Neurobiology of Aging 21 (2000) 845– 861

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Open peer commentary

Cognitive and behavioral heterogeneity in Alzheimer’s disease:
seeking the neurobiological basis
Jeffrey L. Cummings, M.D.*
Departments of Neurology and Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Reed Neurological Research Center,
710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
Received 27 March 2000; accepted 24 May 2000

Abstract
Alzheimer’s disease (AD) is manifested by core features of progressive memory impairment, visuospatial decline, aphasia, and loss of
executive function. In addition, patients may evidence a variety of other cognitive and behavioral features. The neurobiological basis for
this clinical heterogeneity is uncertain but corresponding abnormalities on functional imaging suggest that variations in the distribution of
the pathogenic changes in AD account for some of the observed clinical differences. Behavioral as well as cognitive variability has been
correlated with disturbances on positron emission tomography and single photon emission computerized tomography. Functional imaging
can reveal characteristic brain activity changes in AD, distinguish AD from other dementia syndromes, assess the integrity of transmitter
systems in AD, determine the effect of cognitive enhancing and psychotropic drugs on metabolism and transmitter system function in AD,
and possibly predict treatment responsiveness. Animal models of AD may improve our understanding of clinical variations in human AD.
Thus far, development of cognitive tests for transgenic mice with AD pathology has been limited. Evaluations paralleling human
neuropsychological tests are needed. In addition, technologies facilitating behavioral observations relevant to psychosis, depression, apathy,
and agitation in AD have not been developed for transgenic models. Application of experiments inducing animal equivalents of depression
and psychosis to determine the vulnerability of animal models of AD to these conditions may provide additional insights into human
neuropsychiatric symptoms in AD. The efficacy of psychotropic drugs can be assessed in animal models of AD subjected to the provocative
stimuli used in experimental models of psychopathology. There are a plethora of opportunities for basic scientists to offer insights, develop
strategies, and provide techniques and technologies relevant to understanding the clinical manifestations of AD. © 2000 Elsevier Science
Inc. All rights reserved.
Keywords: Alzheimer’s disease; Cognition; Behavior; Animal models; Imaging; Treatment

1. Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) affecting primarily limbic, paralimbic, and neocortical structures.
At the molecular level, the primary abnormalities include
abnormal processing of amyloid precursor protein (APP),
hyperphosphorylation of tau protein, and apoptotic-like cell
death [1]. Neuronal death in specific transmitter source
nuclei results in deficiencies of acetylcholine, serotonin, and
norepinephrine that contribute to the matrix of pathological
changes underlying the clinical syndrome [2]. Alzheimer’s
type pathology is promoted by the presence of the apoli-

* Tel.: ϩ1-310-206-5238; fax: ϩ1-310-206-5287.
E-mail address: cummings@ucla.edu (J.L. Cummings).

poprotein E4 allele [3] and accompanied by a neuroimmune
response [4]. The tempo of these changes and their regional
distribution results in a recognizable clinical syndrome that
has high predictive value for the pathological diagnosis of
AD [5].
Despite the presence of core clinical features that facilitate accurate clinical recognition, there is substantial clinical heterogeneity among patients with AD. There are variations in both the cognitive and the behavioral
manifestations of the disorder. Currently there is limited
insight into the neurobiological basis of this clinical heterogeneity. In addition, there have been few linkages between
the current growth of basic science research with animal
models of AD and investigation of the possible explanations
for the clinical variability. In this selected review, the principal recognized cognitive, motoric, and behavioral variations of AD are presented and how this heterogeneity might

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J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

be investigated in animal models and other basic science
approaches to AD is considered. Stage-related variability
also is considered.
The purpose of this review is to stimulate dialogue between basic and clinical scientists regarding critical unresolved issues manifest at the clinical level and expressing
important pathobiological aspects of the underlying disease.

to palalalia, unrecognizable verbal output, or complete mutism [10 –12]. Patients with disproportionate aphasia compared to other cognitive deficits have a corresponding predominance of left hemispheric hypometabolism when
studied with fluorodeoxyglucose (FDG) positron emission
tomography (PET) [13–15].
2.3. Visuospatial disturbances

