New Cases Of Alzheimer's Dementia Continue Rise

The number of people with Alzheimer's and dementia – both new cases and total numbers with the disease – continues to rise among the very oldest segments of the population in contradiction of the conventional wisdom, according to research reported today at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009) in Vienna.

Previous epidemiological studies have suggested that the number of people with Alzheimer's and dementia begins to level off and perhaps even go down a bit in people age 90 and above, known as the "oldest old." This is the fastest growing segment of the population in western countries.

"The number of people affected by Alzheimer's and dementia is growing at an epidemic pace, and the skyrocketing financial and personal costs will devastate the world's economies and healthcare systems, and far too many families," says William Thies, chief medical & scientific Officer at the Alzheimer's Association. "We must make the fight against Alzheimer's a priority before it's too late."

"However there is hope. There are many drugs in late stage clinical trials for Alzheimer's that show promise to slow or stop the progression of the disease. This, combined with advancements in early detection, has the potential to change the landscape of Alzheimer's in our lifetimes. But we need more funding for research to see these possibilities through to completion," Thies says.

The research reported at ICAD 2009 includes a study of more than 2,100 individuals age 80 years or older in eight municipalities of Varese province, Italy, and a systematic review and collaborative analysis of studies reporting the prevalence of dementia in Europe.

The Monzino 80-plus Study – Dementia Risk Continues to Rise in the "Oldest Old"

Ugo Lucca, head of the Laboratory of Geriatric Neuropsychiatry at the Mario Negri Institute for Pharmacological Research in Milano, Italy, and colleagues conducted a prospective, door-to-door, population-based study of all people age 80 years or older in eight municipalities of Varese province, Italy, roughly 30 kilometers (20 miles) north of Milan (known as the Monzino 80-plus Study). Their goal was to estimate the prevalence (total number with the disease) and incidence (new cases of the disease) of dementia in this population.

The researchers were able to gather information and an initial dementia evaluation for 2,138 individuals. The mean age of the population at that first evaluation was 87.5 years; 74.1% were women. Mean education was 5.1 years, and mean MMSE score was 21.4. After an average follow-up period of three years, of the 1,085 survivors non-demented at baseline, 995 were re-evaluated for dementia.

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X-Rays for Early Alzheimer's Disease Detection

Researchers at Brookhaven National Laboratory have demonstrated a new, highly detailed x-ray imaging technique that could be developed into a method for early diagnosis of Alzheimer's disease. The technique has previously been used to look at tumors in breast tissue and cartilage in human knee and ankle joints, but this study is the first to test its ability to visualize a class of miniscule plaques that are a hallmark feature of Alzheimer's disease. Their results will appear in a July 2009 edition of the journal NeuroImage.

Scientists have long known that Alzheimer's disease is associated with plaques, areas of dense built-up proteins, in the affected brain. Many also believe that these plaques, called amyloid beta (Aß) plaques after the protein they contain, actually cause the disease. A major goal is to develop a drug that removes the plaques from the brain. However, before drug therapies can be tested,
researchers need a non-invasive, safe, and cost-effective way to track the plaques' number and size.

That is no easy task: Aß plaques are extremely small -- on the micrometer scale, or one millionth of a meter. And conventional techniques such as computed tomography (CT) poorly distinguish between the plaques and other soft tissue such as cartilage or blood vessels.

"These plaques are very difficult to see, no matter how you try to image them," says Dean Connor, a former postdoctoral researcher at Brookhaven Lab now working for the University of North Carolina. "Certain methods can visualize the plaque load, or overall number of plaques, which plays a role in clinical assessment and analysis of drug efficacy. But these methods cannot provide the resolution needed to show us the properties of individual Aß plaques."

A technique developed at Brookhaven, called diffraction-enhanced imaging (DEI), might provide the extra imaging power researchers crave. DEI, which makes use of extremely bright beams of x-rays available at synchrotron sources such as Brookhaven's National Synchrotron Light Source, is used to visualize not only bone, but also soft tissue in a way that is not possible using standard x-rays. In contrast to conventional sources, synchrotron x-ray beams are thousands of times more intense and extremely concentrated into a narrow beam. The result is typically a lower x-ray dose with a higher image quality.

