Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue3.2001:

Nicotinic Receptor Abnormalities of Alzheimer’s
Disease: Therapeutic Implications
Agneta Nordberg
The neuronal nicotinic acetylcholine receptors (nAChRs)
in the brain are important for functional processes,
including cognitive and memory functions. The nAChRs
acting as neuromodulators in communicative processes
regulated by different neurotransmitters show a relatively
high abundance in the human cortex, with a laminar
distribution of the nAChRs of superhigh, high, and low
affinity in the human cortex. The regional pattern of
messenger RNA (mRNA) for various nAChR subtypes does
not strictly follow the regional distribution of nAChR
ligand-binding sites in the human brain. Consistent losses
of nAChRs have been measured in vitro in autopsy brain
tissue of Alzheimer’s disease patients (AD), as well as in
vivo by positron emission tomography (PET). Measurement of the protein content of nAChRs showed reduced
levels of the a4, a3, and a7 nAChR subtypes. The finding
that the a4 and a3 mRNA levels were not changed in AD
brains suggests that the losses in high-affinity nicotinicbinding sites cannot be attributed to alterations at the
transcriptional level of the a4 and a3 genes and that the

causes have to be searched for at the translational and/or
posttranslational level. The increased mRNA level of the
a7 nAChR subtyep in the hippocampus indicates that
subunit-specific changes in gene expression of the a7
nAChR might be associated with AD. The PET studies
reveal deficits in nAChRs as an early phenomena in AD,
stressing the importance of nAChRs as a potential target
for drug intervention. PET ligands measuring the a4
nAChRs are under development. Studies of the influence of
b-amyloid on nAChRs in brain autopsy tissue from patients with the amyloid precursor protein 670/671 mutation have shown that there is no direct relationship
between nAChR deficits and pathology. Treatment with
cholinergic drugs in AD patients indicate improvement of
the nAChRs in the brain, as visualized by PET. Further
studies on neuroprotective mechanisms mediated via
nAChR subtypes are exciting new avenues. Biol Psychiatry 2001;49:200 –210 © 2001 Society of Biological
Psychiatry

From the Department of NEUROTEC, Division of Molecular Neuropharmacology,
Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden.
Address reprint requests to Agneta Nordberg, M.D., Ph.D., Department of NEUROTEC, Division of Molecular Neuropharmacology, Huddinge Hospital B84,

S-141 86 Huddinge, Sweden.
Received June 1, 2000; revised November 13, 2000; accepted December 8, 2000.

© 2001 Society of Biological Psychiatry

Key Words: AD, human brain, nicotinic receptor subtypes, PET ligands, nicotinic agonists, APP 670/671,
cholinesterase inhibitors

Introduction

T

he neuronal nicotinic acetylcholine receptors
(nAChRs) are transmitter-gated ion channels that
belong to a superfamily of ion channels of homologous
receptors including g-aminobutyric acid, glycine, and
serotonin 3 (5-HT3) (Karlin and Akabas 1995; Paterson
and Nordberg 2000; Sargent 1993, 2000). The nAChRs
are obvious candidates for transducing cell surface interactions, not only for acetylcholine but also for other
neurotransmitters (Kaiser et al 2000; Wonnacott 1997).

Experimental data suggest that the nAChRs might act as
neuromodulators in communicative processes in the brain
(Kaiser et al 2000; Lindstro¨m 1997; Wonnacott 1997). It is
therefore of great importance to define by which mechanisms the nAChRs exert their action in the brain. The
nAChRs are found to be involved in a complex range of
central nervous system disorders including Alzheimer’s
disease (AD), Parkinson’s disease, schizophrenia,
Tourette’s syndrome, anxiety, depression, and epilepsy
(Newhouse and Kelton 2000; Newhouse et al 1997;
Paterson and Nordberg 2000). The exact role of nAChRs
and their full potential as a therapeutic target in these
diseases have yet to be clarified. Interestingly enough, a
considerable body of evidence exists to suggest that the
nAChRs are involved in cognitive and memory functions
(Levin 2000; Newhouse and Kelton 2000; Newhouse et al
1997; Sahakian and Coull 1994).
Alzheimer’s disease is the most common form of
dementia and one of the most devastating diseases of the
middle aged and elderly. Although the last decade has
witnessed a steadily increasing effort directed at discovery

of the etiology and neuropathologic and neurochemical
mechanisms involved in the disease, there is still no cure
(Braak and Braak 1998; Cohen-Mansfield 2000; Fratiglioni et al 1999; Hardy 1997; Master and Beyreuther 1998;
St George-Hyslop 2000,). However, extensive research
activities have stimulated the development of new
0006-3223/01/$20.00
PII S0006-3223(00)01125-2

