Nicotine and memory: benefits and therapeutic perspective for Alzheimer's disease

Author: Marco Bosia Fernanda Ciferri
Date: 15/02/2013



Acute administration of nicotine can improve cognitive performance (particularly tasks that require attention), short-term episodic memory and prospective memory task performance. These effects are due to the affinity of this alkaloid for nicotinic acetylcholine receptors since nicotine is the most important agonist of Acetylcholine. Short-term nicotine treatment, utilising nicotine skin patches, have shown that it may be possible to improve cognitive performance in a variety of groups such as normal non-smoking adults, Alzheimer’s disease patients, schizophrenics, and adults with attention-deficit hyperactivity disorder. However, evidence suggests that low doses of nicotine facilitate memory and high doses have no significant effect or may impair memory.

nAchR involved in memory

Nicotinic acetylcholinergic receptors are a class of ligandgated ion channels that are assembled from five subunits out of at least 17 identified subunits and are differentially expressed in both the central and peripheral nervous systems. Neuronal nAChRs have a pentameric structure and are comprised of either α (α7-α10) subunits or a combination of α (α2-α6) and β (β2-β4) subunits.
Both the α7 and α4β2* nAChR subtypes have properties that could contribute to the cognitive-enhancing effects of nicotine. For example, both nAChR subtypes are located in the hippocampus, both are expressed presynaptically and postsynaptically which suggests they could modulate both presynaptic and postsynaptic processes involved in synaptic plasticity and both gate calcium, which could enhance memory through activation of second messengers involved in synaptic plasticity or by facilitating neurotransmitter release.
Modulation of Hippocampus-Dependent Learning and Synaptic Plasticity by Nicotine. 2008

The Role of Hippocampus

The hippocampus plays a critical role in the transfer of short-term memories to long-term memories: the well-known case of patient HM made it possible to understand this fundamental function of medial temporal lobe.
It is clear that, in addition to playing a critical role in the formation of long-term memories, the hippocampus is critically involved in integrating and processing spatial and contextual information. Theories of hippocampal function have proposed that the hippocampus is involved in forming configural associations between stimuli such as those involved in learning a context or to navigate in space. The ability of the hippocampus to aid in the formation of long-term memories and to process configural information may be one reason that the hippocampus is believed to be important for declarative memory function.

Molecular Mechanism

According to several studies it is known that nicotine modulates synaptic plasticity in the hippocampus, facilitating long-term memory. This process is modulated by astrocytes through the release of D-serine, an endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors: hippocampal long-term synaptic plasticity induced by nicotine is annulled by blocking the action of this co-agonist.

Most of the changes in synaptic transmission in the CA1 hippocampal region require the activation of NMDA receptors. These receptors serve as coincidence detectors of presynaptic and postsynaptic activity because they require, besides the presence of glutamate and the co-agonist, a membrane depolarization to remove the Mg2+ blocking from their ion channel.

Due to the electrical stimuli and nicotine activation of nAChRs, the Schaffer collateral terminal releases glutamate that could interact with postsynaptic AMPA and NMDA receptors (AMPAR and NMDAR) in the CA1 pyramidal neuron.
At the same time, nicotine:

  • activates Ca2+-permeable nAChRs located in the postsynaptic neuron (helping of the removal of Mg2+ ions for the NMDA receptor)
  • promotes in astrocytes the Ca2+-dependent release of D-serine.

These brain cells and events would participate in concert to allow nicotine to enhance both NMDA receptor-dependent synaptic transmission and memory.
Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory. 2012

Cholinergic Innervation of Brain

There is widespread cholinergic innervation throughout the brain to a variety of targets, including the hippocampus. Generally speaking, these projections are diffuse and suggest broad, modulatory roles for cholinergic signaling at either muscarinic or nicotinic targets. The medial septum-diagonal band complex is the primary source of cholinergic inputs to the hippocampus via the fimbria-fornix. The importance of these projections in maintaining normal cognitive function is highlighted by the fact that degeneration of the cholinergic neurons of the basal forebrain accompany cognitive deficits that arise is such degenerative pathologies as Alzheimer’s disease.
Nicotinic mechanisms influencing synaptic plasticity in the hippocampus. 2009

Therapeutic perspective

While tobacco smoking is associated with an increased risk of Alzheimer's disease, there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease. Nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans. A study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.

