Archive for August, 2009

Dementia in Older Women

A recent paper published in the Journal Neurology, which analyzed over 900 people, suggests that almost half of all women in their nineties are suffering from dementia. The study carried out in California is one of a few looking specifically at the rates of dementia in the very old. However, given our increased life expectancies, the over ninety group is growing rapidly in many populations, including that of the United States. Importantly, there seems to be a sex difference in the risk for Alzheimer’s or dementia in general over the age of ninety.

In men, for instance, although there was an increase in the likelihood of having dementia over the age of ninety, it did not increase as much as it did in women. In women, the likelihood of having dementia doubled every five years after the age of ninety. Previous studies have suggested that the risk for dementia is higher in women than it is in men. But other studies have disputed this. This present study seems to confirm that the risk for women is greater than men, at least after the age of ninety years.

Therefore, if you divide dementia populations by sex over the age of ninety, about 45% of women will have dementia compared to 28% of men. Importantly the study also suggested that women who had used their brains (intellect) more throughout life and had achieved higher education, were much less likely to develop dementia than those who had not.

Understanding why women in this age group might be at higher risk will take additional studies. But it is known, for instance, that women are more likely than men to develop stroke and heart disease as they age. Both of these are independent risk factors for dementia and exacerbate Alzheimer’s symptoms.

Researchers at the Roskamp Institute are interested in finding new treatments for Alzheimer’s disease and clues from sex differences that confer different risks for Alzheimer’s are important because they may point to more treatment strategies.

Researchers have, for instance, speculated that estrogen is a protective factor for Alzheimer’s disease, but proactive treatment with estrogen has not been shown to be preventative in clinical trials. In the present study, the idea that vascular risk factors (which are more prevalent in women as they age) are contributory to Alzheimer’s is consistent with much of the work of Roskamp Institute scientists showing that in the presence of amyloid, damage to the vasculature is heightened and the consequences of vascular damage has greater impact on the brain in the presence of early Alzheimer’s disease than in normal individuals. These and other clues are leading Roskamp Institute scientists towards new treatments for the disease, some of which should be entering clinical trials in 2008.

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Alzheimer’s and Blood Pressure

The relationship between blood pressure and Alzheimer’s disease is complex. However, we do know that blood pressure raised in mid-life (hypertension) is a risk for the development of Alzheimer’s disease later on. Uncontrolled hypertension is a risk for dementia in general. In fact, stroke related dementias are primarily caused by either clotting or small bleeds in the brain. Hypertension can lead to bleeding, primarily in the brain, but can also damage the heart triggering the release of small clots that lodge in the brain, thus depriving the nerve cells (neurons) of oxygen supply.

It remains unclear to scientists why hypertension is a risk for Alzheimer’s disease, but we do know that in spontaneously hypertensive rats, there is a tendency to accumulate some of the pathology of Alzheimer’s disease.

In 1996, researchers at the Roskamp Institute discovered that the causative protein in Alzheimer’s (the amyloid protein) has a drastic effect on blood vessels. The effect is to increase the propensity of blood vessels to constrict. Subsequently, others show that after a small stroke (when blood vessels close down temporarily) the presence of amyloid tends to keep the blood vessels closed. It is assumed that the consequence of reduced blood flow to the brain, secondary to closed blood vessels, causes deprivation of oxygen and glucose to the neurons, thus causing more damage in a brain with high amyloid levels than one with not.

Translated into clinical terms, this means that the effect of a small stroke on somebody who is in the early stages of Alzheimer’s can be more devastating than somebody who is not. In fact, a study of nuns who were asked to complete mental state questionnaires in life and who subsequently died has revealed an important interaction between small strokes and the clinical signs of Alzheimer’s. Even though some nuns had amyloid deposits in their brain, they did not exhibit the symptoms of amyloid in life. Those nuns that had amyloid deposits but did exhibit the clinical symptoms of Alzheimer’s in life also had multiple small strokes.

Thus, damage to the blood vessels in the presence of amyloid is more devastating than if amyloid is absent. Hypertension tends to damage blood vessels throughout the body, but it is only in the brain that amyloid accumulates and can contribute to poor recovery after vascular injury.

