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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With the project ‘Knowledge stops Dementia’, the Deutsche Stiftung für Gesundheitsinformation und Prävention, together with the Akademie für menschliche Medizin, presents a broad spectrum of measures to prevent the development of dementia. Within preventive measures, speech therapy offers an important therapeutic component that enables dementia patients to maintain contact with their environment. Especially in the early stages of the disease, no time should be lost and no one should hesitate to seek speech therapy treatment. 

A guest article by speech therapist Karen Grosstück from Hamburg

In the course of dementia, many people affected by the disease suffer from problems in finding words, often also problems in understanding complex texts. The change in communicative skills often makes the everyday life of patients and caregivers very difficult. It is a complicated situation for the people concerned and also represents a major challenge for the social environment. Difficulties in communication can affect the relationship between partners or family members and  in the course of time, can also complicate care and support.

If you search for the right word more and more often, you might ask yourself: am I just dizzy or is it already the beginning of dementia?

Difficulty in finding the right word does not necessarily mean the beginning of dementia, but there are typical language symptoms and communicative problems in Alzheimer’s dementia that occur early on. 

These include:

  • Affected persons digress in conversation, abruptly change the topic or prefer to stick to recurring topics
  • Those affected show less and less motivation to initiate conversations or to participate in conversations in everyday life
  • Expressions become increasingly lacking in content
  • Word-finding disorders make it difficult to formulate your own thoughts
  • Language comprehension problems lead to misunderstandings in daily life
  • Conversation contents are quickly forgotten

This is where speech therapy can help. Speech therapists support people with dementia in their ability to communicate and advise relatives in dealing sensitively with altered communication skills. 

What do speech therapists do? 

Speech therapy deals with disorders of speech, speaking, voice and swallowing in children and adults. Speech therapists determine whether such a disorder exists and know how to treat it. After a diagnosis, treatment and consultation follow with the aim of improving the quality of speech, language, voice and swallowing. Speech therapy is a medical remedy and can be performed on an outpatient basis, as prescribed by the physician, or as part of an inpatient treatment. 

What exactly can speech therapy do for people with dementia in particular?

In cases of dementia, speech therapy can cover both speech and swallowing. Logopaedic services should therefore maintain the communication and the nutritional situation, under changed conditions, in the best possible way. The treatment is always based on the everyday life of the person affected and takes into account his or her previous life as well as the current life context. Already at the beginning of the illness, logopedic consultation and preventive offers can help to prevent communication disorders. 

The prerequisite for contact with a person with dementia is an exclusively resource-oriented view. Since learning in the classical sense can no longer take place, it is necessary to discover new possible approaches and adequate them to the patient, in order to support and maintain the abilities as long as possible. The most important resource here is often nonverbal communication. Communicative skills such as facial expressions, gestures and speech melody can remain stable for a long time in Alzheimer’s disease. Thus, the important principle in conversation is: It is more important how something is said and less important what is said. Principles such as “the tone makes the music” and “relationship before content” characterize communication with a person with advanced dementia.

What are the goals of speech therapy for dementia?

  • The preservation of the highest possible communicative independence of the affected person
  • The participation of patients in social life
  • The best possible quality of life for the affected person as well as relief, support and advice for relatives

The earlier a person with dementia has the opportunity to express his or her language problems and work on them in a logopaedic therapy, the more he can benefit from it in the future. Especially at an early stage of the disease, many people try to hide their language deficits, hide word finding disorders and thus get into additional stress situations. Here it helps to be able to discuss the problems with a speech therapist in a protected setting. For many of those affected, it is important to write down their thoughts or biography at this early stage of the illness. Speech therapy can make it possible: it works with the emotional abilities and cognitive reserves of a person and uses the neuronal plasticity of the brain, which is still possible in the case of dementia. 

Where can you find more information and help?

Unfortunately, the benefits of early logopedic treatment for people with dementia are still not widely known. Often patients come to speech therapy too late and are no longer able to benefit from speech-activating treatment. Therefore, it is important to us to point out this largely unknown but extremely effective therapeutic option in the course of the project Knowledge stops Dementia. You can find out more about the topics covered by speech therapy, the methods used in speech therapy, how swallowing can be supported and much more in the brochure ‘Speech Therapy and Dementia’ by the Arbeitskreis Logopädie Demenz Hamburg in cooperation with the Alzheimer Gesellschaft/ Kompetenzzentrum Demenz Schleswig-Holstein. 

