The Relationship Between Stress and Alzheimer’s Disease

Stress markedly alters brain activity. It is thought that the human brain actually does not have a “stress response” but rather only a danger response.  The purpose of this response is to focus all brain resources only on the danger at hand.  While this serves to help with survival, it is counterproductive for normal function. While this response helped with survival for millions of years, it may be causing us problems in our modern environment as this reaction is also triggered by psychosocial stress.  Danger tended to be infrequent and brief.  Stress in contrast, is frequent and ongoing for many.

It seems this hyperactivity in the frontal brain attention area comes at the expense of a lot of other brain functions, some important in processing memory.  While we develop intense memory of the dangerous situation, we do not process everything else occurring at the same time.  No harm is done during 10 minutes of danger but when the same reaction is triggered over days by psychosocial stress, normal memory processing is sacrificed at the expense of focus on the stress.

There has been demonstration that exposing adults to higher levels of short-term stress impairs important memory circuits.  A recent study compared processing of long-term and working memory during higher stress as measured by a test called “Stress and Adversity Inventory”.(1)  Both forms of memory processing were impaired during higher stress scores.

The key question has been does this short-term suppression of memory eventually lead to ongoing memory dysfunction with chronic stress.  A study of 1415 women over 35 years of age has answered that question.(2)  Subjects were evaluated for intervals of stress over three decades during middle age.  Subjects were separated into groups based on having significant stress during none, one, two or all three decades.  Compared to those who experienced no sustained stress, there was an increasing relationship between the number of stressful decades and the risk of developing Alzheimer’s.  The increased risks of developing the disease were 9%, 82% and 183% respectively for 1, 2 or 3 decades of higher stress.

The answer to the question, does memory suppression associated with sustained stress eventually translate to increased risk of Alzheimer’s, appears to be an emphatic yes. Often stress is unavoidable such as with the serious illness of a family member.  Another recent study has suggested the mechanism of this relationship.(3)  An important driver of Alzheimer’s disease is chronic inflammation.  It is typically triggered by toxicities such as with heavy metals, diet, omega-3 fatty acid insufficiencies and chronic infections such as Lyme.  Stress is also a potent driver of chronic inflammation.

This recent study looked at a marker of chronic inflammation, blood levels of IL-6 in one of the most stressed populations, caregivers of a family member with Alzheimer’s.  Subjects not under stress from caregiving were used as the control group.  The first observation was that IL-6 and thus inflammation increased 33% between 55 and 95 years of age in the control group.  This increased tendency for inflammatory levels to elevate with aging has been termed “inflammaging” and is thought to be one of the drivers of the increased degenerative disease risk with progressive age.

The second observation was that the increased levels of IL-6 over the same age transition was 395%, or 10 times greater in the stressed caregivers.  Both age and sustained stress are risk factors for Alzheimer’s disease.  The former is unavoidable, while the second may be in some circumstances.  Some stress is avoidable, while other stress circumstances are not.  In those with unavoidable stress the importance of an otherwise anti-inflammatory lifestyle is paramount.  This involves careful attention to diet, weight, sleep and other factors which are known to contribute to chronic inflammation.

1)  Shields et al.  Recent life stress exposure is associated with poorer long-term memory, working memory, and self-reported memory.  Stress, 2017 ePub.

2)  Johansson et al. Midlife psychological stress and risk of dementia: a 35-year longitudinal population study.  Brain, 2010;133:2217–2224.

3) Kiecolt-Glaser  et al.  Chronic stress and age-related increases in the proinflammatory cytokine IL-6. PNAS, 2003;100(15):9090-9095.

Smaller Doses of Alcohol May Be Protective Against Alzheimer’s

Alcohol consumption has been a two-edged sword in the scientific research.  Study has shown that it can substantially contribute to the development of chronic disease in a number of body systems such as the cardiovascular system and in the liver.  Other study has shown the opposite with alcohol consumption actually being preventative of chronic disease such as that in the cardiovascular system.

This apparent conflict in data is explained by the “dose response curve”.  This is a measure of the outcomes associated with different daily doses of intake.  The graphic shows the dose response curve looking at total mortality.  The risk of non-drinkers is assigned a relative risk of 1.0.  Notice the risk is 0.8 at 20 grams which is approximately 1 ½ -2 glasses of wine consumption, or 20% risk reduction.  With heavy consumption,  risk increased compared to non-drinkers.  The truth is in the dosage.