What does this mean for patients treated at the Roskamp Institute? Patients are advised to take particular care to have their blood pressure and cardiovascular status monitored. High lipid or triglyceride levels can contribute to cerebrovascular (brain/blood vessel) damage and uncontrolled or poorly monitored high hypertension can also be highly detrimental. In addition, we know that other cardiac problems, such as arrhythmias can contribute to cerebrovascular damage, as mentioned, by throwing off small clots.

As we await effective treatments to combat Alzheimer’s directly, we need to ensure that we control other disorders which can contribute significantly to rapid declines in mental status. Interestingly, some antihypertensives seem to be able to control the risk for Alzheimer’s disease as well as controlling blood pressure.

Researchers at the Roskamp Institute have clearly shown that this does not apply to all antihypertensives and they are investigating why some are able to regulate both blood pressure and can reduce the incidence of Alzheimer’s disease while others cannot. This is an important area of research and clearly one that holds out hope for Alzheimer’s sufferers as the search for new treatments continues.

What do the names of Barack Obama, Hillary Clinton, and John McCain have to do with Alzheimer’s disease?

Alzheimer’s disease is a neurodegenerative disorder (i.e., one which attacks neurons in the brain) which robs us of our memories, language, reasoning and thought. However, the clinical picture of Alzheimer’s has a very distinctive pattern which distinguishes it from other forms of dementia (dementia is a general term which simply means the loss of memory, some other mental function, and the loss of normal social functioning). In Alzheimer’s disease, the early signs are almost invariably the same and include loss of memory for recently presented information.

What does this mean practically? It means that someone in the early stages of Alzheimer’s will not remember information presented to them a short time ago. For instance, if somebody receives a phone call, a few minutes later they may not remember who it was who called. Similarly, if they set out for the grocery store, once they arrive there they may not remember what it is they set out for.

Today, we are so used to receiving news all the time from our computers, our televisions, radios, and mobile phones that we don’t realize that we are being presented with new information all the time. The Alzheimer’s sufferer is at a particularly grave disadvantage in this situation. Current events may escape their memory stores and a good test of whether someone may be suffering from the disorder or not is whether they can remember information that appears as news on television or other ways. So, for instance, knowing the big events in the campaign for the US presidential election will be registered by most of us and remembered. The Alzheimer’s sufferer may not know that Hillary Clinton has dropped out of the race nor that Barack Obama has been nominated. Knowledge of these events, which most of us take for granted are lost to the Alzheimer’s sufferer and thus monitoring our loved ones and friends for signs that they are not aware of current events may help us to detect early signs of the disease. Concern that somebody may not be acquiring new information should be a trigger to have them evaluated in a memory disorder clinic.

The Roskamp Institute has two such clinics – one in Tampa and one in Sarasota, Florida and they offer full evaluations for Alzheimer’s and other causes of memory loss.

Double Amyloid Causes Memory Loss

A recent paper (June 22nd from scientists from Harvard University and Trinity College, Dublin) has shown that the amyloid protein is most toxic to memory when it appears in a double form. The researchers extracted the amyloid protein (the small protein that has long thought to be the cause of Alzheimer’s) from the brains of Alzheimer’s disease victims and when the proteins were injected into rats, they noted that, depending on the specific form of amyloid, memory impairment occurred.

Alzheimer, himself, saw the accumulation of amyloid protein in what are now know as plaques, but these accumulations of amyloid represent many, many single amyloid molecules aggregated together.

The researchers found that this highly aggregated form of amyloid was not injurious to memory. However, when the amyloid protein occurred in just a doublet, (i.e., two molecules of amyloid stuck together) then it was in its most toxic form. Single amyloid (which we all produce for much of the time) was harmless to memory. These findings are important because the doublet form of amyloid is soluble and therefore can travel freely throughout the brain. These findings also suggest that the aggregated form that is visible to the eye under the microscope is not the most important form for researchers to prevent.