Nicotinic Receptor Abnormalities in AD

treatment strategies in AD, and several drugs that improve
cholinergic transmitter activity have reached clinical use
(for a review, see Nordberg and Svensson 1998). The role
of nAChRs in AD is discussed below, with the focus
mainly on new therapeutic implications.

nAChRs in the Human Cortex
The nAChRs are distributed in many regions of the human
brain. So far the nAChR subunits a3, a4, a5, a7, b2, b3,
and b4 have been cloned (Anand and Lindstrom 1990;

Chini et al 1994; Fornasari et al 1990; Matter and Ballivet
2000; Raimondi et al 1991; Willoughby et al 1993). The
distribution of the nAChRs and their transcripts have been
mapped in vitro in the human brain, using autoradiography
(Adem et al 1988, 1989; Court and Perry 1994; Sihver et
al 1998b), in situ hybridization (Rubboli et al 1994; Wever
et al 1994), and reverse transcription polymerase chain
reaction (Hellstro¨m-Lindahl et al 1998). In vitro receptor
binding studies in human autopsy brain tissue suggest that
nAChRs are heterogeneous and can be rationalized to
three different nAChR sites (superhigh, high, and low
affinity) (Marutle et al 1998; Nordberg et al 1988; Warpman and Nordberg 1995). The distribution of high-affinity
nAChRs was studied with [3H]nicotine and [3H]epibatidine as radioactive receptor ligands (Marutle et al 1998;
Sihver et al 1998b). Two high-affinity nAChR sites were
identified in the human cortex with [3H]epibatidine, most
likely representing the a3 and a4b2 nAChR subtypes.
Differences in the regional binding between [3H]nicotine
and [3H]epibatidine were observed in the human brain,
with a proportionally higher level of [3H]epibatidine
binding sites in the thalamus and cerebellum. The difference possibly reflects a selectivity for different nAChR

subtypes between the nAChR ligands, nicotine, and epibatidine—that is, a greater selectivity for [3H]epibatidine
for the a3 nAChRs in the human brain (Marutle et al
1998).
The laminar distribution of nAChRs in human cortex
was studied in autopsy brain tissue, using autoradiographical analysis and the nAChR ligands [3H]nicotine, [3H]epibatidine, and [3H]cytisine (Sihver et al 1998b). A general
high binding was observed in layers 1, 11, and V, with
particularly high levels in the layer of primary sensory
motor cortex and the inferior frontal sulcus (Sihver et al
1998b). All three ligands appeared to bind to a common
high-affinity binding site, which most likely represents
binding to the nAChR a4 subunits. A significantly greater
binding for [3H]nicotine and [3H]epibatidine than for
[3H]cytisine is observed in areas of the primary motor
cortex, layer 111b of the occipital cortex, and layer V of
the superior temporal sulcus, most likely representing
binding of an additional nAChR site. High levels of

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201

[3H]nicotine binding have been observed in layers 1 and
V1 of the primary cortex, deeper layer V of the primary
cortex, layer 111 of the superior temporal sulcus, and layer
V1 of the parietal cortex. This suggests the presence of an
additional third nAChR site in the human cortex (Sihver et
al 1998b) that may be the a7 nAChR subtype.
The distribution of messenger RNA (mRNA) for different nAChR subunits has been examined in different
cortical layers (Schro¨der et al 1995). The a4 mRNA seems
to be abundant in all layers except 1 and IV of the frontal
cortex (Schro¨der et al 1995). The a3 mRNA has been
found to be most prominently expressed in the pyramidal
neuron layers 111–V1, moderately expressed in layer 11,
and minimally expressed in layer IV of the human cortex
(Schro¨der et al 1995; Wever et al 1994). A high expression
of a7 mRNA was observed in layers 11 and 111, moderate
in layers V and V1, and low in layers I and IV of the
human cortex (Schro¨der et al 1995). A significant decrease
in [3H]epibatidine binding has been observed with aging

