The human brain is an extremely sensitive organ. Therefore, it must also be particularly protected from toxins and pathogens. The supply of messenger substances and the removal of metabolic products must also be precisely regulated. The blood-brain barrier (BBB) has exactly this function and separates the central nervous system from the rest of the body’s blood circulation.  The BBB acts as a shield, protecting the brain from infectious agents and toxic substances, but must also act as a filter, allowing nutrients to get inside the central nervous system. 

Recent studies have shown that this thin structure plays an important role in Alzheimer’s disease. In fact, it seems to be involved in the process of the disease even before the first pathological changes are identified. You can have further information about the relationship of ApoE4 and BBB breakdown in the article published in our previous news feed “Alzheimer gene triggers early collapse of the blood-brain barrier and predicts cognitive decline”.  

Besides genetics, other factors can contribute to the linkage of the BBB and lead to or perpetuate the cascade of inflammation and neurodegeneration observed in Alzheimer’s disease. Of all the factors that can cause the blood-brain barrier to break down, the alteration of intestinal permeability is given greater consideration because it is a modifiable factor depending on lifestyle measures. Diet composition and gut microbiota play a crucial role in maintaining intestinal integrity and the intestinal-brain axis. On the subject of the ‘gut-brain axis’, why not take a look at our fact sheet, which “Knowledge stops Dementia”’ makes available to you free of charge. 

The importance of the composition of the microbiota becomes clear in the following: specific substances produced by gut bacteria can influence BBB barrier permeability: So-called lipopolysaccharides are endotoxins and pro-inflammatory agents produced by gram-negative bacteria that can potently stimulate BBB disruption. On the other hand, short-chain fatty acids produced by commensal bacteria can protect the BBB from damage. 

In order to bring you more information about this important structure of the nervous system, we have updated the Brain & Body section of the KsD page, adding a review about how the BBB breakdown plays an important role in the accumulation of Alzheimer-specific plaques in the form of amyloid-beta. You will find the complete update in the Brain & Body section – Blood Brain Barrier.

Blood-Brain-Barrier

Figure 1: Physiopathological cycle of Blood-brain-barrier (BBB) injury and Amyloid beta (Aβ) accumulation in Alzheimer’s disease

You will be able to understand which factors can contribute to disrupting the BBB and the close relationship between gut permeability and BBB breakdown, and especially, how important a healthy lifestyle is for your mental health!

Enjoy your reading!

 Link to Brain & Body section here.

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Can the course of early Alzheimer’s disease be delayed by consuming a special mixture of nutrients? This question was investigated in the European study called ‘LipiDiDiet’ led by Prof. Tobias Hartmann. 

The scientists recruited Alzheimer’s patients, who were in the early stages of the disease, to test the effectiveness of a specific nutritional drink called ‘Souvenaid’. Souvenaid was developed as a medical dietary food for the treatment of early-stage Alzheimer’s disease and is marketed by Nutricia (Danone Group). It contains a defined nutrient combination of long-chain omega-3 fatty acids, phospholipids, choline, B vitamins (B6, B12 and folic acid), vitamins C and E, selenium and uridine monophosphate. 

In this randomized double-blind study, the 311 participants were divided into two groups. The treatment group received the drink daily for breakfast. The control group was given daily  the same amount of a placebo drink, but with identical taste, consistency, color and calorie content. Neither patients, physicians nor researchers knew who was given the placebo or the multinutrient drink. 

The primary study endpoint was the slowing of cognitive decline. It was measured by a neuropsychological test battery, i.e., a combination of standardized cognitive testing procedures which measures not only the change in cognitive performance but also the ability to perform certain executive functions, such as planning, strategy and working memory. Furthermore, clinical aspects were also investigated using imaging techniques. Thus, structural brain changes could be directly recorded and assessed. 

Initial interim results after 24 months indicated some efficacy of the sip feed, but the differences in cognitive deterioration between the two patient groups were not significant. 