Current addresses of speech therapy practices in your area with a focus on dementia treatment can be found at https://www.dbl-ev.de/service/logopaedensuche/ and on our website under Knowledge stops Dementia

To the author:

Karen Grosstück works as a speech therapist with a focus on neurological speech and language therapy. She runs a private practice for speech therapy and nutrition in Hamburg. Further information can be found here.

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The fact that our health begins in the gut has been known for thousands of years. Today it is clear that our intestines are more than just a “digestive tube”, as this important organ fulfils a variety of other functions. For example, a disturbance of gut health is directly related to the development of chronic diseases.

 The intestinal flora, i.e. the microbial colonization of the intestinal mucosa, plays a particularly important role in this process. The intestinal flora is also known as the ‘intestinal microbiota’. It is the most important part of our immune system and thus offers us effective protection against infection.

But what few people know is that a correctly composed intestinal flora is also essential for our brain health, as it is directly connected to our nervous system via the intestinal-brain axis. An imbalance in the intestinal flora can lead to devastating consequences for the nerve tissue and in the worst case can cause neurodegeneration and dementia.

Alterations in the composition of the gut microbiota, caused by dietary changes, antibiotic exposure, and infection lead to the loss of the physiologic balance, which is implicated in the development of several diseases in humans, including Alzheimer’s disease. Recent evidence points to a causative link between changes in the intestinal microbiota composition, along with inflammatory changes in brain tissue. Hence, gut microbes may alter the level of neurotransmitter-related metabolites, affecting gut-to-brain communication and/or altering brain function.

Many studies on animal models have provided strong evidence of the importance of microbiota in the pathology of Alzheimer’s disease. Interesting results have been obtained, for example, with mice reared without intestinal microbial colonization and therefore without intestinal microbiota. These ‘aseptic’ mice showed an increased permeability of the blood-brain barrier (BBB) compared to mice with normal intestinal flora. This means that pathogens and other harmful substances from which the brain with an intact BBB is normally protected, are now able to enter the brain tissue. This can lead to an inflammatory reaction in the central nervous system called neuroinflammation, which is directly linked to the development of Alzheimer’s disease (see section causes for further information).

Such results obtained in animal models have also been confirmed by clinical studies:  For example, the intestinal microbiota of elderly people suffering from cognitive disorders was investigated, and an association between plaque deposits in the brain with the occurrence of pro-inflammatory intestinal bacteria and other inflammation markers could be shown.

In summary, all these results provide clear evidence that the effect of the intestinal microbiota on the development of the amyloid pathology may be significant and thus define its important role in the pathogenesis of Alzheimer’s disease.

But the good news is that our gut microbiota is a dynamically modifiable system that is very sensitive to lifestyle and ageing. With this knowledge, we can use a healthy lifestyle to positively influence our intestinal microbiota and develop practical recommendations for the prevention and treatment of Alzheimer’s disease.


Are you curious and would like to know more about this topic? 

To support the project ‘Knowledge stops Dementia’ (https://kompetenz-statt-demenz.de/en/) the Academy of Human Medicine (AMM) has developed a fact sheet on dementia and intestinal health, which provides you with an evidence-based but compact overview of the above described relationships.

If you are interested in this fact sheet, it would be best to take part in the AMM’s current fundraising campaign for KSD.

Click here for the current AMM fundraising campaign… 

And don’t forget: healthy gut, healthy brain!

We thank you in advance for your support!

Your KsD team

References:

  1. Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7(1):13537.
  2. Harach T, Marungruang N, et al.  Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017 Feb 8;7:41802. 
  3. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer’s Disease. J Neurogastroenterol Motil. 2019;25(1):48‐60. 
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Not everyone grows old the same way. The occurrence of dementia is also not the same in every person. While some people can live longer with good cognitive function and no signs of memory loss (even in the presence of severe neurological disease), others suffer from cognitive and memory impairment without so many brain damages in neurological tests. 