in the human cortical brain regions and cerebellum (Marutle et al 1998). The levels of a4 and a7 nAChR mRNA
showed a decrease with aging, whereas the levels of a3
mRNA were unchanged in the elderly brain relative to the
fetal brain (Hellstro¨m-Lindahl et al 1998). Interestingly,
the observed regional pattern of expression of nAChR
subunit mRNA in the human brain does not directly
correspond to the regional pattern of nAChR binding sites
revealed by ligand-binding studies.

nAChR Changes in AD
A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from AD patients
relative to age-matched healthy subjects (Nordberg and
Winblad 1986). More recently, we have have found that
the nAChR deficits in AD brains probably represent an
early phenomenon in the course of the disease, which can
be detected in vivo by positron emission tomography
(PET) (Nordberg et al 1990, 1995, 1997). The cortical
nAChR deficits significantly correlate with cognitive impairment in AD patients (Nordberg, in press; Nordberg et
al 1995, 1997).
When the laminar binding distribution of [3H]nicotine,

3
[ H]epibatidine, and [3H]cytisine was measured in AD
cortical autopsy tissue, marked reductions were observed
relative to control brains (Sihver et al 1999c) (Figure 1). In
addition, a marked reduction in the laminar distribution of
[3H]epibatidine binding was observed in control cortical
tissue with aging (Figure 1). A reduction in the density of
the presynaptic vesicular acetylcholine transporter binding
sites measured by [3H]vesamicol was also seen in the AD
cortical tissue, but the decrease in [3H]vesamicol binding
was less than in nAChRs. The observation suggests that

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A. Nordberg

Figure 1. Laminar distribution of [3H]epibatidine through the entire cortical depth of the human temporal cortex from a control and

an Alzheimer’s disease (AD) patient of young age (top) and from a control and an AD patient of a higher age (bottom). The binding
profiles are means 6 SEMs created from three to six sections. The division of I–VI corresponds to different laminae according to the
Brodmann atlas. Data are from Sihver et al (1999c).

the vesamicol binding sites may be more preserved in the
existing presynaptic terminals of AD cortical tissue,
thereby expressing a compensatory capacity to maintain
cholinergic activity. In addition, the observation suggests
that nAChRs are present on noncholinergic nerve terminals to a significant extent. Basal forebrain lesions in rats,
with the selective cholinergic immunotoxin 192Ig saporin
and ibotenic acid, also show the rich presence of nAChRs
on noncholinergic nerve terminals (Bednar et al 1998),
supporting the assumption of nAChR as a neuromodulator
also in noncholinergic nerve terminals (Kaiser et al 2000).
b-Amyloid (Ab) is also an important factor, which may
initiate and promote AD (Selkoe 1999). Recently, the
possible role of Ab as a neuromodulator in the brain has
stressed the possible regulatory mechanisms between Ab
and cholinergic neurotransmission and nAChRs in the

brain (Auld et al 1998). We have investigated the influence of Ab on nAChRs in autopsy brain tissue from AD
patients carrying the Swedish amyloid precursor protein
(APP) 670/671 mutation and in brain tissue from sporadic
cases of AD (Marutle et al 1999). This mutation at codon
670/671 on the APP gene on chromosome 21 was discovered in a Swedish family, and the mutation is unique in the
sense that it is the only AD mutation that has been shown
to alter the APP metabolism, resulting in an overexpression of the amyloid leading to plaque formation (Mullan et
al 1992). Significant reductions in the number of nAChRs
were measured in cortical regions of Swedish APP 670/
671 mutation (273% to 287%) (Marutle et al 1999) The
reduction in nAChRs was more pronounced than in the
sporadic AD cases (237% to 257%) when compared with
age-matched control subjects. The APP 670/671 carrier