In September 2020, results after 36 months of treatment were published. They revealed significant differences between the two groups: Patients in the intervention group were measured to have 22 percent less brain atrophy, meaning that the brain mass of the treated Alzheimer’s patients had shrunk significantly less than that of the control group. Thus, the degenerative change process in the brain could be significantly slowed down by the nutrient preparation. In particular, the deterioration in the memory region of the brain (hippocampus), was 33 percent less in the treated patients than in the control group. It was also observed in regard to cognitive brain performance: it deteriorated 60 percent less, i.e. significantly less, in the treated subjects than in the no-treated patients.

Thus, the results of this study made it clear that such nutritional supplementation is not an effective concept in the short term. The effects seem to consolidate only with longer-term treatment, which was more than clearly shown by the comparison after 3 years with the interim results after 2 years. The researchers further found that the positive effects of the sip feed increased over the course of the treatment period and were not only focused on the memory region, but also extended to other cognitive areas. For example, the subjects were better able to cope with everyday challenges, such as paying bills, remembering routes, etc., than the control group.

This means that long-term intake of this specific multinutrient combination partially protects brain structures and reduces cognitive and functional decline in early Alzheimer’s disease. Thus, these nutrients appear to play a central role in reducing the neurodegenerative process in AD, suggesting a special nutritional need in AD. 

However, since it can be assumed that the disease begins decades before the first symptoms appear, but this cannot yet be measured with current methods, the timing to start therapy would also be crucial: the earlier, the better. Thus, not only the long-term duration of treatment would be important, but also the early start of treatment in the course of the disease. 

Despite intensive research, there is unfortunately still no medication that could cure Alzheimer’s disease. The currently available drugs can temporarily improve the symptoms, but let the patients fall back into the initial situation after some time. A sustained 3-year benefit of treatment, such as that achieved in this study with a defined nutrient mixture, has not yet been reported in incipient AD. With this in mind, the slower progression of the disease would already be a great success and is certainly a good start. 

These findings emphasize once again that AD is a generalized metabolic disorder in which monocausal therapies alone cannot lead to success, but multifactorial strategies must be used. And the international FINGER study (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) has already impressively demonstrated that multimodal prevention approaches can also pass clinical testing effectively. The ‘Souvenaid’ study is certainly a good start, as a sustained positive effect in terms of cognition, function and brain atrophy in an intervention for incipient Alzheimer’s disease has not yet been reported. Future studies could further clarify whether the efficacy of nutrient supplementation can be further enhanced if started at an even earlier stage, over a period longer than 3 years, as part of a multimodal intervention (e.g. FINGER trial) or in combination with pharmaceutical therapies.

Conclusion: 

The results of the aforementioned studies impressively underline that the multifactorial catalog of measures proposed by Knowledge stops Dementia – and especially a conscious diet that protects the brain – is the royal road in dementia prevention. It offers us a multitude of prevention strategies with which we can reduce our individual risk of Alzheimer’s disease by consistently minimizing avoidable risk factors and by adhering to a healthy lifestyle that includes not only nutrition but also other factors such as exercise, quality of sleep, social contacts, and so on. At the project ‘Knowledge stops Dementia’ you will find a lot more exciting and helpful information on this, so that you can maintain your mental health for as long as possible!

References:

  1. Soininen H et al. (2017) 36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer’s disease . Alzheimer’s and Dementia: 1-12 
  2. Soininen H et al. (2020) 24-month intervention with a specific mulitnutrient in people with predromal Alzheimer´s disease (LipiDiDiet): a randomised, double-blind, controlled trial. Lancet Neurol 16: 965–975 
  3. Ngandu T et al. (2015) A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 365: 2255–2263 
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The diagnosis of Alzheimer’s disease (AD) has challenged neurologists for many years. It’s difficult to determine if someone will develop AD in the future, if the actual cognitive deficit is due to AD or to other cause of dementia and it’s also difficult to predict the pace or speed of disease progression.

