Newhouse and others have been studying the cognitive benefits of nicotine in people with Alzheimer’s and memory loss since the 1980s (Newhouse et al., 1988; Wilson et al., 1995; Jones et al., 1992). Nicotine binds to acetylcholine receptors that populate the cortical neurons lost in AD. (For a review of nicotinic receptors in AD, see Buckingham et al., 2009.) The study authors thought that people with MCI could be ideal patients for a nicotine therapy because they still possess most of the neurons that express the nicotine receptors.

Half of the subjects received a nicotine patch and half a placebo patch. Since one of the most well-known effects of nicotine is to advance concentration (reviewed in Heishman et al., 2010), the researchers applied the Conners Continuous Performance Test. This is a complex but dull task in which subjects see a variety of stimuli and have to hit a button every time they see an "X," for example, Newhouse said. A person who is concentrating will hit that button with the same speed every time the "X" pops up, while someone whose mind wanders will have a more variable response rate. In the people on nicotine, response rate was more consistent than for those on placebo. The effect size was “moderate to moderately large,” Newhouse said. One would not expect positive results from more standard tests of cognition used in Alzheimer’s research, such as the ADAS-cog (Alzheimer’s Disease Assessment Scale-Cognitive Subscale), because those do not focus on attention and working memory, noted Lon Schneider of the University of Southern California in Los Angeles, who was not involved in the study.

While nicotine is unlikely to address all of the deficiencies of MCI and Alzheimer’s, such as episodic memory loss, better attention might help people focus on their activities and social interactions, Schneider said. It might be the caregivers who notice the benefit most, as their loved ones are better able to respond to requests, added Kelly Dineley of the University of Texas Medical Branch at Galveston, who also did not participate in the study.

To examine the real-world effects of nicotine, Newhouse and colleagues asked their subjects’ physicians, who were blinded to the treatment, for a “seat-of-the-pants overview” of whether the patients were doing any better. Although people on the active patch seemed to improve a tad, according to the doctors, these results were not statistically significant—but given the small size of the study, it would have been “miraculous” if they were, commented David Knopman of the Mayo Clinic in Rochester, Minnesota, who also did not participate in the trial. “We were encouraged that at least the trend ran in the right direction,” Newhouse said.

In a slew of secondary measures, the team also found that people on nicotine showed improvements in long-term recall. Also, in a handful of reaction time and memory tests, the researchers observed an effect on the ApoE genotype. People who carried a double dose of the ApoE4 gene—and thus were at increased risk for AD—gleaned the most benefit from nicotine treatment. Similarly, a study of college students also found that ApoE4 carriers got a bigger boost in concentration powers from nicotine than did non-carriers (Marchant et al., 2010). The cholinergic receptors may be more active in ApoE4 carriers, allowing nicotine to have greater impact, Newhouse speculated. The receptors also might be distributed differently depending on ApoE genotype, Dineley suggested.

Side effects from nicotine, including nausea and weight loss, were minimal. “There was no withdrawal, there was no addiction,” Newhouse said. The team is still processing data from a six-month, open-label extension. The work “is one more piece of evidence that nicotinic modulation could be fairly helpful,” Schneider said. Nicotine and related molecules have been underappreciated in the Alzheimer’s field, he noted, but this work makes it clear that a larger study is in order.

The next question, Dineley suggested, is whether nicotine treatment would affect a person’s progression from MCI to full-blown Alzheimer’s. “That would make it a very powerful early intervention,” she said. It would likely be difficult to observe a slowing of progression in a trial, Newhouse said, noting that no other treatment has achieved that goal. Instead, he is interested in analyzing biomarkers that might indicate the disease’s trajectory is slowing.

Until results from a larger are trial are in, it is too early for people worried about memory loss to consider slapping on a nicotine patch, Knopman cautioned. “The fact is, this study had no clinical benefit,” he stated. Scientists are taking a “wait and see” approach before extolling the virtues of nicotine.—Amber Dance.

Reference:
Newhouse P, Kellar K, Aisen P, White H, Wesnes K, Coderre E, Pfaff A, Wilkins H, Howard D, Levin ED. Nicotine treatment of mild cognitive impairment. Neurol. 2012 Jan 10;78:91-101. Abstract