I am honored to share my thoughts on Alzheimer’s disease and other neurodegenerative disorders. I will begin with a short quote by Ralph Waldo Emerson, who said “Memory -without it all life and thought were an unrelated succession. As gravity holds matter from flying off into space, so memory gives stability to knowledge. It is the cohesion which keeps things from falling into a lump. It gives continuity and dignity to human life. It holds us to our family, to our friends.”

Emerson, a great American essayist and philosopher, wrote this in 1879 when he was 76 years old. This was six years before he died with dementia. Perhaps he knew that his memory was failing. Memory is a uniquely valuable resource which allows us to proceed with life’s tasks. The loss of our memory functions is a great tragedy for each person affected, as well as for their families. Memory problems are also an enormous global tragedy, because the commonest cause of memory failure is Alzheimer's disease, which affects as many as 5% of people over 60, and 30-40% of persons over 85. The World Health Organization estimates that Alzheimer disease effects ~ 50 million worldwide with a societal cost of US$ 818 billion per year.

Alzheimer’s wasn’t identified until 1907 as a specific cause of dementia. A person has dementia when he/she has difficulty with memory, language, visual spatial functioning, perception, abstraction, general information and behavior. The word dementia is merely a classification of symptoms and signs and is not a disease in itself. The term senile dementia, though less commonly used, refers only to a person having dementia over the age of 65. Senile dementia or dementia is not a disease. Hence you know immediately that if any doctor ever reports that “senile dementia” is the diagnosis of a loved one, they should know better. Every patient needs to have a specific diagnosis .

Alzheimer’s disease is the commonest cause of dementia in North America and Europe. We now know that it is associated with deposits in the brain of a substance called amyloid beta, which can be referred to as just amyloid. The word amyloid means that it is a protein which is composed of amino acid chains that are very tightly bound to one another. They are very stable and difficult for the body to digest and in the intermediate forms amyloids are toxic and kills neurons. Interestingly, silk is also an amyloid protein and the physical-chemical characteristics are the same. But it is a different protein with a similar structure .

The most important word with regards to ageing is balance. Because after all, isn’t ageing inevitable?Everybody ages. Yet, that is actually quite wrong! Everybody ages in the sense that we all are aging from one day to the other; we are now one day older than we were yesterday. However, to give an example, Princess Diana (1961-1997) is not ageing. Many of you undoubtedly have had loved ones who died long before their time; before they had an opportunity to get old. So one should not consider ageing to be something that happens to everybody; simply because many people are not blessed with the chance to grow old! And those who do should consider it an opportunity. It is an opportunity to make as much of the aging process as possible, to maintain function as long as possible, and to maintain the highest level of health function in absence of disease. Aging is thus not something that is inevitable awaiting all of us; but it is an opportunity.

My research group amongst others have shown that hypertension, diabetes, stroke, obesity, physical inactivity, lifetime of mental inactivity, low levels of education and head injuries, alongwith low levels of consumption of fruit and vegetables and a high fat diet are all risk factors for Alzheimer’s disease. Many of these factors are potentially modifiable- there are things we can all do to lower our risk of getting the disease.

There are also genetic risk factors. But only ~1% of cases of Alzheimer are caused by a gene. These usually occur before the age of 65. The most important genetic risk factor for the disease deals with fat metabolism. This is a good cue to us that diet and metabolism are important. So, it is important to avoid obesity and high fat diet. The vast majority of the cases of Alzheimer’s disease are sporadic (not inherited).

When I consider the opportunity of aging, I suggest that everyone have three goals. This does not apply only

1. 1-Firstly: “not dying”. That’s a reasonable goal – we all agree that we prefer to be alive and prefer to survive to be old
2. 2- We prefer not to have diseases – we want to be free of cancer, heart disease and numerous other ailments. However, I add a third goal which is equally important:
3. 3- To maintain the highest level of functional capacity. I call it “salutogenesis”, arising from the Latin root, salut “health” the creation and maintenance of health.