These findings are of particular interest to researchers at the Roskamp Institute, who showed in 1996 that soluble forms of amyloid could be toxic to blood vessels, increasing the likelihood that they would constrict. This is a particularly bad thing, especially after stroke, and it raised the possibility at that time that the soluble forms of Aß of amyloid might be more important than the aggregated forms.

These new findings also suggest that treatments aimed at lowering the amount of the amyloid doublet, might be those that are most effective in the disease. The new vaccine treatment, for instance, aimed at lowering the amount of amyloid by soaking up the amyloid with an antibody, might be effective at lowering these amyloid doublets. Other drugs that are coming on-line for the treatment of Alzheimer’s also targeted at the amyloid protein will now, no doubt, be examined to see whether they can lower the amount of the amyloid doublet.

Researchers at the Roskamp Institute are dedicated to finding new treatments and cures for Alzheimer’s disease. They were among the first in the world to show that the amyloid protein was most likely central to the disease process. This theory is now being tested in clinical studies throughout the world with exciting recent results suggesting that, indeed, the removal of amyloid might be an effective treatment for the disease (see recent reports on Elan Pharmaceuticals).

First Critical Clinical Tests of the Amyloid Theory of Alzheimer’s Disease

In 1991, researchers currently at the Roskamp Institute published a paper in the highly prestigious Nature journal entitled “Early Onset Alzheimer’s Disease Caused by Mutations of the Amyloid Gene”. This and related findings were historic milestones in the understanding of the causes of Alzheimer’s disease. Today, seventeen years later, Roskamp Institute researchers are delighted to hear that Elan, one of the largest pharmaceutical companies, is having success with an approach which targets the amyloid protein.

The early findings by Roskamp researchers placed amyloid at center stage as the cause of the disease. Now Elan’s vaccine, which is targeted to soak up the amyloid protein, may be a verification that reducing amyloid accumulation is a way to tackle the disease. Although some researchers remain skeptical of the validity of this approach, the early results from Elan’s Phase II study, published this week (June 17) indicate that reducing amyloid levels with the anti-amyloid vaccine has slowed the rate of progression of the disease in some patients. Interestingly, the vaccine approach has been helpful in cases of the disease that do not have a high genetic risk loading. Although there was a hint that all cases of Alzheimer’s (even those with high genetic loading might benefit from the vaccine), there was not a statistically significant difference between placebo group and those individuals that carry an APOE4 gene. This gene is known to increase the likelihood of developing Alzheimer’s early in life and may represent a particularly aggressive form of the disorder. Nevertheless, the fact that there were trends in a treatment improvement in the high risk group and statistically significant improvement in income in the low genetic risk group, strongly suggest that targeting amyloid will be a therapeutically useful strategy.

For Roskamp Institute researchers the new data from Elan is very important as Roskamp Institute researchers have developed drugs that do the same thing as the vaccine, i.e., lower the accumulation of amyloid levels. One of those drugs is in clinical trials already in Europe and trials are set to begin in the US pending FDA approval.

For Alzheimer’s sufferers and Alzhiemer’s researchers alike, the news from Elan is very hopeful.

Elan Vaccine and Alzheimer's Disease Drug development

The Roskamp Institute has a commitment to bring state-of-the-art new therapies to our patients at both the Sarasota and Tampa sites. For Alzheimer’s disease, for instance, the Institute is taking part in the Elan Wyeth clinical trials of a vaccine for Alzheimer’s disease. Important results for the Elan Wyeth vaccine were released on June 17, 2008.

The study of the vaccine called bapineuzumab (AAB-001) in a Phase II clinical trial was conducted in mild to moderate Alzheimer’s disease. The clinical trial lasted eighteen months and overall the bapineuzumab appeared to have clinical activity in treating the disease.

The company found that although the study did not attain statistical significance on the primary efficacy endpoints in the total study population, it was shown that in Alzheimer’s patients who do not carry the APO lipo protein E4 (APOE4) version of the APOE gene there were statistically significant and clinically meaningful benefits associated with the vaccine. The endpoints used included the Alzheimer’s disease assessment scale (ADAScog), the neuropsychological test battery (NTB), the mini-mental state examination (MMSE) and the clinical dementia rating scale (CDR). Interestingly too, when the company looked at brain scans of Alzheimer’s patients in the trial, they found that the MRI indication of loss of brain substance was decreased in those patients that were treated versus the placebo group.

