Alzheimer’s disease – news from battlefield. Part 1

Alzheimers disease – news from battlefield. Part 1

Dariusz Stępkowski

Transcript of the lecture for ?Station Alzheimers  from 24 July 2013

Number of the  cases of Alzheimers disease (AD) worldwide is estimated to be higher than 30 million persons. The United States of America are one of the countries with the highest prevalence of Alzheimers disease. In the first part of my presentation I would like to discuss  the possible  causes of AD epidemics in this country. Conclusions drawn from this analysis may help to understand the causes of the increase  in AD incidents in  other countries around the world.  In the second part of this presentation I will suggest practical activities which can be undertaken to reduce the burden of this disease as on a scale of whole population as well to help individual patients.

Alzheimers disease is a disease of complicated origin ? what does it mean?

Let us start from the statement that the causes of the development of AD remain unknown. Certainly there are many of them. These causes lead to the accumulation of toxic beta-amyloid in extra-cellular spaces in brain. This process is a start point  of cascade of  events leading to the loss of ability to memorize, dementia, death of neuronal cells and at the inevitable end the death of patients. Most probably this process starts about  twenty years before the first symptoms of the disease.

To understand Alzheimers! Intra-cellular network. Homeostasis

To understand  the nature of these preliminary processes leading to AD pathology I would like to  introduce the concept of intra-cellular network. This network consisting of above 20000 proteins (nodes) encoded in our genome, present in every cell of our body, has one property that allows  the organism to survive in changing environment. This property is the ability to maintain homeostasis ? the ability to respond dynamically to chemical, physical, biological and psychical stimuli in order to preserve basic functions that  allow for  the  survival of the organism. Although the nature of this network is very complicated,  for the purpose of understanding processes leading to Alzheimers disease, we may apply the simplification of the network as two dimensional network consisting of spheres connected with springs. Such network is constantly vibrating due to external stimuli. As a result of aging the ability of the network to respond dynamically to stimuli is reduced, with large parts of the network being constantly activated whereas others, being inactive.  One may say that, the ability of the network for homeostasis is reduced with aging.

Kinds of network`s rigidity. Disease as a logistic  problem

Such disturbance of the ability to maintain homeostasis can be imagined as the loss of  the flexibility by  the network. What are the causes of this gain in rigidity? There are two kinds of disturbances in flexibility: innate and acquired. The innate rigidity is encoded in our genome . Every one is in this regard differentially equipped  at the start point of fertilization of oocyte by sperm. This potential basic ability to maintain homeostasis remains constant during life time with the exception for changes in DNA  occurring in single cells of our body under influence of harmful factors. These local changes may eventually lead to  the development of cancer but rather cannot be considered as a cause of Alzheimers disease. Conversely, when one consider acquired rigidity – during our life time under influence of external stimuli, so called epigenetic profile of our cells is changing. This epigenetic profile affects the ability to  read the DNA encoded information in  particular genes and affects the dynamic synthesis of proteins encoded in those genes. This has profound influence on the ability to maintain homeostasis. Epigenetic profile, in contrast to locally occurring mutations, has more overall range in our organism, however some differences exist between organs, tissues and individual cells . Epigenetic profile depends in significant extent on the dietary history. In contrast to the rigidity  of the network encoded in DNA, the epigenetic profile can be partially modified by changing the diet to proper one ? promoting health. The gain of rigidity  inside  the  network leads to logistic problems ? for example in case of Alzheimers disease leads to excessive accumulation of toxic beta-amyloid. In the framework of presented theory any disease can be considered as such logistic problem. In certain places of organism exist either timed or constant excess or deficiency of certain compounds, or substances.

How many nodes of network are rigid in Alzheimers disease?