This relationship between alcohol consumption and brain health has been less clear.  Chronic, excessive use is a risk factor for the development of all forms of dementia.  What has been less understood has been if alcohol and the brain follows a typical dose response curve seen for its intake and other diseases.  Some new research is suggesting it may.

The study examined the impact of 3 different daily doses of alcohol on brain “glymphatic flow” and inflammation in mice.  Brain glymphatic flow is the equivalent to lymphatic flow in the rest of the body.  The lymphatic system is used as a “highway” that the immune system uses to remove different toxic waste generated by infections or other exposures.

It was thought until recently that no lympathic flow occurred in the brain which created a mystery about how it detoxifies efficiently.  Recently some innovative research injected mice with a tracer that glows when exposed to a specific type of light into the lymphatic system to better see all of its pathways.  Surprisingly, the brain lit up as did the rest of the body confirming that there is lymphatic flow in this area.  The term for it was coined as glymphatic flow.

In the recent alcohol study, low alcohol intake increased glymphatic flow 39.8% compared to the control group consuming none. Higher consumption did just the opposite decreasing this flow.  The response in inflammatory markers followed the same pattern, improving with low dose consumption and increasing with high dose.

While this was an animal model study, dose impact studies on the relationship between alcohol and other health risks such as cardiovascular disease have supported the “dose response” relationship with 1-2 drinks daily decreasing the risk compared to non-drinkers and high dose use increasing the risk.  The relationship appears to be similar in the brain.

Lundgaard et al.  Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function.  Scientific Reports, 2018;8:2246.

More New Research on Chronic Inflammation and the Development of Alzheimer’s

Inflammation is a critical process for the protection against short-termed stressors, such as infection.  While it is crucial for survival, it becomes a primary mechanism driving chronic disease when it is sustained and unsuppressed.

This dual role of inflammation is perhaps best explained by Dr. Russel Tracy, Associate Director of Research, University of Vermont School of Medicine; “Aging is not simply the passage of time, it is actually something that our bodies create, a side effect of the essential inflammatory system that protects us from infectious disease.  As we fight off invaders, we inflict massive collateral damage on ourselves… We are our own worst enemy.”

At the epicenter of this understanding is the relationship between ongoing inflammation and Alzheimer’s disease.  Extensive research has supported this relationship while a new study supports the strength of it.(1)  The study measured one of the more accurate inflammatory markers, high sensitivity C-reactive protein (hsCRP), and looked at its predictive power for the subsequent development of Alzheimer’s in subjects 60 and up.  

Elevated hsCRP increased the risk of Alzheimer’s by a striking 137% in the 8 years of follow-up.  This study added considerable strength to the association between chronic inflammation and Alzheimer’s risk.  It also was important as it confirmed a measurable marker that can be used to monitor disease risk.  hsCRP also is a valuable marker that can be used to monitor the effectiveness of a comprehensive lifestyle treatment program once the disease is present.  It is a fundamental biomarker used in the Bredesen Protocol™. 

The useful translation of how this biomarker is helpful in managing the disease relates to the diverse group of factors that cause chronic inflammation including diet, toxicity such as heavy metals, chronic infections and others.  The correction of these factors is successful in dampening chronic inflammation positively mitigating the disease process, and the effect can be monitored over time with repeat measurements of hsCRP.

The best time to be monitoring inflammation and correct it is before the disease develops.  However, it remains equally important in those with the disease as comprehensive lifestyle management reducing inflammation is proving successful in reversing the disease.

          1. Gabin et al.  The association of high sensitivity C-reactive protein and incident Alzheimer disease in patients 60 years and older: The HUNT study, Norway.  Immun Ageing. 2018 Jan 22;15:4.

Genetic Predisposition to Alzheimer’s Does Not Prevent Lifestyle Intervention from Helping

A large, ongoing study of a multipart lifestyle intervention (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) has been investigating the ability of this type of treatment to prevent cognitive decline in older subjects.  One of the latest analyses in this study sought to determine if the most common genetic variant that increases Alzheimer’s risk, the apoE4 gene variation, would prevent these individuals from benefiting from this intervention as persons without the gene variant.