A study supported by the National Institute on Aging and the National Institute of General Medical Sciences: Nicotine treatment of mild cognitive impairment. 2011 showed that transdermal nicotine can improve some measures of attention and short-term memory in older patients with mild cognitive impairment.
The nicotine patch, best known as a smoking cessation aid, is now showing benefit as a treatment for mild cognitive impairment. New evidence suggests the patch improves cognitive test performance in older adults with early memory loss.
The study included 74 non-smokers with mild cognitive impairment. Half of the participants received a nicotine patch of 15 mg/day, and half received a placebo. After 6 months of treatment, the nicotine-treated group regained 46% of normal performance for age on long-term memory. In contrast, patients in the placebo group declined by 26% during the same period.
The study demonstrated that nicotine improved primary and secondary cognitive measures of attention, memory, and mental processing, but not ratings of clinician-rated global impression.
Nicotine has been shown to improve cognitive performance in smokers who have stopped smoking, and previous short-term studies with nicotine have shown attention and memory improvement in patients with Alzheimer's disease.

Another study, Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease. 2011 indicates that 6 weeks of nicotine treatment reduced the levels of Aβ(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).

The study Chronic Stress and Alzheimer’s Disease-Like Pathogenesis in a Rat Model: Prevention by Nicotine. 2011 points out that nicotine and its metabolites (cotinine) inhibit β-amyloidosis, thus reducing amyloid levels by non-specifically binding to Aβ and preventing an α-helix to β-sheet conformational conversion and delaying the onset of aggregation.

MTHFR and memory

The brain is particularly sensitive to folate metabolic disturbances, since methyl groups are critical for its functions. Methylenetetrahydrofolate reductase generates the primary circulatory form of folate required for homocysteine remethylation to methionine. Neurological disturbances have been described in homocystinuria caused by severe MTHFR deficiency.
Volumes (whole brain and hippocampus) and morphology, global DNA methylation, apoptosis, expression of choline acetyltransferase (ChAT) and glucocorticoid receptor (GR), and concentrations of choline metabolites were assessed in hippocampus. Mthfr(-/-) mice had impairments in motor function and in short- and long-term memory, increased exploratory behavior and decreased anxiety. They showed decreased whole brain and hippocampal volumes, reduced thickness of the pyramidal cell layer of CA1 and CA3, and increased apoptosis in hippocampus. There was a disturbance in choline metabolism as manifested by differences in acetylcholine, betaine or glycerophosphocholine concentrations, and by increased ChAT levels. Mthfr(-/-) mice also had increased GR mRNA and protein. Our study has revealed significant anomalies in affective behavior and impairments in memory of Mthfr(-/-) mice. We identified structural changes, increased apoptosis, altered choline metabolism and GR dysregulation in hippocampus.
Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus. 2012

B-vitamin deficiency and cognitive impairment

In older adults, mildly elevated plasma total homocysteine is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease. In B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. 2008 it was reported that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline.
Exposing animals to elevated plasma homocysteine through genetic, pharmacologic, and dietary manipulations has so far failed to produce clear evidence of homocysteine-mediated neurotoxicity.
There is stronger evidence for a direct link between impaired homocysteine metabolism and cerebrovascular disease. Structural and functional vascular changes have been observed in the cerebral arterioles of mice with genetic defects in homocysteine metabolism that were fed diets lacking in folate and vitamin B-12 and high in methionine.
The biochemical mechanism is that B-vitamin deficiency inhibits homocysteine's conversion to methionine or cysteine, causing it to accumulate while methionine is depleted.


Even if more studies are required in order to assess a real therapeutic efficacy of nicotine in treating Alzheimer's disease, so-far results are promising and encouraging since nicotine, as discussed, not only facilitates synaptic plasticity in the hippocampus, thus improving short and long-term memory in older patients with mild cognitive impairment, but also acts against the formation of Aβ peptide, the main component of amyloid plaques which characterize Alzheimer's disease.

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