The action of many drugs is targeted towards single nodes of our intra-cellular network. The pharmacological action of inhibitors of  acetylcholinesterase that are used for the treatment of Alzheimers disease is a good example of such targeting. Acetyl cholinesterase inhibitors reduce the ability of this enzyme  to process acetylcholine –  a neurotransmitter  –  substance used by neural cells to communicate with each other. Patients suffering from AD are characterized by the deficiency of this neurotransmitter in their brains. Due to the action of acetylcholinesterase inhibitors the level of acetylcholine  gets higher and  this leads to the improvement in brain performance. However, although attenuating the symptoms of the disease,  acetylcholinesterase inhibitors do not cure the causes of Alzheimers.
When one consider the effectiveness of therapy, an important  question arises –  how many of nodes of intra-cellular network are disturbed in Alzheimers disease? It is known that depending on applied criteria this number is estimated to be in the range between  few hundreds to more than thousand. Luckily, not all of the nodes are equally important. There are some which are steering the action of many others (the hubs) and  others which steer the hubs (the higher order nods ? let us call them ? the drivers?). These two types of nodes presumably should be the targets of drugs. Based on the knowledge elaborated by new discipline ? the systems biology we may estimate this number with reasonable probability as being in the range between 2 and 10.

What should be the strategy of AD therapy?

The strategy of  drug action targeted to one node is therefore under questioning. In the situation when science does not know yet  what should be the target and how many targets should be attacked by drugs, it is worth to consider why certain kinds of diet promote prophylaxis of Alzheimers disease. Diet by its nature acts in multi-factorial way,  and influence large number of nodes and what is more, influence the ability to dynamic activity of the whole network by changing its epigenetic profile.

The Mediterranean diet is healthy!

The Mediterranean  diet is known for its positive influence on health. This diet is rich in vegetables and fruits, characterized by low consumption of animal fat, high consumption of fish and sea food, plant oils (especially olive oil) and moderate consumption of alcohol. Before we will consider what components of this diet are beneficial for health, let us consider how any diet influence our organism in general.

How diet influence the homeostasis of intra-cellular network?

The diet that we consume consist of thousands of compounds having potential biological activity. Deciphering of their influence on health is even more complicated  when one consider the fact that the derivatives originated from their metabolism may also be bioactive. Some of these compounds will promote health, contrary to others that may  be harmful. Co-presence of many of these compounds will also be important for maintaining the ability for homeostasis to favor the persistence of health . Therefore, our proper dietary choices  should be based on results of epidemiological studies relating consumption of certain foods with lowered risk of developing Alzheimers disease. The proper proportions and amount of certain dietary stimulants of our ?intra-cellular network? can be effective in ?programming? this network in such a way that may be beneficial for our health and to some extent protect from or slow down the progression of AD.

What components of diet are essential for prophylaxis and therapy of Alzheimers disease?
For those reasons, the determination of the proper dietary components is of great importance when one consider the efficient prophylaxis and therapy of Alzheimers disease.

Source:  Prepared from data in National Vital Statistics Reports 2001-2012

To begin, let us take a look at data concerning the death rates of  Alzheimers disease in USA. The curve of increase of death fatalities of Alzheimer’s disease adjusted for the distribution of  age groups in population after quick increase of deaths at the beginning of considered period of time is showing the tendency of lower increase to stabilize in the last period even showing some signs that  the trend may reverse. For all the analyzed  years was used the same system for the classification of the causes of death from Alzheimers, therefore there is a chance that the reversal of the trend is real not just statistical fluctuation. However we have to wait for  data from 2012 and 2013 to be sure. Explanation what caused the increasing trend to stop and eventual reversal of it, is therefore of great importance for elucidating the role of factors influencing Alzheimers disease prevalence and death rates. It should be stated that crude  – not age-adjusted data of death rates also show the slowing increase of death rates but without stabilization of the level  and eventual reversal of the trend. This difference between age-adjusted and not adjusted data is a clue allowing to conclude that we are observing  relative decrease of  death rates among the oldest groups. Elucidation of this phenomenon is probably possible by considering the changes in life style of the Americans, mainly diet.
Alzheimer?s disease ? wzrost zachorowan
Source: Prepared from data from NCHS E-Stats 2008

Obesity in midlife  is a known risk factor for developing Alzheimers disease in the last periods of life. Let us think about the increase in  percent of USA citizens aged 20-74  considered to be  in three categories taken together: over weighted  and   people that are obese and extremely obese. It can be noticed that the number of such  people is quite steeply increasing, this factor may have influence on the death rates for Alzheimers disease in the following years. However, how the  slowing tendency of increase of death rate and  suspected reversal of this trend in last years can be explained together with constant increase of number of people with weight above the normal in the population?

