Richard G. Petty, MD

The Looming Crisis of Alzheimer’s

For those of us who lobby for resources, it is no overstatement to say that Alzheimer’s disease has reached crisis proportions in the United States.

As we are getting older, the incidence, prevalence and mortality of Alzheimer’s disease are all rising.

The 2007 Alzheimer’s Disease Facts and Figures report by the Alzheimer’s Association makes sobering reading. Here are some of the headline facts:

  • Alzheimer’s disease is the most common cause of dementia
  • At the present rate, one in 85 people will have the disease in 40 years
  • There are now more than 5 million people suffering from Alzheimer’s disease, and the report projects an increase of 16 million cases by 2050 unless preventive measures are taken and/or science is able to come up with a prevention or cure
  • One person is now diagnosed with dementia every seven seconds
  • One in every four American families is affected by dementia
  • The incidence of dementia is one in 1,000 before age 65 and one in 20 after age 65.
  • More than $100 billion is spent per year on dementia, which is about 10 percent of all healthcare expenditures

As we have discussed before, the symptoms of dementia may be delayed for 3 to 5 years through healthy lifestyles and behavior modification, and there are many new treatment approaches in the pipeline.

The huge issue is that statistic about one in four families being affected by the disease. And it is a disease: it is not part of normal aging.

Caregivers can suffer terribly.

The Alzheimer’s Association also has some information for those who care for people with Alzheimer’s.

There is also some food information here concerning caregiver stress.

I would also like to direct you to some of the things that I have written here about the wellness of caregivers.

And for everyone, don’t wait until you are thirsty before you dig that well. Work on building you personal resilience and follow the simple lifestyle guidelines that may significantly reduce your risk of developing Alzheimer’s disease.

More Clues to the Biology of Alzheimer’s Disease

Alzheimer’s disease remains a puzzle.

Although there are plenty of people who claim that “The Cause” of Alzheimer’s is… and here you can take your pick of three-dozen theories.

The truth of the matter is that simple explanations – Aluminum, lead, stress, pollution, mycoplasma infections and the rest – fail to explain many of the established observations about the causes of the disease.

From what we know about the genes in the brain, it is highly likely that “Alzheimer’s disease” represents a group of disorders that follow an interaction of sets of genetic and environmental factors.

This notion is supported by a report from investigators at Washington University School of Medicine, St. Louis and several other prominent research centers. The study is published in today’s issue of the journal Neuron and indicates that there a biological link between a protein mutation that causes early-onset Alzheimer’s disease (AD) and a gene variant linked to late-onset AD.

The investigators tried to link the function of two known causative factors in AD. Mutations in amyloid precursor protein (APP) cause early-onset Alzheimer’s disease (AD), but
the only genetic risk factor for late-onset AD is the ɛ4 allele of
apolipoprotein E (apoE), a major carrier of cholesterol in the circulation and in cell membranes.

Previous research has shown that mutations in APP can cause early-onset AD when the protein is “cleaved” or split, producing a short toxic protein that builds up in the brain and kills neurons.

In their experiments with mice and cultured mouse cells, the researchers linked APP to the regulation of apoE and its cholesterol transport function. They found that the normal cleavage of APP in the cell gives rise to a nontoxic fragment (called AICD) that suppresses the gene that produces the cell receptor for apoE, known as LRP1. Crouching in nerve cell membranes, this receptor enables the apoE protein to transport its cholesterol cargo into the cell.

The researchers speculated that the loss of LRP1 function in AD might cause a loss of cholesterol that causes malfunction of neurons.

These observations may turn out to be extremely important. If we can restore the activity of the receptor gene, we might have a new treatment strategy for AD.

Protecting Yourself Against Alzheimer’s Disease

I have a keen interest in healthy aging, and we have talked before about some of the strategies that can help protect you against developing cognitive decline.

New research now shows for the first time that, of all lifelong activities, only a high level of mental or cognitive activity protects against the devastating memory loss of Alzheimer’s disease. High levels of social or physical activity are not enough.

Researchers from the Byrd Alzheimer’s Institute bred mice that are genetically predisposed to developing the pathological changes of Alzheimer’s diseases in their brains.

They then kept the mice in one of four housing environments — high social activity, high physical activity, high cognitive activity, or a single housing control environment and watched them from young adulthood through old age.

