Nicotine May Slow Mild Memory Loss

Posted in GUMC Stories

Scientific studies have shown nicotine improves focus and concentration. So it makes sense that older individuals with diagnosed memory issues might also gain benefit from use of nicotine, the brain stimulant in tobacco.

So says Ken Kellar, Ph.D., a professor of pharmacology at Georgetown University Medical Center (GUMC), who, with Paul Aisen, M.D., and colleagues from Georgetown, as well as teams of investigators at the University of Vermont, Vanderbilt University, and Duke University Medical Center, just found support for this notion in a study published January 10 in Neurology.

The theory seems simple, but confirming it took decades. And, still, the findings were a little bit surprising.

The Trial

In a small, double blind, pilot clinical trial, the researchers found that individuals diagnosed with mild cognitive impairment (MCI) who used nicotine patches for six months showed improvements in attention, memory, and mental processing that were statistically significant in objective tests of cognitive function and, perhaps more important, apparent to both the subjects and their families, compared to MCI patients who were given a placebo (dummy) patch. For example, the team found that after six months of treatment, participants who received nicotine regained up to 46 percent of normal performance for their age on certain long-term memory tests, whereas the placebo group worsened by 26 percent during that time.

Despite these improvements, the overall assessments by clinicians were not rated as significantly improved. But that may be because the clinicians were not in daily contact with the study participants, the researchers say.

MCI is regarded as a state of transition from normal memory to possible dementia. Between 8 and 15 percent of people diagnosed with the condition will progress to a diagnosis of Alzheimer’s disease within about a year.

The surprising part is that the researchers were not necessarily expecting to see “efficacy” or benefit from the nicotine patches in such a small trial (74 nonsmokers with an average age of 76 were enrolled). This phase I study was designed only to gauge the safety of nicotine administered by transdermal patch in nonsmokers. This trial found it to be safe and well tolerated by those MCI patients randomized to receive it.


“When we started this project, we were not looking for efficacy because we thought the numbers of patients enrolled in this study would be too low to show statistically significant clinical improvement,” says Kellar.

“Now we may have some early evidence that could suggest nicotine may change the course of MCI, and possibly slow progression to Alzheimer’s disease,” he says.

Kellar adds that these preliminary findings should not be interpreted as a license for anyone with suspected memory loss to slap on a nicotine patch. “There are a lot of things we don’t know yet, and so we need to be very cautious,” he says. “Certainly, use of nicotine should be supervised by a physician because it can have side effects in some people.”

But even getting to the point where Kellar and his colleagues could posit that nicotine might help stave off some of the effects of dementia took a long time.

Kellar’s lab has been interested in the relationship between Alzheimer’s disease and nicotinic acetylcholine receptors in the brain since the mid-1980s. At that time, his lab and two other labs discovered that autopsied brains from patients with Alzheimer’s had a large loss of these receptors, which are stimulated by both acetylcholine and nicotine. The initial findings have since been replicated by numerous studies performed around the world.

Researchers don’t know what this loss means to progression of the disease, or if stimulating the remaining receptors might help, but Kellar and two of his longtime colleagues, Paul Newhouse, M.D., from the University of Vermont (later Vanderbilt University), and Ed Levin, Ph.D., from Duke University Medical Center, decided to design a study to test nicotine use in people with MCI. “We think if you are going to interrupt the course of development of Alzheimer’s disease, you have to do it at the earliest time possible.”

That was eight years ago. Their study, the first placebo-controlled, double blind clinical trial of nicotine’s effect on MCI funded by the National Institute on Aging, was held at three centers. Aisen (now at the University of California at San Diego) and Kellar directed the study at GUMC, which enrolled 24 participants.

New Questions

The investigators don’t know how nicotine appears to improve MCI, but they theorize that the chemical may rev up functioning in cells that are in decline and also help keep brain cells alive. They also found a tantalizing mechanistic clue: subjects with the known Alzheimer’s disease susceptibility gene, apolipoprotein E-4 (APOE4), did slightly better using nicotine than did MCI patients on nicotine who did not have the gene. “Folks with APOE4 are at significantly higher risk of developing the disease, so we are very cautiously hopeful that nicotine might help reduce that risk,” Kellar says.

The researchers plan to pursue a larger trial at multiple centers to validate and expand their findings. And Kellar hopes investigators globally will study the potential MCI treatment as well. “If a lot of people get involved, we could have a definitive answer within a few short years,” he says. “That’s not too soon for thousands and thousands of people who hope for help as soon as possible.”

By Renee Twombly, GUMC Communications
(Published January 9, 2012)