Nicotinic Receptor Abnormalities in AD

Figure 2. (A) Correlation between neuronal plaques and [3H]nicotine binding in the temporal cortex and parietal cortex of four
patients (P1–P4) carrying the Swedish amyloid precursor protein
(APP) 670/671 mutation. (B) Correlation between neurofibrillary
tangles and [3H]nicotine binding in the temporal cortex and
parietal cortex of four patients (P1–P4) carrying the APP
670/671 mutation. Data are from Marutle et al (1999).

was approximately 15 years younger than the sporadic
patients. Both positive and negative correlations were
observed between the number of nAChR binding sites and
the number of neuronal plaques and neurofibrillary tangles, respectively, in the temporal cortex and parietal
cortex of mutation carriers. This finding suggests that
these processes may be closely related but not directly
dependent on each other (Figure 2). Different brain regions may show different kinetics for the development of
neurofibrillary tangles and neuritic plaques. We have
recently characterized the nAChRs in APP 670/671 transgenic mice and found compensatory mechanisms for some
of the nAChR subtypes, which correlates to behavior and
pathology in the transgenic mice (Paterson et al, unpublished data).
A decrease in the protein levels of the a3 and a4
nAChR subunits was recently measured in the temporal
cortex and of the a3, a4, and a7 nAChR subtypes in the
hippocampi of AD brains relative to age-matched control
subjects (Guan et al 2000b). A decrease in protein levels of

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203

the a4 nAChR but not of the a3 and a7 nAChRs was
reported by Martin-Ruiz et al (1999). The explanation for
the differences in results obtained by Martin-Ruiz et al
(1999) and Guan et al (2000b) is unknown. Lee et al
(2000) recently also reported a significant decrease in the
a7 nAChR protein level of the AD hippocampus. Interestingly, a reduction in the protein level of a7 has also
been measured in the frontal cortex of patients with
schizophrenia (Guan et al 1999), whereas no decrease was
measured in the a4 nAChR protein level (Guan et al
1999). The deficits in nAChRs seen in AD brains may be
related to alterations of the nAChR synthesis on different
levels such as transcription, translation and postranslation
modifications, and receptor turnover.
Examination of the regional expression of mRNA of the
nAChR a4 and a3 subunits has shown no difference in
autopsy AD brain tissue in any region analyzed (Hellstro¨m-Lindahl et al 1999; Terzano et al 1998), whereas the
level of the a7 mRNA was significantly higher in the
hippocampus (Hellstro¨m-Lindahl et al 1999). The studies
suggest that the nAChR deficits in AD brains mainly
reflect posttranscriptional events (Hellstro¨m-Lindahl et al
1999; Schro¨der and Wever 1998). The mechanisms for
changes in protein levels of nAChRs in AD are unclear.
Possible factors such as amyloid peptide accumulation,
hyperphosphorylation of tau protein, oxidative stress, and
modification of cell membrane during the development of
AD may be related to decreased protein levels of nAChRs
(Farooqui et al 1995; Smith et al 1996). Interestingly
enough, lipid peroxidation has been shown to decrease the
number of nAChRs in PC12 cells (Guan et al 2000a).

Visualization of nAChRs in AD by PET
Significant progress has been made during recent years in
developing and applying functional brain imaging techniques to allow for early diagnosis of AD and evaluation
of drug treatment efficacy. Positron emission tomography
might be a suitable method for functional studies of
pathologic changes in the brain, not only revealing dysfunctional changes early in the course of the disease but
also providing a deep insight into the functional mechanisms of new potential drug treatment strategies. A limited
number of PET ligands are so far available for mapping
the cholinergic system in the human brain (Table 1).
[11C]Physostigmine, [11C]MPA4A, and [11C]PMP have
been used in PET studies to measure acetylcholinesterase
in brains of healthy volunteers (Kuhl et al 1999; Namba et
al 1999; Pappata et al 1996). Positron emission tomography studies have revealed a reduced cortical acetylcholinesteserase activity in AD patients (Iyo et al 1997; Kuhl
et al 1999). A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with

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A. Nordberg

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Table 1. Positron Emission Tomography (PET) and Single Photon Emission Computed
Tomography (SPECT) Ligands for Visualization of Cholinergic Activity in the Human Brain
Parameter
Acetylcholinesterase
Cholinergic terminals
Nicotinic receptors