When the researchers tested the mice in a battery of memory tasks in old age, only the mice given a lifelong high level of cognitive activity were protected against memory impairment. In fact, these “high cognitive activity” mice performed as well as normal mice that do not develop Alzheimer’s disease. However the Alzheimer’s mice raised in one of the other three environments performed poorly in multiple memory tasks.

Not only was memory protected in Alzheimer’s mice by a high level of cognitive activity, but also brain levels of the abnormal protein beta-amyloid were substantially reduced. This protein, thought to be key for Alzheimer’s development, remained at soaring levels in the brains of Alzheimer’s mice raised in social or physical activity environments. Moreover, the researchers found that only the Alzheimer’s mice raised with high cognitive activity had an increase in connections between brain cells. Alzheimer’s mice raised in one of the other three housing environments had much fewer connections between their brain cells.

The new study is published in the Neurobiology of Learning and Memory Journal.

The lead researcher is Gary Arendash, and he had this to say:

“Our results call into question the earlier human studies suggesting social or physical activity provides protection against Alzheimer’s. Alzheimer’s begins in the brain several decades before any symptoms´ show up. That means adults in their forties and fifties need to make lifestyle choices now to decrease their risk of getting Alzheimer’s disease later.”

This is all correct, but there is still an important question: can we really extrapolate from mice to humans? Mice are social creatures, but not to the same extent as humans beings. The lion’s share of the human brain is dedicated to social activities, so you would expect that social activities will be particularly important in the maintenance of the human brain.

Alzheimer’s Disease: Diabetes of the Third Kind?

Insulin may have some extremely important roles in the mind as well as the body.

Though best known for its role in promoting glucose uptake into cells, insulin has at least five hundred known functions in the human body. For many years nobody was sure whether insulin was important to the brain: neurons in the brain are unusual in that they do not need insulin to enter them. But then we discovered that insulin acts on other important metabolic processes in neurons. In the brain it also does duty as a chemical messenger and as a growth factor, and brain insulin signaling is crucial for the creation of memory. Over the years a number of theorists have suggested that some neurological and psychiatric illnesses could be a result of disturbances in insulin-related processes in the brain.

It is now beginning to look as if they may have been correct.

Some recent evidence has suggested that Alzheimer’s disease and diabetes mellitus share a number of common pathways and Alzheimer’s disease is associated with peripheral insulin resistance.

New research has been published by investigators from Northwestern University in the FASEB Journal – the journal of the Federation of American Societies for Experimental Biology – that may finally nail down the reason why insulin signaling may stop working in Alzheimer’s disease.

The research team used mature cultures of neurons from the hippocampus of the brain to study synapses – the connection between neurons – that have been implicated in learning and memory mechanisms. They wanted to examine the effect of a toxic protein, known to attack memory-forming synapses, that is called “ADDL” for “amyloid ß-derived diffusible ligand.” ADDLS are small, soluble aggregated proteins that accumulate in the earliest stages of Alzheimer’s disease. The researchers had previously found that ADDLs bind very specifically at synapses, which in turn initiates deterioration of their function, shape and composition. They now went on and studied the synapses and their insulin receptors before and after ADDLs were introduced. Regions of the nerve with normal numbers of insulin receptors have no ADDL binding, but when the ADDLs are added they remove insulin receptors from nerve cells, effectively making them insulin resistant.

And an insulin resistant neuron cannot participate in the formation of memories.

This finding implies that there is a fundamental connection between diabetes and Alzheimer’s disease, and this may in turn help us to see whether existing diabetes treatments might protect neurons from ADDLs and improve insulin signaling in people with Alzheimer’s disease.

The first type of diabetes is Type 1, a.k.a. insulin-dependent or juvenile onset. The second is Type 2, a.k.a. non-insulin-dependent diabetes. So is Alzheimer’s Type 3?

It has also been known for some time that physical exercise is one of the factors that may help reduce the chance of developing Alzheimer’s disease, and we may now have a mechanism by which it can help.

This is an extraordinarily interesting and important discovery that should lead to a whole new research angle, perhaps with medicines that are already available.

Glaucoma and Alzheimer’s Disease

There is a fascinating study by colleagues from University College London (UCL) that has just been published in the Proceedings of the National Academy of Sciences that has found a “clear link between what causes Alzheimer’s and one of the basic mechanisms behind glaucoma.”

The research could speed up the development of new treatments for Alzheimer’s and revolutionize the treatment of glaucoma, the most common cause of blindness in the Western world.

If glaucoma is indeed confirmed as a marker or risk factor for Alzheimer’s then the early warning signs it gives could help ensure that patients have more opportunities to delay the onset of dementia.