Subjects between the ages of 60 and 77 were blindly randomized to the intensive management group which included diet, exercise, cognitive training, and vascular risk management, while the control subjects received only general health advice.  Equal numbers of participants in each group carried the high risk (3-10 times) apoE4 gene or the normal risk apoE3 gene.

Cognitive function was measured before the study with a comprehensive neuropsychological test battery and after 6 years.  Those participating in the intensive management group had significantly better cognitive scores at the end of the 6 years, and the benefit was the same in both the normal or high genetic risk subjects.  The two important conclusions are that a comprehensive lifestyle management program does prevent cognitive decline and that this prevention occurs both in those with and without the apoE mediated risk. 

These results are reassuring as approximately 1 in 6 adults have the higher risk apoE4 gene.  While this genetic variant increases their risk to the development of the disease, it does not prevent the benefits of a comprehensive lifestyle management program from helping.  The increased risk associated with the apoE4 gene appears to require those with it to be more meticulous about their lifestyle both to prevent the disease onset as well as to manage it once cognitive decline appears.

The above statement does not give a free ride about being less concerned about lifestyle management to those with the “normal risk” apoE3 gene.  The normal risk for Alzheimer’s is still 1 out of 6 by age 65-70, and 1 out of 3 by age 80.  Dale Bredesen, MD the innovator of the successful lifestyle program called ReCODE, explains the relationship between lifestyle and Alzheimer’s risk best based on extensive research.  He comments that Alzheimer’s appears to not be just a brain disease but rather a brain manifestation of systemic metabolic disease.  An example of this relationship is the 2-3 times greater risk of Alzheimer’s in those who develop type two diabetes which is highly related to lifestyle.

ApoE4 remains a risk factor for the development of Alzheimer’s disease.  While it increases this risk, it fortunately does not compromise the ability of a comprehensive lifestyle management program to help the disease once signs of it are present.  Importantly, the apoE4 genotype serves as a warning of the disease risk and the important preventative role of a comprehensive lifestyle program before the disease manifests.  The best treatment is not to develop the disease in the first place.

The Role of Dietary Greens in Brain Health

One of the hallmarks of the Bredesen Protocol™ for Alzheimer’s disease is that most of the treatment is lifestyle based.  There is a tendency to not think that lifestyle factors as simple as what one eats could have such a profound effect on such a complex disease.  A recent study of 1,068 older adults, the Rush Memory and Aging Project, showed just how important a single dietary factor can have pronounced effects.

The subjects' diets were analyzed specifically looking at how many servings of greens including spinach, kale, collards, greens and lettuce/salad were consumed daily.  All subjects had annual cognitive testing over 5 years.  Those consuming 1.5 or more servings daily had cognitive performance scores a striking 11 years younger than those with the lowest consumption (<1 serving/week).  The results remained valid after accounting for other factors that could affect brain health, such as seafood and alcohol consumption, smoking, high blood pressure, obesity, education level and amount of physical and cognitive activities.

The suspected mechanism driving this relationship is likely that greens are a major source of “methylation factors” in the diet.  Methylation is a primary mechanism through which our genes are regulated.  This includes both keeping genes that may increase our disease risk turned off and activating those involved in reactions that tend to be disease preventative.  Methylation factors include vitamin B12, B6, folate, the amino acid methionine and choline.  Methylation reactions occur thousands of times daily in all of our cells literally determining healthy function. 

The methylation cycle involves several enzyme reactions that use the above nutrients to activate.  The end product of these reactions is a methyl group which performs the gene regulation.  The cycle also produces “waste products” such as homocysteine which can increase brain cell degeneration if it is not efficiently removed.  This requires adequate amounts of vitamin B6.

Many studies have found that the brain is very sensitive to loss of proper gene methylation with age causing an increased rate of memory decline.  Acceleration of this decline in gene methylation with age by inadequate dietary provision of the needed nutrients appears to greatly accelerate this process.  Although the concept that just eating multiple servings of greens daily seems too simple to be involved in such a complex disease such as Alzheimer’s, appreciating the scientific concept behind the relationship establishes the importance.

It is likely that some persons are more susceptible to the level of nutrients involved in the methylation cycle.  Genetic variations called polymorphisms can cause any single enzyme in the cycle to be weak under-producing its reaction.  For example, the enzyme that converts dietary folate to the form used in the cycle, 5-methylated folate is variant in perhaps as many as 1 in 5 Westerners.  As higher amounts of dietary folate have been shown to help compensate for this gene variant, these individuals are very sensitive to dietary amounts.

