lthough earlier research has suggested nicotine decreases the brain plaque associated with Alzheimer’s disease, results of a new mouse study point to the opposite conclusion.

The research finds that, far from easing Alzheimer’s, nicotine actually increases fibrous brain tangles, another hallmark of the disease.

“It is possible that nicotine might have a beneficial effect on plaque but a worsening effect on the tangles, so you would essentially convert the disease from one form to another,” said lead researcher Frank M. LaFerla, associate director of the Institute for Brain Aging and Dementia at the University of California, Irvine.

The researchers report their findings in this week’s issue of the Proceedings of the National Academy of Sciences.

An estimated 4 million Americans suffer from Alzheimer’s disease, a brain-wasting disorder with no cure. The Alzheimer’s Association projects that number will reach 14 million by the middle of the century.

In Alzheimer’s, two different pathologies are at work in the brain. These are amyloid plaques caused by beta-amyloid protein deposits and neurofibrillary tangles containing clumps of altered tau proteins.

The data that showed that nicotine could benefit Alzheimer’s was found in mice that had brain plaque only, LaFerla explained.

In that experiment, “treating the mice with nicotine seemed to help by reducing the plaque load in the brain,” he explained. “From that, people have been saying that nicotine might be a useful compound.”

In Alzheimer’s disease, there is a loss of the neurotransmitter called acetylcholine, LaFerla noted. In fact, two of the treatments for Alzheimer’s interact with the enzyme that breaks down acetylcholine. Nicotine was thought to mimic the action of acetylcholine in one brain receptor, he explained.

In their experiments, LaFerla’s team wanted to see if nicotine had a beneficial effect on both plaque and tangle accumulation. The researchers gave nicotine to mice genetically engineered to develop both of these neurological markers of Alzheimer’s disease.

The researchers found that nicotine made matters worse. Nicotine increased the effect of altered tau proteins, causing brain tangles to develop sooner, LaFerla said.

Accelerated tangle development has been noted in specific types of Alzheimer’s patients, LaFerla noted. For example, the brains of Alzheimer’s patients who were chronic smokers displayed more tangles compared with nonsmoking Alzheimer’s patients, he said.

“It seems that smokers have a higher tangle burden in their brain,” LaFerla said. “Smoking is not useful if you are doing it to prevent Alzheimer’s disease.”

“Some primarily cross-sectional studies suggest that smoking is associated with reduced odds of Alzheimer’s disease, although many others dispute that finding, and several recent longitudinal studies actually report an increased risk of disease,” said Dr. David A. Bennett, director of the Rush Alzheimer’s Disease Center at Rush University Medical Center.

There has been an interest in the possible role of nicotine receptors or other biologic mechanisms linking smoking to dementia, Bennett said. “These data provide evidence of a link between nicotine receptors and the pathology of Alzheimer’s disease. I think it’s a very interesting article that provides evidence in support of the deleterious effects of smoking,” he added.

Another researcher, Steven H. Ferris, director of the Alzheimer’s Disease Center at New York University School of Medicine, said he’s not sure if these findings are enough to halt the use of nicotine in Alzheimer’s treatment, but he believes researchers should at least be on the lookout for negative results.

“While it would be premature to leap to the conclusion from this mouse data that nicotinic drugs might make Alzheimer’s disease patients worse, the study at least raises that possibility,” Ferris said.

“Since a number of nicotinic agonists are in the drug development pipeline, some in clinical trials, it may now be important to be extra alert for possible negative outcomes,” he added.