The researchers discovered that the same “plaque” proteins are a key process in the development of both diseases. Clumps – or plaques – of beta-amyloid proteins that kill brain cells in Alzheimer’s patients, also kill optic nerve cells in the eyes of glaucoma sufferers. A link has bee suspected for some time: around 1.8-2.0% of the population will develop glaucoma, the figures in Alzheimer’s is as high as 25%.

Dr Francesca Cordeiro, who led the team at UCL’s Institute of Ophthalmology, said:

“We’ve seen for the first time that there is a clear link between what causes Alzheimer’s and one of the basic mechanisms behind glaucoma.”

Glaucoma is a group of diseases of the optic nerve involving loss of retinal ganglion cells in a characteristic pattern of optic neuropathy. People with glaucoma gradually lose their wider field of vision. Many do not realize it until they barge into things.

The textbooks will tell you that glaucoma is caused by increased pressure in the eye, known as intraocular pressure. Standard treatments attempt to lower this pressure, but with only limited success. People with normal pressure can also suffer from glaucoma, suggesting it is not the only cause.

The researchers have shown that drugs that prevent the build-up of “plaque” proteins in the brains of people with Alzheimer’s disease were successful in treating glaucoma in rats. One such drug, bapineuzumab, is already being used to treat Alzheimer’s patients in clinical trials in Britain and the United States.

The UCL researchers showed that the effects on glaucoma were even stronger when combined with two other novel Alzheimer’s treatments – “Congo Red” and a drug called a beta-secretase inhibitor.

This is very exciting work and we should know fairly soon whether these new approaches to treatment will help both glaucoma and Alzheimer’s disease.

Clearly this does not mean that everyone with Alzheimer’s will develop glaucoma or vice versa. Both problems have multiple causes and can follow quite different trajectories. But links like these are the stuff of medical progress.

Insulin Resistance and Cognition

I have talked a lot about insulin resistance and the problems that it can cause. It is one of the biggest threats facing the human population, with at least a third of Americans now being insulin resistant. It looks as there may be another complication of insulin resistance that we need to add to the list.

Researchers from Canada presented some interesting data (NR385) at the 2007 Annual Meeting of the American Psychiatric Association in San Diego last month.

There has been a great deal of concern that some newer antipsychotics may cause insulin resistance and perhaps diabetes, and the FDA has required all the newer antipsychotics to carry a warning about this potential problem. We also know that although these medicines can be very effective in treating some symptoms, they do not usually help cognition very much.

The researchers recruited 37 people with chronic schizophrenia and did neurocognitive tests on them while also measuring their insulin resistance.

They found a significant correlation between insulin resistance and neurocognitive functioning. It looks as if insulin signaling is important for processing information in the brain and insulin resistance interferes with the process.

Though this study look at a highly specialized group: people with chronic schizophrenia – there is some recent evidence to suggest that insulin resistance may be a factor in Alzheimer’s disease, and that people may develop cognitive impairments if they go on to develop insulin resistance syndrome or impaired fasting glucose.

Yet another good reason for using diet, exercise and sleep to try and present insulin resistance and maintain healthy glucose levels.

Regular readers will recall that there are five pillars of healthy aging and the prevention of cognitive decline:

  1. Blood pressure
  2. Physical activity
  3. Mental activity
  4. Supplements and moderate alcohol
  5. Social engagement and level mood

We should now add avoidance of insulin resistance to the list. Taken together, the evidence suggests that we can dramatically reduce our risk of cognitive decline as we get older.

Personal Mastery and the Wellness of Caregivers

Looking after aging relatives can be incredibly difficult, particularly if they have a chronic illness such as Alzheimer’s disease.

There is also evidence that the caregivers of people with Alzheimer’s disease have increased rates of cardiovascular disease and they die prematurely. It has been assumed that the cardiovascular problems are a result of stress causing overdrive of the sympathetic nervous system.

There was some interesting research (NR241) presented last month at the 2007 Annual Meeting of the American Psychiatric Association in San Diego. The investigators did not have to come far: they are from the University of California in San Diego.

The investigators looked at 70 spousal caregivers of people with Alzheimer’s disease and used an experimental task to measure the activity of their sympathetic nervous systems. They also measured the caregiver’s levels of “Mastery:” the belief that one is capable of handing one’s problems. Mastery is one of the components of resilience, a key characteristic of a person who can handle stress well.