It is already known that Alzheimer’s pathological brain alterations (amyloid plaques and Tau-tangles) start long time before the appearance of clinical symptoms. We also know that lifestyle interventions are the only effective treatment to fight cognitive decline, especially when initiated in early stages of disease. That’s why, a test which could predict when the process starts and the rhythm of progression would be a useful tool in the clinical practice.

Many tests are nowadays available (see Diagnosis section for more information), but they are expensive and difficult to be used in the day by day clinic. They usually require brain image techniques that are either expensive and time consuming or invasive medical procedure like lumbar puncture – which is not free of adverse effects. 

Two new AD-tests have been developed within the last year and hope to finally bring ease and precision to the diagnosis of AD.

Published in Neurology in August 2019, a study presents a blood test that was able to measure the level of Aβ42/Aβ40 with high correspondence with amyloid PET status (brain image test). It showed that plasma Aβ42/Aβ40, especially when combined with age and ApoE4 status (see Genetics section for further information), accurately diagnoses brain amyloidosis and can be used to screen this pathological alteration in individuals with normal cognitive function, i.e., before presenting symptoms. It also showed that individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Thus, the test could be used to screen individuals likely to present brain amyloid deposit and hence, at risk for AD. 

In another study published in Lancet Neurology in May 2020, the authors developed and validated an ultrasensitive blood immunoassay for p-tau181. Tau phosphorylated at threonine 181 (p-tau181) level has been already measured in is cerebral spinal fluid (CSF) and is a highly specific biomarker for Alzheimer’s disease pathology. With this study, the authors showed that blood p-tau181 levels can predict tau and amyloid β pathological alterations and differentiate AD from other neurodegenerative disorders with high accuracy. Additionally, it predicts cognitive decline and hippocampal atrophy over a period of 1 year, making it suitable as a marker of disease progression.

Both tests have the advantage to be done in a blood sample, and were able to predict the risk of developing cognitive decline and its progression. They represent simple, practical and scalable tests for the diagnosis of AD. They are not yet available in the market, but have the potential to be incorporated into clinical practice as a rapid screening test to rule out AD and to guide therapy in patients with dementia. 

Considering the relevance of lifestyle measures for AD treatment and prevention, these tests provide security and certainty of when to start or intensify actions to control cognitive impairment. They can be also used to easily screen individuals at risk to future prevention trials, to promote lifestyle intervention and to improve our knowledge about this challenging disease.

Conclusion:

Two  new tests for Alzheimer’s disease that determine highly specific biomarker substances in the blood, have been developed. These fast, precise and inexpensive tests may have important clinical applications: as a screening tool in the primary care setting; to monitor the disease progression; to differentiate AD patients from patients with other neurodegenerative disorders; and as a way of ensuring that subjects enrolled in clinical trials indeed have Alzheimer’s disease and that the treatments they are testing are effective. They will certainly become an important tool to ensure an accurate and early diagnosis and to motivate doctors and patients to implement lifestyle changes in order to prevent cognitive deterioration. KsD will keep its readers informed about the availability of these or other tests (please register today for our newsfeed).

References:

  1. Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422-433. doi:10.1016/S1474-4422(20)30071-5. https://pubmed.ncbi.nlm.nih.gov/32333900/
  2. Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019;93(17):e1647-e1659. doi:10.1212/WNL.0000000000008081 https://pubmed.ncbi.nlm.nih.gov/31371569/
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You go to a doctor – usually a neurologist – ask about natural or lifestyle-oriented therapeutic methods for dementia – and you often look into blank eyes, at worst into an aggressively wrinkled forehead “Don’t give me that, all dangerous nonsense, there are only a few pharmacological approaches that may really work!” 

In your journey of self-directed prevention and treatment of cognitive impairment and dementia you will often, probably even frequently, encounter this incredible narrow-mindedness among many medical doctors who question lifestyle-related causes and risk factors, and denigrate a causal therapeutic approach based on changes in lifestyle, the supply of vital resources and the reduction of pollutants as a story from the “realm of fantasy”. Hopefully you have not experienced it personally. 

