sized brain in your 70s, you need to get busy.  And let me tell you, that 70 sneaks up on you really fast!

This week's ALZForum carried an interesting story about research correlating control of cardiovascular risk factors in the mid-30s with brain size when someone was 70 or older.  Specifically, poor vascular health at age 36 signaled a smaller brain and greater white matter damage at 70.  The upshot of the story was that poorly controlled cardiovascular risk factors led to greater brain atrophy.

The study noted that this was unrelated to increased levels of beta amyloid and tau protein, the hallmarks of Alzheimer's disease.  So, while poor cardiovascular health can be a risk factor for Alzheimer's disease, it doesn't need Alzheimer's disease to damage your brain.

So how did they figure this out?  It's an interesting story.

In 1946 the British government identified every baby born during the week of March 3-9 in England, Scotland, and Wales and interviewed their mothers.  This was 13,687 babies and their mothers.  From this group, they selected a cohort of 5,000 to follow through their lives.  When some of these were more recently gathered (2014), some were in wheel chairs and others were talking about the marathon they had just completed.  Of course, some of their classmates had died.  Genes have a lot to do with these distinctions, but so does lifestyle.  (No news here...)

The 5,000 were tracked for educational attainment, socioeconomic status, diet, and exercise.  When they were all 36 (in 1982) they began tracking the cohort more specifically for cardiovascular risk, notably blood pressure.  Then in 2014, "egged on" by members of the cohort, the researchers began imaging the brains of about 500 of them at 2-year intervals.  This was both MRI and PET scan imaging.  The PET scans looked specifically for amyloid accumulation in the brain.

What surprised me the most was that they could not correlate an increase in beta amyloid and tau accumulation (meaning Alzheimer's disease) with cases of poor vascular health.  The surprise is that we have been saying that vascular disease is a risk factor for Alzheimer's disease, and these results seem to contradict that.  The article briefly quoted different authorities commenting inconclusively on this.  One authority suggested the incongruous result might be explained by the design of the research, while another said we just might be wrong about the relationship between Alzheimer's disease and cardiovascular risk factors.  I struggled with both explanations.

Something that Millennials should note is that they compared different ages at which cardiovascular risk factors went out of whack leading to greater brain atrophy.  The strongest correlation was at age 36.  Of course, that was the age of the cohort when the researchers started explicitly measuring those elements.  And so, likely at age 70, these subjects had hypertension etc. for the longest period of time.   Nevertheless, if you are 36 or older, it's time -- or past time -- to assess your cardiovascular risk factors and make any necessary lifestyle amendments!  Lifestyle factors -- notably diet and exercise -- are the biggest controllable contributors to cardiovascular health.

The researchers made an effort to correlate their findings with the ongoing Framingham Heart Study.  The Alzheimer's Association sees the British research with its rich cohort of study subjects to be worthy of further funding.  So they are chipping in $7 million to expand the British research.

Photos from the Alzheimer's Association Conference

Yesterday I posted that I had done photography for last weeks conference here in Tri-Cities, WA.  They posted some of my pictures here on their Facebook page.

Diet, Depression, Alzheimer's Disease, and Your Gut

This week I saw two unrelated articles that involved the connection between the health of your gut and brain health.  One discussed the influence of the gut on depression, and the other discussed research in China with seaweed sugars that affect the gut and may improve cognition for people with Alzheimer's disease.   

The first was an article in The Atlantic Monthly regarding how the DASH diet fights depression.  The article was actually published in 2018 but was recycled by Pocket.  We discuss the DASH diet in Beating the Dementia Monster but not for treating depression.  The DASH diet is a modified Mediterranean diet that is intended to lower blood pressure.  Brain health and cardiovascular health are intertwined, so the neurologists like to say, "What's good for the heart is good for the brain."

The Atlantic article posits an interesting coincidence -- that a leading risk factor for death worldwide is poor diet, and depression is a leading cause of disability worldwide.  It refers to research suggesting that poor diet makes us sick, and resulting depression can make us even sicker.  It then cites research finding that the DASH diet reduces depression by 11%.

How is this supposed to work?  The DASH diet is heavy with plant fiber that ferments in the gut microbiome.  The microbiome is the ecological community of microbes in the gut that participates in the digestion of food.  According to the article, fermentation creates short-chain fatty acids which regulate the immune system and influence gene expression in the brain.  It says this contributes to increased production of proteins called neurotrophins, which act like manure to the brain as they promote the growth of new brain cells in the hippocampus.  (We recall that Alzheimer's disease attacks the hippocampus.)

Anything sound familiar here?  In Beating the Dementia Monster we described how much of my improvement can be attributed to production of the brain-derived neurotrophic factor (BDNF) during exercise.  So it seems that you can get BDNF through both exercise and diet.  (But you need them both!)

Then last week's ALZForum carried the article on Chinese research entitled, "China Approves Seaweed Sugar as First New Alzheimer's Drug in 17 Years."

At least from the standpoint of spending, China is emerging as a world leader in Alzheimer's research.

The article discussed research that found some improvement in people with Alzheimer's disease who were given a drug called GV-971, or oligomannate, which is based on seaweed sugar.  This was a stage 3 (final) drug trial.  The results seemed promising, but it didn't look like a game-changer.  Its mechanism of action is said to be that it alters the gut biome in a beneficial way.  While the drug seems to have an open path to approval by the Chinese government, there are some issues with the data.

The biggest issue seems to be some odd behaviors in the placebo group, where their cognitive test scores seemed to improve at first but then plummet.  Some noted that Chinese people don't see doctors regularly, but all of the test subjects needed medical attention during the trial.  They wonder if unusual (for them) medical attention might have influenced cognition.  I speculate, for example, that doctors may have influenced the placebo population to make lifestyle changes, or they may have given them new drugs for ailments they found.  

Some also identified anomalies in the data that bring the results into question.  One (Chinese) scientist at Rutgers University pointed to research showing that GV-971 in mice had promoted inflammation, not helped brain health.  This brings into question the Chinese explanation for it's mechanism of action. 

An open question whether GV-971 does more than donepezil (sold under the trade name Aricept) and the other acetylcholinesterase inhibitors.  These treat symptoms without changing the course of the disease.  And donepezil made me sick.

China will likely approve the drug for use in China and then promote it in the USA and other countries.  They also plan some worldwide studies.  American researchers seem to be skeptical, but they seem to think that if it's safe, well, why not use it?

I probably would/will.