Muscarinic receptors

Radioligand
11

Imaging
technique

[ C]MP4A
[11C]PMP
[123I]IBVM
[11C]Nicotine

PET
PET
SPECT
PET

[11C]Benztropine
[11C]QNB
[11C]NMPB

PET
SPECT
PET

References
Iyo et al 1997
Kuhl et al 1999
Kuhl et al 1996
Nordberg et al 1990, 1995
Nyba¨ck et al 1994
Muzic et al 1998
Dewey et al 1990
Weinberger et al 1991
Zubieta et al 1998

MP4A, N-methyl-4-piperidyl-acetate; PMP, methylpiperidin-4-yl propioate; IBVM, iodobenzovesicamol; QNB, quinuclidinylbenzilate; NMPB, N-methylphenylbenzilate.

cognitive decline (Shinotoh et al 2000). The presynaptic
vesicular acetylcholine transporter vesamicol ([123I]iodobenzovesamicol) has been used in vivo as a marker of
presynaptic cholinergic activity in single photon emission
computed tomography (SPECT) studies (Kuhl et al 1996).
Greater reduction in [123I]iodobenzovesamicol binding
was observed throughout the cerebral cortex in AD patients with early onset of the disease (Kuhl et al 1996). The
loss in cortical acetylcholinesterase activity was less pronounced in mildly demented AD patients relative to
autopsy material and did not strictly correlate with cerebral glucose metabolism impairment (Kuhl et al 1999).
The development of methods for the synthesis of
radiolabeled nicotinic ligands with short half-life [11C] has
enabled the study of the binding of [11C]nicotine in both
normal and AD brains by PET (Nordberg et al 1990,
1995). The use of [11C]nicotine in PET studies was
reviewed by Mazie´re and Delforge (1995), who identified
some problems with the tracer due to high nonspecific
binding, rapid metabolism, and rapid washout from the
brain. [11C]Nicotine has drawbacks such as rapid dissociation from the receptor ligand and strong dependence of
accumulation on cerebral blood flow. Different kinetic
modeling approaches have been developed to improve the
analysis of the PET studies, and the dual tracer kinetic rate
constant (k2*) model for [11C]nicotine compensates for
some of the problems (Lundqvist et al 1998). The measurement of [11C]nicotine in the human brain in vivo by
PET (k2*) agrees with the distribution of nAChRs observed by in vitro radioligand binding in human brain
tissue autopsy (Nordberg 2000b). A significant decrease in
[11C]nicotine binding (increase in k2* value) was measured in the temporal cortex, frontal cortex, and hippocampus (Nordberg et al 1995, 1997). Selective cortical deficits
in [11C]nicotine binding are often observed by PET early
in the course of the AD disease (Figure 3A). A significant
correlation can be observed between cognitive function
and nicotinic receptor binding (k2*) (Figure 3A). The

findings might be promising in that PET imaging combined with genetic testing (e.g., apolipoprotein E typing)
could be used to detect subjects with a greater risk of
developing AD.
The past several years have seen an expanded effort to
develop PET probes for noninvasive study of nAChRs.
This has also led to the search for new nAChR PET
ligands. A ligand with a selectivity for the a4b2 nAChRs
would be particularly preferable because the a4b2 has
been recognized as the predominant subtype that is deficient in AD (for a review, see Sihver et al 2000). Several
PET ligands have been synthesized, including [11C]ABT418, [11C]MPA, and [76Br]BAP (A-85380) (Sihver et al
1998a, 1999a, 1999b) (Figure 4). [11C]MPA and
[76Br]BAP (A-85380) showed a more distinct binding
pattern in the rat brain relative to [11C]nicotine and
[11C]ABT, as revealed by autoradiography (Figure 3B).
Administration of the PET ligands to monkeys also revealed a slower binding dissociation, and higher specific
binding for [11C]MPA and [76Br]A-85380 than for
[11C]nicotine and [11C]nicotine (Sihver et al 1999a,
1999b). The very high affinity for [76Br]A-85380, the high
specific in vivo uptake seen in monkeys (Figure 3C), and
thereby the possible a4b2 nAChR selectivity increase
interest in using the ligand in human PET studies. The
application of A-85830 analog with an [11C] label is
ongoing. Positron emission tomography studies using
2-[18F]A-85380 and SPECT studies with [123I]5-A-85380
have recently been performed in monkeys (Fujita et al
2000; Sihver et al 2000). Both PET and SPECT studies
reveal a high uptake of the radioligand to areas rich
in a2b2 nAChR such as the thalamus (Figure 3C).
Recently, several epibatidine analogs such as
norchloro[18F]fluoroepibatidine (Ding et al 2000) have
been developed, but it is still uncertain whether the
epibatidine analogs can be applied in humans due to risk
of toxicity.
Positron emission tomography studies not only allow

