ST. PAUL, Minn. – Different types of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin, appear to be equally effective in lowering the risk of Alzheimer’s disease, according to the largest study of its kind published in the May 28, 2008, online issue of Neurology®, the medical journal of the American Academy of Neurology. Experts have debated whether a certain group of NSAIDs that includes ibuprofen may be more beneficial than another group that includes naproxen and aspirin.

Using information from six different studies, researchers examined data on NSAID use in 13,499 people without dementia. Over the course of these six studies, 820 participants developed Alzheimer’s disease.

Researchers found that people who used NSAIDs had 23 percent lower risk of developing Alzheimer’s disease compared to those who never used NSAIDs. The risk reduction did not appear to depend upon the type of NSAID taken.

“This is an interesting finding because it seems to challenge a current theory that the NSAID group which includes ibuprofen may work better in reducing a person’s risk of Alzheimer’s,” said study author Peter P. Zandi, PhD, with Johns Hopkins Bloomberg School of Public Health in Baltimore, MD. “The NSAID group that includes ibuprofen was thought to target a certain type of plaque in the brain found in Alzheimer’s patients. But our results suggest there may be other reasons why these drugs may reduce the risk of Alzheimer’s.”

The study’s lead author Chris Szekely, PhD, with Cedars Sinai Medical Center in Los Angeles, says the discrepancy between studies such as this one and the negative clinical trials of NSAIDs in treatment or prevention of Alzheimer’s need to be further explored.

Data used in the study were collected with support from the National Institutes of Health and the Canadian Institutes of Health Research.

Scientists have long questioned whether the abundant amounts of amyloid plaques found in the brains of patients with Alzheimer’s actually caused the neurological disease or were a by-product of its progress. Now, using new research techniques, scientists have shown that a two-molecule aggregate (or dimer) of beta-amyloid protein fragments may play a role in initiating the disease. The study, supported by the National Institutes of Health, suggests a possible new target for developing drug therapies to combat the irreversible and progressive disorder.

Ganesh M. Shankar, Ph.D., and Dennis J. Selkoe, M.D., of Brigham and Women’s Hospital and Harvard Medical School, conducted the study in collaboration with other researchers at Harvard and in Ireland at University College Dublin, Beaumont Hospital and Royal College of Surgeons Ireland, and Trinity College Dublin. The National Institute on Aging (NIA), part of NIH, funded the study which appears online in the June 22, 2008, Nature Medicine.

Alzheimer’s disease is marked by the build-up of plaques consisting of beta-amyloid protein fragments, as well as abnormal tangles of tau protein found inside certain brain cells. Early in the disease, Alzheimer’s pathology is first observed in the hippocampus, the part of the brain important to memory, and gradually spreads to the cerebral cortex, the outer layer of the brain. In this study, researchers tested cerebral cortex extracts from brains donated for autopsy by people aged 65 and older with Alzheimer’s and other dementias, as well as those without dementia. The extracts contained soluble one-molecule (monomer), two-molecule (dimer), three-molecule (trimer) or larger aggregates of beta-amyloid, as well as insoluble plaque cores. The researchers then injected the extracts into normal rats or added the extracts to slices of normal mouse hippocampus.

Shankar, Selkoe and colleagues discovered that both the soluble monomers and the insoluble plaque cores had no detectable effect on the hippocampal slices. However, the soluble dimers induced certain key characteristics of Alzheimer’s in the rats. The dimers impaired memory function, specifically the memories of newly learned behaviors. In the mouse hippocampal slices, the dimers also reduced by 47 percent the density of the dendrite spines that receive messages sent by other brain cells. The dimers seemed to be directly acting on synapses, the connections between neurons that are essential for communication between them.

To confirm this effect, the researchers then injected certain antibodies against beta-amyloid protein fragments. These latched onto and inactivated the dimers, preventing their toxic effects in the animal models. However, much work remains to be done before inactivation of dimers could move into the clinic.

“Scientists have theorized for many years that soluble beta-amyloid may be critical to the development and progression of this devastating disease. Now these researchers have isolated a candidate causative agent from brains of people with typical Alzheimer’s and directly tested it in an animal model,” said NIA Director Richard J. Hodes, M.D. “While more research is needed to replicate and extend these findings, this study has put yet one more piece into place in the puzzle that is Alzheimer’s.”

The animal findings were consistent with what the researchers found when they examined the brain tissues of people who had been clinically diagnosed with Alzheimer’s and those without dementia. They detected soluble dimers and some trimers of amyloid in the brains of patients with Alzheimer’s, but none or very low levels in those free of the disorder. Some people free of the disorder, however, did have insoluble amyloid plaques in their brains.

“These findings may help explain why people with normal cognitive function are sometimes found to have large amounts of amyloid plaques in their brains, which has been a puzzle for some time,” said Marcelle Morrison-Bogorad, Ph.D., director of the NIA Division of Neuroscience. “Their findings noted that the brain of an individual who was never clinically diagnosed with dementia was found with abundant insoluble Alzheimer’s plaques, but no soluble beta-amyloid.”

Selkoe and Shankar noted that further insights into the early stages of this disease process may answer questions not only about Alzheimer’s, but also about age-related memory impairments. “The approaches we used to isolate dimers and the widespread availability of tissues from brain banks, open new avenues of investigation into how these aggregates induce Alzheimer’s disease,” said Selkoe. “We still need to find out why dimers in particular are so destructive to neurons.”

CHICAGO -- Alzheimer’s disease is now the sixth leading cause of death in the United States, according to the Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. 

The CDC estimates that 72,914 Americans died of Alzheimer’s disease in 2006. With an unprecedented historic population shift of 78 million aging baby boomers in the country and this disease poised to strike 10 million boomers - it is clear this escalating epidemic must be addressed now.

Today, as many as 5.2 million Americans are living with Alzheimer’s disease. The Alzheimer’s Association’s 2008  Alzheimer’s Disease Facts and Figures report revealed one out of eight baby boomers will develop this disease that currently has no effective disease-modifying treatments to halt or delay its progression. Experts predict by 2010, there will be almost a half million new cases of Alzheimer’s disease each year; and by 2050, there will be almost a million new cases each year.

“The CDC’s announcement that Alzheimer’s disease jumped from the seventh to the sixth leading cause of death should serve as a wake-up call to the nation,” said William Thies, PhD, vice president of Medical and Scientific Relations at the Alzheimer’s Association. “The fact that there are no effective treatments for Alzheimer’s has allowed the disease to pass diabetes.  It is vitally important that we increase Alzheimer’s research funding to slow or stop the progression of this devastating disease.”

Researchers are closing the gap in developing accurate ways to diagnose and treat Alzheimer’s.  Although there are several promising drugs currently in Phase III clinical trials, insufficient research funds are committed to research focused on Alzheimer’s disease treatment and prevention.  This situation is further compounded by the fact that for the past five years the NIH budget has been essentially flat. The personal and economic impact of Alzheimer’s is so large that no one entity can solve the problem alone.  It will require all levels of government and the private sector working together to diminish the human and economic cost. It must begin with accelerating research.