The cognitive reserve (CR) hypothesis has been posed as a compensatory mechanism to cope with age- related brain damage and to explain the  interindividual variability in the ability to maintain cognitive function in the presence of brain disease.

To put it simply, some people have better cognitive reserve than others and are able to protect their brains from disease, including dementia. It can be explained by neuroplasticity, i. e., different parts of the brain are able to reproduce the same function, so in case of damage to one region, the function would be rerouted to another healthy region.  People with greater cognitive reserve are more likely to make this kind of “switch” and, thus, stay cognitively fit. 

Education, higher levels of social interaction and working in cognitively demanding occupations are considered evaluation measures of CR.  However, emerging evidence has suggested that CR is an active construct that develops from continued life experiences. One reserve enhancing factor during a certain period alone could not fully explain the accumulation of cognitive activities over the life course. 

A study published in june 2019 in JAMA Neurology journal has verified the hypothesis that high lifespan CR accumulation is associated with a reduction in clinical dementia risk and has estimated the strength of this association in the presence of brain pathologies.

The authors concluded that a high CR indicator throughout life- encompassing education, early life, mid life, and late life cognitive activities, and social activities in late life –  is associated with a reduction in dementia risk, even in people presenting many signs of  Alzheimer’s disease and vascular pathologies in their brain image examination.

These findings provide more evidence that high CR is a protective factor against dementia. It also shows that accumulative educational and mentally stimulating activities to enhance CR, should be continually encouraged throughout life and might be a feasible strategy to prevent dementia.

If you want to know more about this interesting ability of the human brain and find out how to improve your cognitive reserve, visit the KsD webpage. You can protect your brain and prevent AD!

Conclusion: 

Cognitive reserve is the ability of the brain to tolerate damage resulting from aging, AD or other causes of dementia. The higher the CR, the less likely a person is to develop symptoms of dementia, even in the presence of brain pathological injury. The CR can be improved by mentally stimulating and social activities that promote neuroplasticity and improve cognitive function. New evidence shows that these cognitive stimulating measures should be done throughout life, not only for a period of time, in order to build a strong “lifespan” cognitive reserve. A high cognitive reserve can protect your brain and avoid the symptoms of AD!

Reference:

Xu H, Yang R, Qi X, et al. Association of Lifespan Cognitive Reserve Indicator With Dementia Risk in the Presence of Brain Pathologies. JAMA Neurol. 2019;76(10):1184–1191

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The 2020 report of the Lancet Commission on Dementia Prevention, Intervention, and Care lists 12 modifiable risk factors that could help prevent dementia. This new report provides some important updates to the previous document, published in 2017.

The 2017 report had already recognized that acting on certain modifiable factors could help reduce a person’s risk of developing dementia. These factors are:

  • a lower level of education
  • hearing loss
  • hypertension
  • obesity
  • smoking
  • depression
  • low social contact
  • physical inactivity
  • diabetes

To the original nine factors, the new report has added 3 more:

  • head injuries
  • excessive alcohol intake
  • air pollution

Head injuries – Traumatic brain injuries are usually caused by car, motorcycle, and bicycle accidentes; military exposures; firearms; boxing, horse riding, and other recreational sports, most of them occurring during midlife. Falls are the most common cause of brain injuries later in life.

Excessive alcohol intake – Even though it has been previously shown that low doses of alcohol can prevent cardiovascular diseases, heavy drinking is associated with brain changes, cognitive impairment, and dementia – a risk known for centuries. Drinking more  than 21 units of alcohol per week (1 unit of alcohol=10 ml or 8 g pure alcohol) is  associated with a high  risk of dementia. 

Air pollution – Airborne particulate pollutants accelerate neuro- degenerative processes through cerebrovascular and cardiovascular disease, Aβ deposition, and amyloid precursor protein processing. High nitrogen dioxide (NO2) concentration, fine ambient particulate matter (PM)  from traffic exhaust and PM  from residential wood burning are associated with increased dementia incidence.

Together, the 12 modifiable risk factors account for around 40% of worldwide dementias, which consequently could theoretically be prevented or delayed. 