What they found make very good sense: the caregivers with the highest levels of personal mastery had the lowest levels of sympathetic activity, suggesting that a sense of mastery may protect against the physiological effects of acute stress.

This provides us with yet more evidence that psychosocial interventions that increase mastery may reduce the risk of cardiovascular disease amongst the caregivers of people with dementia.

Successful Aging

One of the most promising changes in psychology is the ever-greater emphasis on what makes us healthy, rather than constantly looking at the things that make us sick. There is an important approach called Behavioral Activation (BA) Theory, which emphasizes environmental and behavioral factors as determinants of our overall well-being. According to the theory, reduced engagement in pleasurable activities may be an important precursor of reduced well-being. This makes good sense: it is estimated that as much as 90% of our higher cortical functions are designed for social interactions.

This is something that I wrote in Healing, Meaning and Purpose:

“Nothing in the Universe exists in isolation: We live in a Universe of relationships. It is inconceivable that anything can exist except in relationship to something else. The entire Universe is made up of integrated systems that function, develop and evolve together. A failure to construct and maintain healthy relationships can be a cause of much distress.

Several years ago I reported some interesting observations. At the time, I was doing a lot of research on diseases of blood vessels. I had developed a laboratory method for taking some of the cells that line blood vessels from volunteers and then growing them in a cell culture dish. We discovered that if we did not have enough cells in the dish, they would all die of “loneliness.” The exception is cancer cells, which in culture will grow on their own, like weeds.”

As an example in a paper published in February in the Archives of General Psychiatry it was shown that lonely individuals may be twice as likely to develop the type of dementia linked to Alzheimer’s disease in late life as those who are not lonely. The theory has been shown to predict psychiatric well-being in a number of populations, including the caregivers of people with Alzheimer’s disease, people with chronic pain, cancer patients and community-dwelling older people.

It is also known that psychiatric well-being, particularly emotional well-being, may play an important role in cardiovascular health. This may be due to an increase in the activity of the sympathetic nervous system that increases not only blood pressure, but also the levels of inflammatory mediators and coagulant factors in the blood.

In research from the University of California at La Jolla that was presented on Monday at the 2007 Annual Meeting of the American Psychiatric Association in San Diego, California, twenty two people with a mean age of 70 were studied, to see if there was a link between their behavioral activation, i.e. how satisfied they were with their leisure activities, their affective well-being and their blood pressure.

The findings were as expected: the less satisfied and engaged people were, the higher was their blood pressure.

This is only preliminary data, but it confirms something that we have said before: as we get older it is as important to stay socially engaged as it is to do mental exercise.

And if you known someone who is older and isolated, you might want to go and see them.

“The most terrible poverty is loneliness and the feeling of being unloved.”
–Mother Teresa of Calcutta (Albanian-born Indian Nun, Humanitarian and, in 1979, Winner of the Nobel Peace Prize, 1910-1997)

“What makes loneliness an anguish is not that I have no one to share my burden, but this: I have only my own burden to bear.”
–Dag Hammarskjöld (Swedish Statesman, Secretary-General of the United Nations from 1953-1961, and, in 1961, Winner of the Nobel Peace Prize, 1905-1961)

Attachment and Well-Being In the Elderly

Attachment theory is a psychological concept that was developed by John Bowlby in Britain and Harry Harlow
in the United States in the late 1950s. The idea is that humans and
many other animals have evolved an adaptive tendency to maintain
proximity to an attachment figure.

Attachment is defined as an emotional bond that one person forms
between himself or herself and another specific person. Originally the
theory was developed to explain the relationship of a parent and child,
but over tie it has become realized that attachments can occur
throughout life, and if they become abnormal, they can lead to
loneliness, isolation and psychopathology. There has recently been a resurgence of interest in attachment styles, and how they interact with emotional and behavioral expression during the development of dementia.

There was some interesting research presented today at the 2007 Annual Meeting of the American Psychiatric Association
in San Diego, California. Investigators from Charlottesville, Virginia
looked at 39 older patients (27 were women): 49% were aged between 65
and 74 and the remainder was over 74.

  • 41% of women and 33% of the men said that their activities were limited by physical and/or emotional problems
  • 41% of the women and 17% of the men endorsed at least two out of three indicators of depression
  • When they examined their attachment styles, 28% were secure, 59% avoidant and 13% enmeshed
  • An avoidant attachment pattern is more common among the elderly than it is among younger people
  • Understanding attachment style could be very helpful in
    understanding how people react to their healthcare providers and their
    preferred coping styles

For anyone working or living with elderly people, attachment theory
is well worth investigating. There is already some preliminary evidence
that specific interventions may help older people with avoidant

Alzheimer’s: “A Disease of Civilization?”