2. Cognitive heterogeneity in Alzheimer’s disease
2.1. Diagnosis of Alzheimer’s disease
Confidence in the diagnosis of AD is stratified according
to definite, probable and possible levels [5]. Definite AD
requires that the patient evidence the clinical syndrome of
probable AD while alive and has biopsy or autopsy evidence consistent with AD. A diagnosis of probable AD is
based on a typical clinical syndrome including gradual onset
and progressive decline for at least six months in memory
and at least one other cognitive domain in a patient who is
not delirious and who has no other potential explanations
for the cognitive changes. Possible AD is invoked when
patients have gradually progressive impairment in a single
cognitive domain without an alternate explanation or have a
second disease that is capable of inducing a dementia syndrome but which is not considered responsible for the cognitive abnormalities.
The current approach requires that memory abnormalities be present in all patients diagnosed with probable or
definite AD. However, the memory disturbance may be
accompanied by a wide variety of other cognitive disturbances that result in a diverse array of clinical syndromes.
Aphasia, apraxia or visuospatial disturbances may be disproportionately severe and a frontal lobe variant is recognized in which pronounced executive dysfunction accompanies other manifestations of AD [6].
2.2. Aphasia
Language disturbances in AD begin with abnormalities
of verbal fluency characterized by a reduced ability to perform generative naming tasks such as producing as many
animal names as possible in one minute [7]. The language
disturbance then progresses to an anomic type of aphasia
where patients exhibit lexical selection defects when asked
to name objects or drawings of objects but continue to
respond to phonemic cueing by producing the correct semantic response [8]. The language disturbance progresses to
a transcortical sensory type of aphasia with impaired comprehension but retained repetition [9]. The naming abnormality may progress to a semantic anomia with an inability
to recognize the correct name of an object or person. The
aphasia advances to a disorder with Wernicke-type features
including reduced comprehension and impaired repetition.
In the final stages of the illness, the patient may be reduced

Patients with AD also may present with disproportionate
visuospatial abnormalities. These patients have marked difficulty with Performance IQ measures, Block Design tasks,
and complex constructions [13,14,16]. They may exhibit
spatial disorientation in spontaneous behavior including
wandering, getting lost indoors, becoming lost in familiar
neighborhoods and being unable to recognize familiar
places [17]. Patients with predominant visuospatial impairment have more marked metabolic abnormalities of the
right hemisphere, particularly posteriorly, when studied
with FDG PET [13–15].
2.4. Posterior cortical atrophy
Posterior cortical atrophy represents another variant presentation of AD. Patients exhibit features of Balint’s syndrome (sticky fixation, ocular ataxia, and simultanagnosia)
and marked visuospatial disturbances [18 –21]. Memory and
insight are more preserved than in the classic form of AD.
Patients with posterior cortical atrophy have reduced metabolic activity in the parietal and occipital cortices [22].
2.5. Frontal variant
Patients with AD routinely have bilateral parietal lobe
hypometabolism on PET early in the clinical course with
progressive involvement of prefrontal structures as the disease progresses. Some patients, however, exhibit involvement of the frontal lobes early in their clinical course [23].
Neuropsychologically, these patients with the frontal variant of AD manifest disproportionate impairment of verbal
fluency and attention as well as severe deficits on tests of set
shifting and response inhibition [24]. Patients with the frontal variant also manifest marked behavioral disturbances
[6,25].
2.6. Comment
These studies show that there is clinical variability in the
presentation of AD and that there is a correlation between
the site of metabolic impairment as revealed by PET and the
characteristics of the clinical syndrome. The explanation for
the regional vulnerability of nerve cells to injury and death
in AD is the key to explaining this clinical heterogeneity.
The cause of early involvement of hippocampal structures,
the predilection for dysfunction of the parietal neocortex
and variability among individuals in laterality and prefer-

J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

ential posterior (posterior cortical atrophy) or anterior (frontal variant of AD) involvement remains unknown. Understanding the regional vulnerability of some cells or
disproportionate resistance of others represents an important
aspect of the research agenda for basic scientists relevant to
the clinical understanding of AD.