How do you deal with it? You try to inform yourself more broadly, for example via the websites of Kompetenz statt Demenz, but of course you may still wonder, where is the evidence?

Mikroskop

For this reason, we have provided a selection of current studies and reviews on the page “Alzheimer Research” and listed them chronologically together with the conclusions drawn by the authors. The studies listed there clearly show that targeted interventions, whether with micronutrients, sport and exercise, sleep hygiene or mental measures, may indeed help to regain lost cognitive abilities. They thus provide you with an important support for your argumentation on your difficult way through the narrow-mindedness and helplessness of the conventional medicine. The studies are sorted by category and the most recent studies are listed first. 

Intervention studies – also double-blind placebo-controlled – are the most interesting ones, as they directly assess the effects of a treatment. However, it does not always have to be a double-blind placebo-controlled study, because effects become visible even without blinding and some interventions cannot be blinded by the authors anyway (e.g. in the area of movement or mental interventions). 

Meta-analyses are interesting in the sense that they “pool” several or even many individual studies. However, the “pooling” of several studies is difficult and can contain statistical errors, and the selection of studies can also exhibit a “bias” (systematic error). A positive result of a metastudy at least provides additional safety. 

Reviews are also very helpful, as they look at a topic from an overview perspective and summarise it.

So if you are interested in a brief overview of the background of different therapeutic approaches and their scientific background, just go to this page: Alzheimer Research

You will also find direct links to the studies on Pubmed and some are also available free-of-charge in the full version. If you want to print the whole thing to go, just click on the right mouse button and “Print” and you will get the page in a quite clear print format.

A final note: Science never makes absolute statements “ex cathedra” but reflects the state of current research. Studies may be incorrect or even manipulated and their content may be overtaken by new findings. Therefore it is important to stay up to date and we at “Kompetenz statt Demenz” continuously follow up the relevant topics. For this reason, the most recent studies always come first and some may disappear from the list over time, but this is the sign of the further development of scientific knowledge.

Conclusion: Don’t let yourself be confused on your own path of self-responsible treatment and prevention of dementia and make up your own mind as much as possible! Use reliable sources of information to support your decision for any type of treatment and do not allow yourself to be discouraged. We at ‘Kompetenz statt Demenz’ hope to make our contribution!

PS: And if you happen to come across an important paper, please send us the link!

Photo by Michael Longmire on Unsplash

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A study published in The American Journal of Medicine 2018, has demonstrated that maintaining a healthy diet in midlife is independently associated with a larger hippocampus years later and may protect against cognitive decline. The hippocampus is a structure located in the temporal lobe of each brain hemisphere and is directly involved in the process of memory. The volume of the hippocampus can be determined by brain magnetic resonance imaging (MRI). Decreasing of its volume is related to cognitive impairment and is used in clinical practice for the diagnosis of Alzheimer’s disease (hippocampus atrophy).

MRI Brain Diet

In this study, the quality of the diet of 459 participants (average age at baseline = 49 years) was assessed with a food-frequency questionnaire, which was administered in 1991-1993 and 11 years later, in 2002-2004. At the end of the follow up, around 13 years after the first questionnaire, participants underwent brain MRI with study of the hippocampus. Long-term healthy diet (showed by higher cumulative score on the Alternative Healthy Eating Index), was associated with a larger total hippocampus volume. This association was independent of sociodemographic factors, smoking habits, physical activity, cardiometabolic factors, cognitive impairment, and depressive symptoms and was more pronounced in the left hippocampus than in the right hippocampus.

A healthy diet, based on recommendations in the Alternative Healthy Eating Index 2010 (AHEI-2010) score is rich in vegetables, fruits, whole grains, nuts, legumes, omega-3 fats, and polyunsaturated fatty acids, and is light on sugar-sweetened drinks, red and processed meat, trans fat, and sodium-rich products. It is also characterized by low alcohol intake. 

The findings of this study support the hypothesis that overall diet may affect brain structures with a specific impact on hippocampus volume. 