The Roskamp Institute (Institute) is engaged in a Phase III study of the vaccine for Elan Wyeth and these encouraging results suggest that the larger clinical trial may also be beneficial. The vaccine targets are a small protein called amyloid, which researchers at the Institute believe is associated and triggers the disease pathology.

In fact, researchers at the Institute were among the first in the world to show that an accumulation of amyloid could cause Alzheimer’s disease. This they did by working with early-onset families (where the disease occurs in the 40, 50, or 60 year age groups) and showing that genetic errors in the amyloid gene were all that was responsible for the early build-up of the amyloid protein in the brain.

The Elan Wyeth vaccine is engineered to identify amyloid and remove it from the body and as such, holds potential for halting the disease progression. It is expected that the vaccine would be given every few weeks throughout the life of the Alzheimer’s sufferer.

This and other innovative treatments are available to our clinic population at the Roskamp Institute.

Alzheimer's Disease Drug development

An article in the Wall Street Journal on the 18th of June 2008, encapsulates the current expectation, hope and knowledge in the field of Alzheimer’s disease research. Researchers at the Roskamp Institute (Institute) have been part of the history of the discovery of new possibilities for stopping this devastating disease.

The article importantly discusses the recent work of Elan and Wyeth and their vaccine approach to Alzheimer’s disease. The reason this is central to the work of the Institute is that the same target of the vaccine is the protein that was highlighted by Institute researchers in the early 1990s as being causal in the disease process. The protein called amyloid accumulates in the brains of those with Alzhiemer’s disease and early genetic studies by members of the Institute team showed that amyloid definitely could cause the disease in certain individuals. Articles published in Nature in the early 1990s verified the causal relationship between the buildup of amyloid and the development of Alzheimer’s disease.

Now, almost twenty years later, Elan and Wyeth have developed a vaccine called bapineuzumab, which targets amyloid and reduces its accumulation in the brain. Although the exact mechanism of the antibody vaccine is not known, it is believed to act as a sponge in the blood supply, sucking amyloid from the brain and disposing of it harmlessly around the body.

Interestingly, the Wall Street Journal article points out that although the vaccine Phase II study failed on some of its clinical endpoints, there was enough of a positive signal in the data to enthuse not only Wall Street but researchers world-wide that the lowering of amyloid may be an effective approach to stopping this devastating disease. Many drug companies world-wide are pursuing treatments for Alzheimer’s which lower amyloid. The Institute is one such not-for-profit group which has developed drugs which lower amyloid levels and which are now in clinical trials around the world.

It is estimated that the pharmaceutical industry and biotech companies will spend more than a billion dollars this year researching into new treatments for Alzheimer’s. A Phase III study for the vaccine is underway and is being conducted at clinical sites around the country, including the Roskamp Institute site in Sarasota, Florida. The Institute researchers and clinicians are gratified, not only that they contributed to the early understanding of the causes of Alzheimer’s disease, but that drugs now are coming into clinical trials that target amyloid and look as if they may well be effective in stopping this dreadful disorder.

Another very interesting aspect of the Phase II results from Elan and Wyeth, is that the vaccine seemed to have more benefit in some genetically non-predisposed individuals than others. A gene known as the APOE gene dictates our risk for Alzheimer’s disease, particularly regarding whether we are likely to get the disease when we are 65, 75, or 85. Two copies of the E4 version of APOE, for instance, increase the risk of getting the disease earlier in life. The Elan and Wyeth vaccine looks as if it wasn’t particularly effective in that group, although the numbers treated that were E4 carriers was quite small, as it is in the general population. However, for those not at high genetic risk, the results were significant in that, after eighteen months, there was statistically valuable reduction in the rate of decline of cognitive processes. Integrating genetic tests into clinical trials for Alzheimer’s disease has now become a standard and is one of the adjunct research tests conducted at the Institute.