In this study, researchers from Brookhaven and Stony Brook University used DEI in a high-resolution mode called micro-computed tomography to visualize individual plaques in a mouse-brain model of Alzheimer's disease. The results not only revealed detailed images of the plaques, but also proved that DEI can be used on whole brains to visualize a wide range of anatomical structures without the use of a contrast agent.

The images are similar to those produced by high-resolution magnetic resonance imaging (MRI), with the potential to even exceed MRI pictures in resolution, Connor says. "The contrast and resolution we achieved in comparison to other types of imaging really is amazing," he says. "When DEI is used, everything just lights up."

The radiation dose used for this study is too high to safely image individual Aß plaques in humans - the ultimate goal -- but the results provide researchers with promising clues.

"Now that we know we can actually see these plaques, the hope is to develop an imaging modality that will work in living humans," Connor says. "We've also now shown that we can see these plaques in a full brain, which means we can produce images from a live animal and learn how these plaques grow."

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Alzheimer's-associated Enzyme Can Disrupt Brain Activity

An enzyme involved in the formation of the amyloid-beta protein associated with Alzheimer’s disease can also alter the mechanism by which signals are transmitted between brain cells, the disruption of which can cause seizures. These findings from researchers at the MassGeneral Institute for Neurodegenerative Disorders (MGH-MIND) may explain the increased incidence of seizures in Alzheimer’s patients and suggest that potential treatments that block this enzyme – called beta-secretase or BACE – may alleviate their occurrence. The report will appear in the journal Nature Cell Biology and is receiving early online release.

“We have found a molecular pathway by which BACE can modulate the activity of sodium channels on neuronal cell membranes,” says study leader Dora Kovacs, director of the Neurobiology of Disease Laboratory in the Genetics and Aging Research Unit at MGH-MIND. “That implies that elevated BACE activity may be responsible for the seizures frequently observed in Alzheimer’s patients.”

Alzheimer's disease is characterized by plaques within the brain of the toxic amyloid-beta protein. Amyloid-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes – BACE and gamma-secretase – which releases the amyloid-beta fragment.
Signaling impulses in nerve cells are transmitted via voltage-gated sodium channels, structures on the cell membrane that transmit electrochemical signal by admitting charged sodium particles into the cell’s interior. Sodium channels consist of an alpha subunit, which makes up the body of the channel, and one or two beta subunits that help to regulate the channels’ activity.

Previous studies from Kovacs’ team and others showed that the BACE and gamma-secretase enzymes that release amyloid-beta from APP also act on the beta2 subunit of neuronal sodium channels. The current study was designed to examine how this processing of the beta2 subunit may alter neuronal function.

Lead author Doo Yeon Kim, and colleagues first confirmed that the beta2 subunit, similar to APP, can be acted on by BACE and gamma-secretase, releasing a portion of the beta2 molecule from the cell membrane. A series of experiments using brain tissue from animal models and from Alzheimer’s patients revealed the following series of cellular events: Elevated levels of the free beta2 segment within the cell appear to increase production of the alpha subunits, but those molecules are not incorporated into new sodium channels on the cell surface. The resulting deficit of membrane sodium channels inhibits the passage of neuronal signals into and through the cells.

Neuronal sodium-channel dysfunction is known to cause seizures in both mice and humans. In a supplement to the current paper the investigators present evidence that sodium channel metabolism is altered in the brains of Alzheimer’s patients compared with non-demented individuals of similar age.

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Simple Test Predicts 6-year Risk of Dementia

A simple test that can be given by any physician predicts a person’s risk for developing dementia within six years with 87 percent accuracy, according to a study led by researchers at San Francisco VA Medical Center (SFVAMC).

The test, developed in the study by the researchers, is a 14-point index combining medical history, cognitive testing, and physical examination. It requires no special equipment and can be given in a clinical setting such as a doctor’s office or at a patient’s bedside.

The new index is the “bedside” version of a longer, more technically comprehensive “best” test, also developed during the study, that is 88 percent accurate.