Some other studies have demonstrated the influence of diet in brain structures. In most of these studies, diet quality was assessed by Mediterranean diet score, and higher scores (healthier diet) were found to be associated with larger cortical thickness, lower white matter hyperintensity burden, and preserved white matter microstructure. All these findings indicate better preservation of normal brain structure. 

Another previous study, published in 2015 in the BMC Medicine, had already shown that higher intakes of unhealthy foods, normally present in the Western diet, were independently associated with smaller hippocampal volume. This finding was originally observed on experimental animal models and suggested that a high-energy diet rich in saturated fats and refined sugars adversely affect neuronal plasticity and function. Animals maintained on a high-energy diet rich in fat and sugar showed lower performances in hippocampus-dependent spatial learning, object recognition, reduced hippocampus levels of brain-derived neurotrophic factor (BDNF) and impaired in blood-brain barrier integrity.

Accounting for the importance of hippocampus with long-term, declarative, episodic memory, as well as for flexible cognition network, this study reaffirms the need to recognize diet and nutrition as potential determinants of cognition, mental health and social behavior.

Conclusion:

A Long-term healthy diet (and not various episodic restrictive diets) is the key to promote brain health and prevent dementia.

Thus, routine dietary counseling as part of a doctor’s office visit is very important at a patient’s level, but it should also be a high-priority public health goal.

To know more: https://kompetenz-statt-demenz.de/en/prevention-treatment/nutrition/the-mind-diet/

  1. Akbaraly, T et al. Association of Long-Term Diet Quality with Hippocampal Volume: Longitudinal Cohort Study. The American Journal of Medicine 2018 https://www.ncbi.nlm.nih.gov/pubmed/30056104
  2. Gu Y, Brickman AM, Stern Y, et al. Mediterranean diet and brain structure in a multiethnic elderly cohort. Neurology 2015;85 (20):1744–1751. https://www.ncbi.nlm.nih.gov/pubmed/26491085
  3. Mosconi L, Murray J, Tsui WH, et al. Mediterranean diet and magnetic resonance imaging-assessed brain atrophy in cognitively normal individuals at risk for Alzheimer’s disease. J Prev Alzheimers Dis. 2014;1(1):23–32.https://www.ncbi.nlm.nih.gov/pubmed/25237654
  4. Staubo SC, Aakre JA, Vemuri P, et al. Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness. Alzheimers Dement. 2017;13(2):168-177. https://www.ncbi.nlm.nih.gov/pubmed/27461490
  5. Jacka, F.N, Cherbuin, N, Anstey, KJ et al. Western diet is associated with a smaller hippocampus:a longitudinal investigation. BMJ 2015; 13:215 https://www.ncbi.nlm.nih.gov/pubmed/26349802
  6. Stranahan AM, Norman ED, Lee K, et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middleaged rats. Hippocampus. 2008;18(11):1085–1088. https://www.ncbi.nlm.nih.gov/pubmed/18651634
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Red wine drinkers are generally good-natured people and known for mastering life with pleasure and relaxation. These alone are two protective factors against dementia, because stress is poison for the brain (but more about this later on). In addition, a secondary plant substance present particularly in red wine is increasingly attracting the interest of research and prevention in Alzheimer’s disease: resveratrol.

Resveratrol has numerous biological and pharmacological protective effects and became well-known back in the mid-1990s in connection with the ‘French Paradox’. It stands for the observation that French people live longer than Germans and Americans despite their supposedly unhealthier lifestyle, especially because of their higher alcohol consumption, and that the frequency of heart attacks in France is three times lower than in the USA. In the following years, resveratrol became the focus of research and showed anti-inflammatory, antioxidant, cancer-inhibiting, heart protecting and life-prolonging properties in numerous test models both in vitro and in vivo and was considered a new miracle cure.

Resveratrol and Alzheimer

The first indications that resveratrol could also be responsible for the protective effect of red wine in Alzheimer patients were shown by epidemiological studies conducted by a French research group in 1997, which showed an inverse correlation between moderate wine consumption and the occurrence of Alzheimer’s disease: in the group of moderate wine drinkers (250 – 500 ml per day) the risk of dementia was reduced by a factor of 5.