847

the disease [36]. Thus, additional investigation is needed to
understand the longitudinal course of the pathology of AD
as it relates to the clinical manifestations. Moreover, disparity between the staging of plaques and the staging of
tangles in some patients, as well as the occurrence of
plaque-only AD both suggest that there is some degree of
independence of the characteristic pathologies of AD possibly relevant to clinical findings.

3. Extrapyramidal variant of Alzheimer’s disease
Many patients with an AD-like syndrome and extrapyramidal dysfunction manifested by mild parkinsonism suffer from dementia with Lewy bodies (DLB) [26]. Some
patients however, with AD and no evidence of Lewy bodies
on autopsy, exhibit extrapyramidal syndromes during life.
These patients have an increased number of neurofibrillary
tangles and neuropil threads in the substantia nigra compared to patients with AD and no extrapyramidal signs [27].
Patients with AD and parkinsonism also have been found to
have a loss of dopamine transporter sites in the rostral
caudate and putamen compared to AD patients without
parkinsonism [28]. Cognitively, patients with dementia and
extrapyramidal signs exhibit more severe cognitive deficits
than those without, even when the patient groups are
matched for dementia duration [29 –31].
Clinical-pathological correlations, thus, have revealed
some aspects of the underlying neurobiology of the variability of the motor manifestations of AD. However, the
explanation for the more severe involvement of the substantia nigra or greater deficits in dopamine transporters in
caudate and putamen in some patients is unknown, and this
issue deserves further study.

5. Behavioral heterogeneity in Alzheimer’s disease
Behavioral alterations and neuropsychiatric symptoms
may occasionally herald the onset of AD and these changes
become steadily more frequent as the disease progresses. A
wide range of noncognitive behavioral manifestations are
observed in patients with AD. Depression is present in
25–50% of patients, disinhibition in 20 –35%, delusions in
15–50%, hallucinations in 10 –25%, agitation in 50 –70%,
anxiety in 30 –50%, aggression in 25%, and sexual disinhibition in 5–10% [37– 46]. In addition, wandering, hyperorality, disturbances in eating and elements of the KluverBucy are seen in a variable number of patients [40]. Patients
may experience the onset of psychiatric symptoms including depression and disinterest prior to the emergence of
cognitive changes; and hallucinations, delusions and mood
changes may accompany the first symptoms of dementia
[47,48]. Most behavioral disturbances worsen over the
course of the illness but they fluctuate and may not be
present on every examination [49]. Noncognitive neuropsychiatric disorders and cognitive abnormalities are not
closely associated [50]. Fig. 1 shows the percentages of
patients with a variety of neuropsychiatric symptoms
grouped according to severity of cognitive decline [42].

4. Stage-specific variability
5.1. Psychosis
Insidious onset and gradual progression are characteristic
of AD. The rate of progression is relatively predictable and
similar across different patient groups, but heterogeneity
emerges when the rate of progression is compared among
individuals. The stage of progression can be expressed numerically using rating scales such as the Global Deterioration Scale [32] or the Clinical Dementia Rating scale [33].
The decline in patients with advanced disease has been
assessed using the Severe Impairment Battery (SIB) and has
been shown to exhibit substantial variability [34]. Variations in the rate of progression of the illness may relate to
differences in the rate of accumulation of total pathology,
differences in the rate of the accumulation of different types
of pathological changes (neurofibrillary tangles, neuritic
plaques, cell loss, Lewy bodies, neurochemical deficits), or
the appearance of new pathologies as the disease progresses.
For example, neurofibrillary tangles may be present in normal aged individuals but undergo accelerated production
when neuritic plaques are present [35], and cholinergic
deficits may not become evident until the middle stages of

Psychosis is common in patients with AD. Persecutory
delusions, misidentification syndromes (i.e. Capgras syndrome), and hallucinations are the common types of psychotic disorders [51–53]. Hallucinations may be the presenting manifestation of AD [54] but more commonly
appear later in the disease course [42,51,55,56]. Most studies have found that delusions are more common among
older patients with AD [49,55–58]. Investigation of the
relationship between delusions and cognitive impairment
has produced variable results. Some studies have found no
relationship between the type of cognitive impairment and
the presence of psychosis [50,59,60]. Jeste and colleagues
[61] and Flynn et al. [62] found correlations between the
presence of delusions and frontally-mediated cognitive abilities such as conceptualization, verbal fluency and abstraction, while Bylsma and coworkers [63] documented more
severe anomia in patients manifesting delusional disorders.
Ballard and colleagues [64] found that deafness and adverse
life events were both associated with delusions, while visual