The goal of aging is not only not dying, and not being sick, but also being healthy. Ifone gets a disease when one is old,the influence that the disease has on us depends on how healthy we are. The manifestations of brain disease in aging are not caused only by the impairment of brain tissue, and not only by the decline of brain function, but by one’s reserve capacities. The reserve capacity is the ability of the body to preserve health in the face of challenges.

I suggest that all of us possess four reserves:

1. 1-cognitive reserve (also called cerebral, brain reserve or resilience),
2. 2-systemic (also called physical reserve),
3. 3-psychological and
4. 4-social reserves.

The risk of Alzheimer’s disease can be lowered by enhancing each of these 4 reserves. For example, people who have had a stroke are at a higher risk of getting Alzheimer’s disease or vascular dementia, even if it is a relatively minor stroke. About 20 to 30% of older personshave had a silent stroke [where they were not aware that they had it]. Hypertension is a risk factor for the stroke and thus it is important to monitor and control hypertension. Head injury is a risk factor, even with minor injuries, and thus attention has to paid to avoidance of all head injuries.

The best model here may be Olympic sprinters. If they had to carry a 50lb packs on their back, they would still be able to run fast. Function would decline, but the decline would be less that the decline suffered by a person who was less fit who had to carry a 50lb pack on his/her back. That is because of the greater systemic reserve capacity of the Olympic athlete.

Unfortunately,although Alzheimer’s disease is the most common form of dementia,several studies have shown that many people have the disease manifestations at a cellular level in the brain, but they do not manifest symptoms of dementia. The explanation for this can be that the capacity of their reserves, including their physical function, psychological makeup, their social environment and cognitive reserve was high. It is thus important that we all pursue a life which involves learning and high levels of physical and mental activities from the time weare young, through the middle and later ages. For maintaining social reserve, it is helpful for people to be in supportive environments at all stages of life, and to deal with stress as well as possible.

At the University of Louisville, my research group involves scientists in the department of neurology, biochemistry, pharmacology and medicine and we have collaborators in several universities in the United States, Japan and in England. We are investigating what causes the initiation of dementia; particularly Alzheimer’s and also Parkinson’s disease.

A good example of the power of prevention is the comparison between the disease in Africa and in North America. My colleagues and I have studied Alzheimer’s disease in Cleveland and also in Kenya in the Kikuyu tribe[the largest ethnic group in Kenya],in Arabs living in Israel and also inAfrican American and white subjects in Cleveland and Louisville. We and others have found that Alzheimer’s disease is less common in black Africans and more common in African Americans. It is likely that the difference is not genetic [there is no reason to think that the genes of Africans are greatly different from the genes of Africans-Americans]. The clue is that obesity, stroke, heart disease, diabetes, and hypertension are all uncommon in elderly Africans and yet common in African Americans. The difference is because of environmental factors involving diet and lifestyle.

The best way to understand this interaction is to consider the millennia of human evolution. Each of us have ~20,000 genes. The reason we have these genes is because they were adaptive for our ancestors for the past ~100,000 years of human evolution. They were selected because of their adaptive value, but this selection happened in a different environment when our ancestors were hunter gatherers. They were not selected because they were adaptive in our current environment and lifestyle replete with remote controls, cell phones, computers, refrigerators and cars! Our genes evolved at a time when every person had to be very physically and mentally active. Because we needed to pay attention: if we wanted adrink of water we had to go out to get it from the water source; and we had to pay attention to the time of day, weather, to the animals who might also be there and may have harmful intent. Thus, genes that are in us are not helping to protect us from a high fat diet or to protect us from dietary excess; or maintain our health while we lead a sedentary life. Physical activity is really the key to numerous things, including cognitive reserve, as well as systemic, psychological and social reserves. It enhances the production of growth factors in the brain that help to make the neurons resilient and resistant to damage.

The US National Institute of Healthand Agency for Healthcare Research had a consensus conference in 2010 where they considered the evidence of protective factors against the development of Alzheimer’s disease. After reviewing the evidence,they concluded that there is no double-blind, placebo-controlled trial of these preventive factors. Just because there is no convincing evidence, does not mean wecannot make reasonable recommendations. All of usneed to have an intellectually meaningful life, and to be physically active. Whatever one does, it should involve learning and it should involve interaction with other people and involve ideas and thought. When it comes to food habits,our ancestors did eat meat, but only when they were successful in hunting, which wasn’t every day. They ate more grain, more fiber, and more vitamins, less calories, more protein, and less salt. In the population that we studied in Africa where the risk of Alzheimer’s disease was low, the main health problem in aging Kikuyu men was low blood pressure. They rarely had heart attacks.