It showed that resveratrol not only unfolds its positive effects in a single way, but also has a multi-mechanistic effect. It has a beneficial effect on various processes, all of which play a decisive role in the development of Alzheimer’s disease:

  1. reduction of amyloid plaques 
  2. reduction of neurofibrillary tangles 
  3. regulatory role in autophagy processes 
  4. anti-inflammatory effect 
  5. antioxidant effects

Detailed explanations on these topics can be found on the page: Resveratrol

Clinical studies

Based on these convincing results, the therapeutic potential of resveratrol in Alzheimer’s patients is currently being tested in clinical trials. Two recent pilot studies have shown that resveratrol can easily cross the blood-brain barrier in humans and penetrate brain tissue – as it has been detected in cerebrospinal fluid. Resveratrol was well tolerated by all volunteers and had no side effects up to a dose of 5 grams per day. Both double-blind studies show evidence of positive effects of resveratrol in humans. 

In addition, resveratrol is already part of the multifactorial approach of the American neurologist Dale Bredesen, who, with his therapy known as ‘ReCode’ (Reversal of Cognitive Decline), has managed to clinically reverse Alzheimer’s courses in early stages (see also the interview with Dr. Bredesen in the media library).

Conclusion:
Whether fed with a glass of red wine in the evening or by other non-alcoholic means – but preferably from natural sources – the secondary plant substance resveratrol appears to be responsible for protective effects in the development of dementia due to its diverse mechanisms of action. It could therefore be a promising preventive and possibly therapeutic approach in the fight against Alzheimer’s disease.

In this sense: treat yourself to a glass of red wine or grape juice in the evening and enjoy life. Your grey cells will be grateful!

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Lanabecestat is a potent inhibitor of Amyloid beta (Aβ) formation – the main component of amyloid plaques. Aβ is formed through cleavage of amyloid precursor protein (APP) by proteases known as secretases (β and γ). The Beta-site-APP-cleaving enzyme 1 (BACE1) cleaves APP at the β-secretase site, after which APP is cleaved by γ secretase to generate Aβ peptides. Lanabecestat inhibits BACE1 and was able to reduce levels of Aβ1-40 and Aβ1-42 in the brain, cerebrospinal fluid (CSF), and plasma in several animal models, as well as in human CSF and plasma. Besides that, Lanabecestat is brain permeable meaning that an adequate amount of this substance is able to reach the brain after oral intake.

Taking these facts into account, two clinical trials were designed to test if the oral administration of Lanabecestat would be effective in two different groups of patients: patients with mild cognitive impairment (the AMARANTH study) and patients with mild AD (the DAYBREAK-ALZ study). The main question in both studies was: can Lanabecestat slow the progression of cognitive deterioration?

Unfortunately, both studies had to be earlier terminated because no benefits were found in the groups using the substance compared with the group taking placebo, only side effects were noted.

The substance was able to reduce Aβ levels in CSF and was associated to a greater reduction in Aβ plaques density compared to placebo. But no positive clinical effect was shown.

Even though Lanabecestat was generally well tolerated, psychiatric adverse events were numerically greater in treatment groups compared with placebo group and were consistent with dose dependence. Lanabecestat exposure was also associated with hair color changes and weight loss. 

Full text: https://jamanetwork.com/journals/jamaneurology/fullarticle/2755347


Conclusion:

In two new, randomized clinical trials, Lanabecestat (a potent Aβ inhibitor) did not slow cognitive or functional decline of AD compared with placebo. One more hope of treatment has failed. It appears unlikely that current BACE inhibitors will be an effective disease modifying treatment for symptomatic AD but future studies are still needed to determine if reduction in Aβ production can provide meaningful clinical benefit in earlier stages of the disease continuum or in other high-risk populations. 

 PREVENTION is still the best solution!

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