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Fig. 1. (a,b) Neuropsychiatric symptoms in patients with Alzheimer’s disease divided according to severity of Mini-Mental State Examination (MMSE)
changes. Mild ϭ MMSE 30 –21; Mod ϭ MMSE 20 –11; Severe ϭ MMSE 10 – 0; Euph ϭ euphoria; Apa ϭ apathy; Disin ϭ disinhibition; Irrit ϭ irritability;
AMB ϭ aberrant motor behavior; Del ϭ delusions; Hall ϭ hallucinations; Agit ϭ agitation; Dysph ϭ dysphoria; Anx ϭ anxiety.

J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

impairment was associated with visual hallucinations. Studies have consistently shown that patients with psychosis
exhibit more rapid cognitive decline than those without
psychotic symptoms [65–70].
Functional imaging studies using PET or single photon
emission computed tomography (SPECT) have identified
differences between delusional and nondelusional AD patients even when adjusted for overall severity of dementia.
Sultzer and colleagues [71] found that the presence of psychosis was associated with hypometabolism in the frontal
lobes. Similarly, Mentis and colleagues [72] found that
misidentification syndromes correlated with bilateral dorsolateral frontal hypometabolism in patients studied with PET,
and Kotrla and colleagues [73], using SPECT, found asymmetric hypoperfusion (worse in the left frontal lobe) in
patients manifesting psychotic disorders. Starkstein et al.
[74] documented lower cerebral blood flow in the left and
right temporal lobes in a SPECT study of AD patients with
delusions, and Ponton and coworkers [75] found that patients who developed delusions had higher right temporal
cerebral blood flow and greater deterioration in right temporal perfusion compared to patients who did not develop
delusions during the observation period. Hirono et al. [55,
56] reported contrasting results identifying increased glucose metabolism in the left inferior temporal gyrus and
significantly decreased metabolism in the left medial occipital region in those with delusions compared to those without. Overall, these findings suggest that frontal and temporal
regions are more affected in patients exhibiting psychotic
disorders. Fig. 2 shows a PET with frontal hypometabolism
in a patient with delusions.
A few studies have sought correlations between pathological changes in AD and the presence of neuropsychiatric
symptoms prior to death. Zubenko and colleagues [76]
examined neuropathological and neurochemical changes in
the brains of 27 autopsy-confirmed patients with AD, sampling the middle frontal and superior temporal cortex, the
prosubiculum and the entorhinal cortex of the hippocampus.
Psychosis was associated with significantly increased neuritic plaques in the prosubiculum and increased neurofibrillary tangles in the middle frontal cortex. Nonsignificant
trends toward increased pathology were evident in the other
cortical regions examined. Neurochemically, psychosis was
associated with relative preservation of norepinephrine in
the substantia nigra with a trend toward higher norepinephrine levels in most of the brain regions assessed. There was
a significant reduction of serotonin in the prosubiculum with
trends toward reductions in the other brain regions. Forstl et
al. [77] found that misidentification syndromes were associated with lower neuronal counts in CA-I region of the
hippocampus, but in this sample, there were also fewer cells
in the dorsal raphe nuclei (source of serotonin) in the affected patients, but less severe cell loss in the parahippocampal gyrus. Perry et al. [78] noted that in patients with
DLB levels of choline acetyltransferase were lower in pa-