It is clear that the contribution of risk factors to the development of dementia begins early and continues throughout life, so it is never too early or too late to initiate any measures that will mitigate the negative effect of the 12 risk factors. Changes in any risk factor alone can prevent or delay dementia symptoms and should always be encouraged.

What can be done?

Preventive actions require both policy and individual engagement. Public health programs should be developed to increase social, cognitive and physical activities and to improve cardio-vascular health.  

Furthermore, the entire food system (including production and marketing) should be revised and changed: the goal is to stimulate the consumption of natural and nutritious foods and to reduce the consumption of sugary and ultra-processed foods.

Public health programs should be offered to the general population (with special attention to high-risk groups), including:

  • hypertension and diabetes treatment in midlife
  • prevention of head injury through traffic awareness campaigns and use of safety equipment at work and sports
  • support smoking cessation
  • reduce air pollution, promoting use of bicycles and public transport. Reduce second-hand tobacco smoke exposure.
  • encourage use of hearing aids for hearing loss and reduce hearing loss by protection of ears from excessive noise exposure
  • provide all children with primary and secondary education
  • support treatment and prevention of depression
  • limit alcohol intake.

At individual level, a healthy lifestyle including a balanced diet, regular physical activity, social and intellectual activities throughout life and prioritizing contact with nature should be sought. 

Conclusion: At this point the project “Knowledge stops Dementia” can help by keeping you up to date on what is known and new about dementia prevention and treatment! On our webpage you find an increasing amount of information covering the topics above, hopefully supporting you in the implementation of personal measures for prevention and recovering.

We are happy to support you in living a healthy life and minimising your personal risk of dementia. At the same time, we also offer support for your loved ones who are already suffering from some form of dementia. Don’t forget to register for our newsfeed! Not only you but also your children and grandchildren can only win!

Photo by Deva Darshan on Unsplash

Reference:

Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446.

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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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Although scientists have known for a long time that apolipoprotein E4 is a leading genetic risk factor for Alzheimer’s disease, it has long been unknown how exactly it leads to memory loss. US researchers now believe they have an answer. 

The gene Apolipoprotein E (ApoE) encodes an important lipid carrier protein in the brain, which is present in three different variants: ApoE2, ApoE3 and ApoE4. As with almost all genes, humans carry two copies of ApoE, which can be either the same or different variants. Compared to the most common ApoE3 variant, ApoE4 significantly increases the risk of Alzheimer’s: it is 4-fold higher in people with one copy of ApoE4 and up to 15-fold higher in people with two copies of this variant. Alzheimer’s patients who carry ApoE4 are more likely to develop symptoms of the disease earlier than carriers of other variants of ApoE (1). Read more about this in the chapter ‘Genetics‘.

This so-called late-onset Alzheimer’s disease is the most common form of dementia and is characterized by the extracellular accumulation of misfolded amyloid-β (Aβ) and intracellular aggregation of Tau proteins to form neurofibrillary tissues in the brain. It was long thought that the ApoE4 gene variant favours Aβ and Tau accumulation and thus contributes to the faster onset of Alzheimer’s disease. However, it is now clear that other damaging processes also play a role. For example, changes in the blood-brain barrier (BBB) have been shown to be early markers of this neurodegenerative disease. The degree of BBB dysfunction correlates directly with the extent of cognitive impairment, but which factors are responsible for its degradation was previously unknown. There is, currently, growing evidence that ApoE4, the leading genetic risk factor for Alzheimer’s disease, is related to BBB degradation (2).

But what exactly happens to the BBB and how is this in turn related to ApoE4 and the Aβ and Tau accumulation? 

To fill this knowledge gap, the permeability of the BBB in healthy people and in patients with mild cognitive impairment was investigated and the results were correlated with their ApoE status. The researchers found that people who were cognitively healthy and carried either one or two copies of the ApoE4 variant had leaking BBBs in the hippocampus and parahippocampus – brain regions that play a role in memory formation and are involved in learning processes. This leaky BBB was more pronounced in ApoE4 carriers who suffered from a slight cognitive decline. In contrast, the BBB was intact in cognitively healthy ApoE3 carriers;  But ApoE3 carriers who already showed cognitive impairment, presented also a leaky BBB.. Remarkably, these effects preceded all signs of tissue loss in  affected brain regions, confirming that BBB dysfunction is a very early event in the onset of neurodegeneration, meaning that the integrity of this important barrier is lost before cognition weakens (3).

