The same nicotine patch that helps smokers kick the habit boosts the concentration powers of people with mild cognitive impairment, according to a study in the January 9 Neurology. The authors report the results of a pilot trial, the first for nicotine and MCI. At six months in duration, it's the longest trial to date to test the cognitive benefits of the drug, said lead author Paul Newhouse of the Vanderbilt University School of Medicine in Nashville, Tennessee. People on the patch, versus placebo, performed better on a concentration task. “We think it is very promising in terms of early intervention in pre-Alzheimer’s and MCI,” Newhouse said. “We think that the results justify larger studies.”
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
- Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL. Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology (Berl). 1988;95(2):171-5. PubMed.
- Wilson AL, Langley LK, Monley J, Bauer T, Rottunda S, McFalls E, Kovera C, McCarten JR. Nicotine patches in Alzheimer's disease: pilot study on learning, memory, and safety. Pharmacol Biochem Behav. 1995 Jun-Jul;51(2-3):509-14. PubMed.
- Jones GM, Sahakian BJ, Levy R, Warburton DM, Gray JA. Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer's disease. Psychopharmacology (Berl). 1992;108(4):485-94. PubMed.
- Buckingham SD, Jones AK, Brown LA, Sattelle DB. Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. Pharmacol Rev. 2009 Mar;61(1):39-61. PubMed.
- Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology (Berl). 2010 Jul;210(4):453-69. PubMed.
- Marchant NL, King SL, Tabet N, Rusted JM. Positive effects of cholinergic stimulation favor young APOE epsilon4 carriers. Neuropsychopharmacology. 2010 Apr;35(5):1090-6. PubMed.
- Ren K, Thinschmidt J, Liu J, Ai L, Papke RL, King MA, Hughes JA, Meyer EM. alpha7 Nicotinic receptor gene delivery into mouse hippocampal neurons leads to functional receptor expression, improved spatial memory-related performance, and tau hyperphosphorylation. Neuroscience. 2007 Mar 2;145(1):314-22. PubMed.
- Mehta M, Adem A, Kahlon MS, Sabbagh MN. The nicotinic acetylcholine receptor: smoking and alzheimer's disease revisited. Front Biosci (Elite Ed). 2012;4:169-80. PubMed.
- Arias E, Gallego-Sandín S, Villarroya M, García AG, López MG. Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells: role of nicotinic receptors. J Pharmacol Exp Ther. 2005 Dec;315(3):1346-53. PubMed.
- White HK, Levin ED. Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease. Psychopharmacology (Berl). 1999 Apr;143(2):158-65. PubMed.
- White HK, Levin ED. Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology (Berl). 2004 Feb;171(4):465-71. PubMed.
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- 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: A 6-month double-blind pilot clinical trial. Neurology. 2012 Jan 10;78(2):91-101. PubMed.