Nicotinic Receptor Abnormalities in AD

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2001;49:200 –210

205

Figure 3. (A) (Top) Horizontal positron emission tomography images of the uptake and distribution of [11C]nicotine at the level of the basal
ganglia (left) and the frontal association cortex–parietal cortex (right) in the brain of an Alzheimer’s disease patient with mild dementia. The
figure represents a summation picture of the brain uptake of [11C] radioactivity after an intravenous injection of a tracer dose of [11C]nicotine.
The color scale indicates radioactivity expressed in nCi/cm3/body weight. Red, high uptake; yellow, medium uptake; green, low uptake. The
patient shows left-side cortical deficits in [11C]nicotine. (Bottom) Correlation between cognitive function (Mini-Mental State Examination
[MMSE] score) and nicotinic receptor binding (k2* rate constant) in the temporal cortex of Alzheimer’s patients. p , .001. (B) Binding of
different nicotinic acetylcholine receptor ligands in the rat brain as visualized by in vitro autoradiography of coronal (left) and sagittal (middle)
rat brain sections. (Right) The nonspecific binding obtained in the presence of 100 mmol/L (2)nicotine is shown in the sagittal sections. The
binding density increases in the sequence black, yellow, red, white. ctx, cortex; hip, hippocampus; th, thalamus; cbl, cerebellum; str, striatum;
MPA, (R,S)-1-methyl-2-(3-pyridyl)azetidine; BAP, bromo-3-[[2(5)-azetidinyl]methoxy] pyridine. Data are from Sihver et al (1998a, 1999a).
(C) (a) Positron emission tomography image of [76Br]Br-A-85380 in a rhesus monkey brain (transverse section). The total uptake was
determined at a baseline scan (left), and a second scan was performed 3.5 hours later after injection of 0.5 mg/kg cytisine to block the uptake
of [76Br]Br-A-85380 (right). The ratios of total to block were 2.5 in the thalamus and 1.2 in the cortex. (b) Distribution of [76Br]Br-A-85380
binding in the rhesus monkey brain (horizontal section) as revealed by in vitro autoradiography (left). Nonspecific binding was determined
in the presence of 100 mmol/L (2)nicotine (right). ctx, cortex; th, thalamus; cbl, cerebellum. Data are taken from Sihver et al (2000).

measurement of nAChRs in steady-state situation in AD,
but also allow measurement of nAChRs during functional
activation studies. We have recently performed studies

where functional activation patterns in the brain during an
episodic memory task in healthy subjects as well as in AD
patients have been measured by cerebral blood flow

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A. Nordberg

Figure 4. Chemical structure of tentative nicotinic acetylcholine receptor positron emission tomography ligands. IPH, (6)exo-2-(2iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane; FPH, (6)-exo-2-(2-fluoro-5-pyridyl-7-azabicyclo[2.2.1]heptane.

changes with PET (Ba¨ckman et al 1997, 1999). In some
ongoing studies we are now measuring the changes in
nAChRs in different brain regions before and during task
performances such as attentional tests. This type of study
will provide further insight into the regional network in the
brain, where nAChRs play an important role, and how
drug treatment can improve brain function.