Follow-up studies have shown that BBB damage in ApoE4 carriers is associated with pericyte degeneration (2). Pericytes border on the endothelial cells are cells of the inner walls of the blood vessels, and thus protect the brain capillaries. They normally maintain the integrity of the BBB by preventing the breakdown of the connections between endothelial cells that make up the capillary walls (3).  Pericyte destruction observed in ApoE4 carriers was independent of the accumulation of Aβ and Tau (2).

The mechanism of pericyte damage is now also known: these cells secrete the ApoE4 protein, which activates the protein cyclophilin A (CypA). This triggers a downstream signaling pathway that involves the activation of the inflammatory protein matrix metalloproteinase-9 (MMP9) in pericytes and possibly also in endothelial cells (4). This leads to an interruption of the connections between adjacent endothelial cells, which ultimately results in the disruption of the BBB in the hippocampus and parahippocampus. This mechanism is illustrated in the following figure (modified after Ref. 4):

Illustration Gen

These observations thus shed new light on ApoE4, and contradicts the widely held idea that this gene variant contributes to Alzheimer’s disease simply by promoting Aβ and Tau accumulation. 

Instead, the malfunctioning of the BBB seems to be responsible for the fact that ApoE4 carriers are susceptible to Alzheimer’s disease. This would also explain why ApoE4 carriers have a worse prognosis after a stroke or craniocerebral trauma than carriers of other ApoE variants (5). 

Interestingly, these early mechanisms that trigger the cognitive impairment seem to be different among  ApoE4 and ApoE3 carriers. It is possible that activation of the CypA pathway and damage to pericytes in ApoE3 carriers are not  involved in cognitive impairment. However, it remains unclear, whether a leaking BBB caused by pericyte-independent factors such as endothelial cell damage by Aβ (6) contributes to cognitive impairment in ApoE3 carriers . Many other questions also remain unanswered, such as whether and how BBB degradation directly leads to cognitive impairment, or whether it is a cause or a consequence of the disease process. The role of the BBB in ApoE2 carriers, which was not investigated in the present study, is also still unknown. But the research results shed more light on understanding the role of the ApoE4 gene. It may be possible to diagnose people  with the ApoE4 gene at an early stage  by examining the brain vessels, and individualized   therapy approaches could be taken early to effectively counteract premature cognitive decline. 

Conclusion: 

Damage to the pericytes that protectively surround the brain capillaries and seal the blood-brain barrier leads to a decline in cognition. In people with the gene variant ApoE4, this breakdown of the blood-brain barrier appears to be accelerated via an inflammatory pathway. This damage to the brain capillaries occurs at a very early stage, even before the tissue loss in the hippocampus occurs and cognition decreases. These new findings may offer the chance of early diagnosis in high-risk patients via the brain vessels, which is a promising approach in the fight against premature cognitive decline.Furthermore, they reinforce that the breakdown of the blood-brain barrier is the triggering mechanism in the pathophysiology of Alzheimer’s disease, being the accumulation of  Aβ  and Tau, secondary events.  

References:

  1. Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C. & Bu, G. (2019): Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature Rev. Neurol. 15, 501–518
  2. Montagne, A. et al. (2020): ApoE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 71–76
  3. Profaci, C. P., Munji, R. N., Pulido, R. S. & Daneman, R. (2020): The blood–brain barrier in health and disease: Important unanswered questions. J. Exp. Med. 217, e20190062
  4. Ishii, M. & Iadecola, C. (2020): Lipid carrier breaks barrier in Alzheimer’s disease. Nature 581, 31-3
  5. Mahley, R. W., Weisgraber, K. H. & Huang, Y. (2006): Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc. Natl Acad. Sci. USA 103, 5644–5651
  6. Cortes-Canteli, M. & Iadecola (2020): Alzheimer’s Disease and Vascular Aging  C. J. Am. Coll. Cardiol. 75, 942–951

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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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