I have had the pleasure of receiving some excellent comments after the recent article about Alzheimer’s disease.

One suggestion was that Alzheimer’s is a modern illness caused by mercury in dental fillings. This has been a popular idea for several years, and I knew an holistic dentist in Philadelphia who told me about some people who seemed to be relieved of an array of symptoms after their mercury-containing fillings were removed.

Over the last few years I have spent a long time reading books on the topics and analyzing published studies in detail.

These are some of the books with which I started:

  1. Warren T. Beating Alzheimer’s: A Step Towards Unlocking the Mysteries of Brain Diseases. Garden City Park, New York: Avery Publishing Group Inc., 1991.
  2. Huggins HA. It’s All in Your Head: The Link Between Mercury Amalgams and Illness. Garden City Park, New York: Avery Publishing Group Inc., 1993.
  3. Walker M, Whitaker J. Elements of Danger: Protect Yourself Against the Hazards of Modern Dentistry. Charlottesville, Virginia: Hampton Roads Publishing Company Inc., 2000.
  4. Hardy JE. Mercury Free: The Wisdom Behind the Global Consumer Movement to Ban "Silver" Dental Fillings Glassboro, New Jersey: Gabriel Rose Press Inc., 1996.

One of the best resources that I’ve found for people interested in the potential problems that may be caused by dental amalgams is here.

Clearly there is a potential for harm. At one time I considered having my fillings removed, but in the end I didn’t.

Why did I make that decision?

After all, mercury is neurotoxic, which is one of the reasons for all the concern about thimerosal in vaccines, and its alleged link to autism. And I would prefer to avoid getting Alzheimer’s disease. I have no family history of it. In fact the opposite: my father was estimated to have an IQ in the 170-180 range when he was in his nineties. But it is still a concern.

While some people seem to have benefited form having their fillings removed, many have not. So there must be some other factor or factors, likely including a genetic predisposition. People have created genetically deformed animals with all the signs of Alzheimer’s disease, but without a molecule of mercury in sight.

It is constantly being said that Alzheimer’s disease is a modern illness, and that its appearance roughly coincided with the introduction of mercury fillings. But that’s not true. Alois Alzheimer did describe the classic pathological signs of the disease in 1906. It was only made possible by the development of a new silver staining method developed by Alzheimer’s colleague Franz Nissl. For the first 70 years after it was first described, Alzheimer’s disease was regarded as a “Pre-senile” dementia.

But dementia had been described at least two thousand years earlier by Lucretius.

Some of those early descriptions probably included a ragbag of different illnesses, but for at least 2,000 years, from Rome to China, there were clear descriptions of something that looks just like modern Alzheimer’s disease. There are descriptions by the great English physician Thomas Willis, and the term “demented” entered the English language in 1644. There was a famous description of Sir John Roberts of Bromley, who was described by his physician, William Salmon as “decayed in his intellectuals.” That was in 1694.

There are extensive descriptions of “senile dementia” from many of the famous names in the history of psychiatry, including Cullen, Pinel and Esquirol. So the idea that it is a modern illness is not correct. Has it been becoming more common? Possibly, but it is difficult to say, because in 1905 the average life expectancy in the United States was 47 years.

When I really started analyzing the research in detail, I was not impressed by the data linking mercury with Alzheimer’s disease and multiple sclerosis. There are definitely some reports (1.2.) of possible links between neurodegeneration and mercury, but the most recent epidemiological studies have failed to find a link. Indeed there has been a great deal of research indicating that – for most people – amalgams are safe. ( 1. 2. 3. 4.) although it is important that the research should continue. Last year the U.S. Food and Drug Administration (FDA) panel called for an additional review of scientific studies on the safety of dental amalgam fillings. Some of the responses are here.

My own take on this is as follows:

  1. The evidence for a causal link between mercury – primarily from fillings – and Alzheimer’s disease is thin.
  2. The quality of the evidence for many other conditions, such as multiple sclerosis is also not of good quality.
  3. There is still a great deal that we do not know about the medical consequences of mercury containing amalgams, particularly in children and pregnant women.
  4. I am going to continue to update this information as more data is published.

At the moment I still have my fillings.

But there is another reason: the few that I have were done in England, and for years now there have been restrictions on the use of mercury-containing amalgams.

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