These are the first tools to accurately predict dementia, according to lead author Deborah Barnes, a mental health researcher at SFVAMC. Barnes described the tests in a presentation at the 2007 International Conference on Prevention of Dementia, in Washington, DC, sponsored by the Alzheimer’s Association.

“There are tests that accurately predict an individual’s chances of developing cardiovascular disease and other maladies, but, until now, no one has developed similar scales for dementia,” says Barnes, who also is an assistant professor of psychiatry at the University of California, San Francisco (UCSF).

As measured by the “bedside” index, the risk factors for developing dementia are an age of 70 or older, poor scores on two simple cognitive tests, slow physical functioning on everyday tasks such as buttoning a shirt or walking 15 feet, a history of coronary artery bypass surgery, a body mass index of less than 18, and current non-consumption of alcohol.

People who score 0 to 3 on the “bedside” test have a 6 percent chance of developing dementia within six years. A score of 4 to 6 indicates a 25 percent chance. People with a score of 7 or higher have a 54 percent chance of developing dementia within six years.

The 18-point comprehensive, or “best,” test measures for all “bedside” risk factors plus factors that would be more difficult to measure as part of a routine clinical visit. These include brain magnetic resonance imaging (MRI) findings of enlarged ventricles –– the fluid-filled cavities between brain tissue -- or diseased white matter –– the nerve cells that transmit signals between grey matter; thickening of the internal carotid artery, which brings blood to the head and neck; and the presence of one or two copies of the e4 allele, or subtype, of APO-E, the gene that codes for the protein known as Apolipoprotein. The presence of APO-E e4 alleles is a known risk factor for Alzheimer’s disease.


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Nursing Home Placement Associated with Accelerated Cognitive Decline in Alzheimer’s Disease

People with Alzheimer’s disease experience an acceleration in the rate of cognitive decline after being placed in a nursing home according to a new study by the Rush Alzheimer’s Disease Center. The study, published in the June issue of the American Journal of Psychiatry, finds that prior experience in adult day care may lessen this association.

The observational study involved 432 older persons with Alzheimer’s disease who were recruited from health care settings in the Chicago area. At baseline, they lived in the community and 196 participants were using day care services from two to six days a week for an overall mean of 1.7 days a week. At six month intervals for up to four years, they completed nine cognitive tests from which a composite measure of global cognition was derived.

On average, cognition declined at a gradually increasing rate for all participants. During the study period, 155 persons were placed in a nursing home, and placement was associated with a lower level of cognition and more rapid cognitive decline.

Study participants who had previous adult day care experience fared better. As level of day care use at study onset increased, the association of nursing home placement with accelerated cognitive decline substantially decreased. Thus, people using day care 3 to 4 days a week at the beginning of the study showed no increase in cognitive decline upon nursing home placement.

“The findings suggest that experience in day care may help individuals with Alzheimer’s disease make the transition from the community to institutional residence,” says study author Robert Wilson, a neuropsychologist at the Rush Alzheimer’s Disease Center.

The study also found that a higher level of education was associated with accelerated cognitive decline upon nursing home placement. Yet, day care use markedly reduced the association of education with accelerated cognitive decline in the nursing home; further evidence that there is a robust association between day care experience and cognition during the transition to a nursing home.

The authors considered the possibility that nursing home placement is simply a sign of increased severity of Alzheimer’s disease. Yet, the nursing-home-related increase in cognitive decline was observed even after simultaneous control for cognitive and noncognitive indicators of dementia severity at the time of nursing home entry.

Alternatively, the increased cognitive decline upon placement may reflect difficulty adapting to an unfamiliar environment, consistent with clinical reports of increased confusion and behavior problems in those with dementia during acute hospitalization or trips away from home. Patients who had prior adult day care services may have been better able to adjust to the unfamiliar environment.

“The findings suggest that the transition from the community to a nursing home is particularly difficult for people with Alzheimer’s disease and that those planning for their care should consider the possibility that experience in adult day care programs may help prepare affected persons for institutional living,” says Wilson.

The research was supported by grants from the National Institutes on Aging, which leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people, including Alzheimer’s disease and age-related cognitive decline.


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