The analysis of dietary history of the population of  Americans

The question about the causes of changes of death rates trends for Alzheimers disease can be answered in view of  the analysis of dietary history of the American population. I have performed such analysis together with Grażyna Woźniak  from the Nencki Institute. We used publicly available statistical data from US governmental agencies. Whole description of this analysis and conclusions will be published in a manuscript currently being  under preparation. Now I am going to present only the most important conclusions that we have drown, based on the presented above theory and obtained by us and other scientists results. We hope that our conclusions will help the patients to undertake immediately measures which may in our opinion slow down the progression of disease.

List of the most important components of anti-Alzheimers diet

  1. Vitamin D
  2. Right proportions between consumed kinds of food, especially fatty acids
  3. Fresh vegetables and fruits
  4. Moderate consumption of alkohol

Other conclusions:
Avoidance of excess of calories
Supply of proper amounts of micro-nutrients

This  slide presents components of diet  that are most important for the prophylaxis and therapy of Alzheimers disease. Among them: vitamin D, proper ratio of different fatty acids, fresh vegetables and fruits, and moderate consumption of alcohol are of the great importance.  The predicted link between vitamin D deficiency and the increased death rates due to Alzheimers disease is further supported by the data showing the relation between higher potential exposure to sun (number of sunny hours in the particular states) and reduced AD death rates in particular states of the U.S.A. As can be seen our conclusion about proper diet, that is based on the analysis of dietary habits of whole population of United States,  is roughly consistent with what is characteristic for Mediterranean  diet. Information about optimal quantities of important for maintaining of health diet components, will be presented in the second part of the presentation.  The other conclusion from the performed analysis stress the adverse effects of diet characterized by the excess calories intake which may favor the development of AD. Good news are that this  negative effect of caloric overload can be partially abrogated by keeping the proper balance between different diet components. The diet characterized by the huge calories intake but also diversity of  food components will be not as unhealthy  as the diet lacking such ?golden balance?. Not only macro-component intake but also supplementation with micro components is very important for both prophylaxis and therapy of Alzheimers disease.
The novelty that arise from our analysis is highlighting the important role of vitamin D together with other enumerated factors in the prevention of AD development.  Our analysis support the hypothesis that the adverse effects of bad diet kept from early childhood till old age can be partially limited by changing the dietary habits by the old people which may improve the quality of their life as the patients and even slow down the progression of the disease.

Is it possible to reduce the risk of developing the disease and influence its severity by changing the dietary habits?
The answer to the question whether we can reduce the risk of developing the disease  and slow down its progression  by changing the diet  is ?YES?


 I would like to thank  my wife and son for constant support in life and work, Grażyna Woźniak my colleague from Nencki Institute for valuable help and working with me on this project, scientist colleagues from other countries whose work although not cited in this presentation was an inspiration to start the research and to the interpretation of results, Alzheimers Association for passion in inspiring for help, American agencies FRED, USDA and CDC  for providing publicly accessible reliable statistical data amenable for our analysis,  my son Tomasz for valuable comments and help in writing the English version of the presentation, my wife Barbara for valuable comments and proof editing of polish version  of the presentation, family and friends and  all helpful people,  especially colleagues from Nencki Institute, Nencki Institute for more than 30 years of financing my research, Station Alzheimers for the opportunity to present my conceptions and results to the most interested in the Alzheimers disease auditorium and staff of  Alzheimers Center in Warsaw for care of one of my family members in a daycare facility and where I have also  the possibility  to  contact also other patients which  is a constant stimulation for further work.

Associate Professor Dariusz Stępkowski PhD, DSc  is an employee of Nencki Institute of Experimental Biology, Polish Academy of Sciences in Warsaw. His scientific interests concern studies in the fields of molecular motors, processes of amyloidogenesis occurring in Alzheimers disease and a set of other diseases including: prion diseases, Parkinson’s and Huntington’s diseases and molecular causes of Alzheimers disease.