Eating greens by itself is not a total solution to disease prevention and treatment.  The Bredesen Protocol™ derives its success from testing and treating many different factors most of which are lifestyle related.  However, one part of this comprehensive protocol does involve eating multiple servings of greens daily.

The study is to be published in the journal Neurology later this year.

One of The Strongest Alzheimer’s Preventions

A broad group of lifestyle and behavioral factors have been associated with the risk of developing Alzheimer’s disease including diet, stress, exercise and others.  A new study has increased the importance of one that has been previously known, educational attainment.

The study, CoSTREAM, looked at genetic patterns that have been previously shown to highly correlate with the likelihood of educational attainment. This gene pattern was also highly associated with a reduced likelihood of developing Alzheimer’s.  For every year of educational completion the risk of Alzheimer’s was reduced 11%.  If education included the completion of college, risk was further reduced 26%.

The researchers commented that this association is consistent with the reducing rate of Alzheimer’s disease in the United Kingdom which contrasts to the sharply increasing rate in the United States.  Along with greater emphasis on diet, exercise, and smoking reduction the UK has increased educational emphasis.

The effect is thought to relate to the development of "cognitive reserve". Just as physical exercise causes muscle to build up decreasing the risk of injury and age-related muscle loss, education builds up brain structure and offsets age related brain loss.

While recent losses in financial support for higher education in the US have occurred

 based on “costs”, this may be short-sighted given the staggering cost projections associated with Alzheimer’s disease over the next 30 years.  Saving a dollar now but costing hundreds more in the near future is never a winning strategy.

The best plan is for each individual to do everything to facilitate their own higher education and to continue “brain exercise” with life-long learning.

Larsson et al.  Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis.  BMJ 2017; 359.

Alzheimer’s Genetic Risk Factor Requires Careful Management of Omega-3 Fatty Acid Levels

Some of the risk of developing Alzheimer’s disease is mediated by genetic variation.  The most common and involved variation is a variant of the gene that makes the apoprotein apoE.  This apoprotein is involved in many processes in brain cells including the removal of the toxic protein β amyloid which causes tissue damage if it builds up in excess.

Risk of the disease is greatly increased in those with the variant form of the gene called apoE4.  Nine percent of adults have the apoE4 variant and their disease risk is increased between 3 and 10-fold depending on the presence of 1 or 2 copies of the gene variant.

While the presence of apoE4 increases the disease risk, the final triggering of the disease requires the presence of different environment triggers such as chronic inflammation or insulin resistance.  Both of these processes are worsened by low cell levels of omega-3 fatty acids which must come from diet.  New study has found that this relationship is compounded by the fact that it requires higher amounts of omega-3 FA intake to maintain cell levels in those with the apoE4 gene variant.

The study looked at blood and brain cell omega-3 FA levels in rats that share the traits of development of Alzheimer’s with humans.  The levels were significantly lower in those animals with the apoE4 variant.  The lower levels of omega-3 FAs correlated with cognitive and behavioral deficits typical to human Alzheimer’s.  The lower levels of omega-3 FAs appears to come from increased “catabolism” or breakdown of these fatty acids.  The solution is that those with the apoE4 variant require higher levels of dietary and supplemental omega-3 FAs to maintain cell levels and prevent cognitive decline.

The difficulty in managing omega-3 FA levels is that there is wide variation of intake levels from person to person required to maintain adequate cell levels.  This can be managed by actually measuring cell levels and adjusting supplementation until these levels are adequate.  This is done with a red blood cell test.  Blood cell levels have been correlated with levels in brain cells validating this testing.  The test above shows a low omega-3 FA cell level at 3.72%.  Levels need to be 10% or greater for optimal brain protection.  

The test at the left shows an ideally managed omega-3 FA level at 11%.  The dietary levels required to maintain these levels varies from person to person so supplementation levels should be managed by cell level testing rather than by using an arbitrary consumption level. 

There are several risk factors that have to be managed more carefully in persons with the apoE4 gene variant.  Omega-3 FA levels is clearly one of them.  If someone is genetically predisposed to Alzheimer’s disease, development of it is not a given and it can be prevented with careful lifestyle management.

Nock et al.  Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline.  Molecular and Cell Biology of Lipids, 2017:1862;1068–1078.