nAChRs: Target for AD Treatment?
Transmitter replacement therapy is the mainstay treatment
for AD. Cholinergic therapy is based on the assumption
that low levels of acetylcholine are responsible for the
cognitive decline associated with AD. Cholinesterase inhibitors including tacrine, donepezil, rivastigmine, and
galantamine have in clinical studies shown palliative
effects on symptoms and some trend to slow disease
progression (Giacobini 2000; Nordberg and Svensson
1998; Van den Berg et al 2000). It is likely that the
therapeutic benefit of cholinesterase inhibitors occurs at
least in part through activation of the nAChRs, by the
direct action of increased levels and/or through a direct
activation of the allosteric site on the nAChR (Maelicke et
al 1995, 2000).
Positron emission tomography and SPECT studies performed in AD patients under treatment with cholinergic
drug therapy have shown an improvement in the cerebral
blood flow and glucose metabolism (Nordberg 1999). In
addition, PET studies also have revealed an improvement
in nAChRs in AD patients during long-term treatment
with cholinesterase inhibitors such as tacrine and NXX066 (Nordberg 2000; Nordberg et al 1992, 1998). Since an

enhanced activity of acetylcholinesterase has been measured in cerebrospinal fluid following long-term treatment
with tacrine (Nordberg et al 1999), possibly as a result of
an increased acetylcholinesterase gene expression, it might
be an advantage to use drugs interacting with nAChRs.
Nerve growth factor intraventricularly administered to AD
patients for 3 months resulted in an increased [11C]nicotine binding (Eriksdotter-Jo¨nhagen et al 1998), whereas
treatment with the 5-HT3 blocker ondansetron showed a
decreased number of cortical nAChRs (Nordberg et al
1997). The few PET studies performed so far in AD
patients illustrate that the nAChRs might be sensitive
markers for modulatory processes induced by AD drugs.
The potential therapeutic benefit of nAChR stimulation
in AD is based upon the fact that nicotine improves
memory in animals, healthy subjects, and AD patients
(Levin 2000; Newhouse and Kelton 2000; Newhouse et al
1997; Rusted and Warburton 1992). Activation of the
nAChR modulates the release of several neurotransmitters
(Kaiser et al 2000; Wonnacott 1997) that mediate important physiologic mechanisms including cognitive
functions. Administration of the nicotinic antagonist
mecamylamine to elderly subjects and AD patients has
produced cognitive impairment (Newhouse and Kelton
2000). Acute administration of nicotine to AD patients has
resulted in a measurable short-term improvement in learning, memory, and attentional performance (Jones et al
1992). The therapeutic effect did not seem to diminish
during chronic administration of nicotine to AD patients
(Wilson et al 1995). Recently, the nicotinic agonist ABT418 improved verbal learning and memory on a selective
reminding task in AD patients (Potter et al 1999). The

Nicotinic Receptor Abnormalities in AD

cholinesterase inhibitors produce similar improvement in
cognitive function in AD patients (Nordberg et al 1998).
Although epidemiologic data are somewhat conflicting
about the possibility that smoking can protect against AD
(Doll et al 2000; Van Duijn et al 1995), experimental data
suggest that a neuroprotective effect against Ab toxicity
might be obtained via the nAChR (e.g., the a7 subtype)
(Kihara et al 1997; Svensson and Nordberg 1998; Zamani
et al 1997). Estrogen, which in epidemiologic studies has
been shown to reduce the risk of AD (Henderson 1997),
has in experimental studies in PC 12 cells shown neuroprotective effects against Ab toxicity that are at least
partly mediated by the a7 subtype nAChR (Svensson and
Nordberg 1998). It is reasonable to assume that to obtain
significant neuroprotective effects the drug probably must
be given during a very early stage of AD, probably a
presymptomatic level. There are tremendous possibilities
for the development of nAChR agonists as potential
therapeutic agents in AD.

This study was supported by grants from the Swedish Medical Research
Council (Project No. 05817), Loo and Hans Osterman’s foundation,
Stohne’s foundation, the Swedish Alzheimer foundation, Foundation for
Old Servants, and Swedish Match.
Aspects of this work were presented at the symposium “Nicotine
Mechanisms in Alzheimer’s Disease,” March 16 –18, 2000, Fajardo,
Puerto Rico. The conference was supported by the Society of Biological
Psychiatry through an unrestricted educational grant provided by Janssen
Pharmaceutica LP.

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