Considerable recent evidence has shown that our partner organisms residing within us -called the microbiota- are critical for health. These organisms live in our mouth, intestines, ears, nose and on our skin and are comprised mostly of bacteria, but also have fungi and viruses. Theseare with us from birth till death and all of our ancestors for the past 1 billion years have had them. They are vital to our health and fitness, because they contribute to our metabolism, regulate our immune system and help protect us from disease causing organisms. Our microbiota are completely dependent upon what we eat for their food. Therefore, diet is critical in determining the nature of the bacterial population in the gut. Bacteria that eat fiber, which are indigestible carbohydrates found in plants,produce molecules that help to reduce inflammation in the blood. This is critical in aging, because inflammation is apart of heart disease, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and cancer, as well as arthritis. A high-fiber diet is therefore desirable.One cup of cooked kidney beans has 10 grams of fiber and a500 gmof lambhas zero fiber. Brown rice is also important, as it has five to ten times more fiber than white rice. One of my favourite Indian dishes is Rajma and I have become quite adept at making it! So is another incredible Orissa cuisine called Sontula which sometimes can include 7-8 vegetables.

It is tempting to consider the new science of the microbiota in regardto the ancient teaching of Ayurveda. Probiotics are desirable bacteria that are taken as supplements to add to the bacterial populations in the body. The most widely used probiotics are lactobacilli which are found in yogurt. Ayurveda has many teachings suggesting the use of yogurt. Studies have shown that it is possible to change the nature of bacterial populations in the gut by changing diet in a period as short as 2 weeks. When this happens the genes of the bacteria are being altered to enhance health. I call this “gene therapy in the kitchen” and encourage everyone to consider this. By changing your diet you change the genes of your microbial partners living inside you.

Amongst other considerations to improve the immune system, vitamin B12 is very important for the nervous system and it is difficult to absorb sufficient B12 from food if one does not eat meat. Therefore, people who don't eat much meat should have their vitamin B12 levels checked. Also, Indian spices have an important rolein Ayurveda, such as ginger and turmeric which have anti-inflammatory properties. I also believe that it is advisable to consume yogurt every day.

Ralph Waldo Emersonalsosaid,“A man is what he thinks about all day long”, and we could say that about aging. The quality of aging is related to what we think about all day long, what our body is doing all day long, and what we are eating all day long. This includes injuries we subject ourselves to all day long; and how we are able to manage and enhance our physical, psychological, social and cognitive reserve capacities to maintain health with age.

Modifiable and non-modifiable risk and protective factors for development of Alzheimer's disease are shown in the list below. Changes in lifestyle activities should be discussed with your primary care physician.

PROTECTIVE FACTORS FOR ALZHEIMER’S DISEASE

LITERATURE

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Friedland RP, Nandi S. A modest proposal for a longitudinal study of dementia prevention (with apologies to Jonathan Swift, 1729). J Alzheimers Dis. 2013;33(2):313‐315. doi:10.3233/JAD-2012-121459

Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog. 2017;13(12):e1006654. Published 2017 Dec 21. doi:10.1371/journal.ppat.1006654

Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors [published correction appears in Lancet Neurol. 2008 Oct;7(10):867]. Lancet Neurol. 2008;7(9):812‐826. doi:10.1016/S1474-4422(08)70169-8

Stern Y, Arenaza-Urquijo EM, Bartrés-Faz D, et al. Whitepaper: Defining and investigating cognitive reserve, brain reserve, and brain maintenance [published online ahead of print, 2018 Sep 14]. Alzheimers Dement. 2018;S1552-5260(18)33491-5. doi:10.1016/j.jalz.2018.07.219

Zimmer C, Fiber Is Good for You. Now Scientists May Know Why, New York Times JAN. 1, 2018