849

rietal and temporal lobes in patients with hallucinations
compared to those without.
These studies tentatively suggest that there are more
severe neuropathological and neurochemical changes in
frontal and temporal regions in AD patients with psychotic
symptoms compared to those without. However, relatively
small numbers of patients have been comprehensively assessed in life with correlation of neuropsychiatric symptoms
and autopsy findings. In the few available studies, only a
small number of brain regions were investigated and only a
few neuropathological and neurochemical parameters were
assessed. Thus, there is a substantial knowledge gap in
understanding the neurobiological basis of delusions and
hallucinations in patients with AD. The tendency for neurofibrillary tangles and neurites to form in limbic and paralimbic brain regions mediating emotional functions suggests
itself as a pathological process potentially contributing to
the occurrence of psychosis and other neuropsychiatric
symptoms [79] (Fig. 3).
5.2. Agitation
Agitation is a common phenomenon in AD occurring in
30 –70% of patients [42,80 – 82]. Delusions are more common among patients with agitation [80,81,83] but the delusions do not account for all of the variance in the occurrence
of agitation and many patients with agitation do not exhibit
psychotic symptoms. Agitation is associated with executive
dysfunction and more severe functional impairment [25,49].
Agitation exhibits a statistically significant correlation with
hypometabolism in the frontal and temporal lobes [71] and
with diminished levels of neuropeptide Y in the cerebrospinal fluid [84]. Autopsy investigations show an association
between physically aggressive agitation and greater neuron
numbers in the substantia nigra [85]. Further studies are
needed to elucidate the neurobiology of this enigmatic syndrome in AD.
5.3. Depression
Reports vary concerning the prevalence of major depression in AD with investigators reporting rates as low as 2%
and as high as 85%. Reported rates of dysthymia range from
25–50% [39,43,59,60,86 –92]. Depressed mood may precede the onset of AD [93] and commonly worsens as the
disease progresses [42]. Patients with a family history of an
affective disorder are more likely to experience a depressive
episode in the course of AD [94,95], and some studies have
found a relationship between younger age at onset and
greater depression [96]. Patients with AD and depression
have greater impairment of activities of daily living than
patients with AD and no depression even after matching for
overall severity of cognitive impairment [97–100]. Depressed patients with AD do not exhibit greater impairment
of attention, language, memory and visuospatial functions
than patients without mood changes, but they have been

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J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

Fig. 2. Positron emission tomogram (PET) of a patient with Alzheimer’s disease and delusions. Note the reduced frontal metabolism.

reported to exhibit greater impairment of executive function
[101].
Lopez and coworkers [102,103] reported a significant
correlation between global scores of deep white matter
lesions and cognitive components of depression (low selfesteem and suicidal ideation) in patients with AD. The
highest regional correlations found were between these
symptoms and lesions in the frontal lobe white matter.
Functional neuroimaging has been somewhat inconsistent in
identifying regional correlates of depression. Sultzer and
colleagues [71] found an association between depression

and reduced metabolism in the parietal lobes and Starkstein
and coworkers found a similar relationship between cerebral
hypoprofusion in temporal-parietal regions and depression.
More significant relationships emerged between reduced
hemispheric hypoperfusion (dorsolateral, frontal, temporal
and parietal) and major depression compared to dysthymia.
Hirono et al. [57], however, showed relationships between
depression and hypometabolism in the superior frontal cortex bilaterally and the left anterior cingulate cortex.
Postmortem studies of patients with AD and major depression have consistently shown reductions in locus cer-

J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

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Fig. 3. Coronal whole brain slice showing the regional distribution of neurofibrillary tangles and neurites (red and yellow high concentration, blue and green
low concentration). Note the tendency for this type of pathology to occur in the insula, temporal regions, and substantia innomata (image courtesy of M. Mega
and the UCLA Laboratory of Neuroimaging).

uleus cell populations [104 –107]. Some, but not all studies,
also have found greater reductions in cell numbers in the
substantia nigra in depressed compared to nondepressed AD
patients [107].
Zubenko and colleagues [108] documented neurochemical changes in postmortem samples of patients with AD
and depression. Patients with mood changes exhibited
marked reductions in the level of norepinephrine in several
cortical regions (middle frontal and temporal cortex). These

regions had relative preservation of choline acetyltransferase and nonsignificant reductions in serotonin. Dopamine
levels were increased in the entorhinal cortex of depressed
compared to nondepressed AD patients. Chen and colleagues [109] found normal serotonin levels in the frontal
and temporal cortex of depressed patients, but there was a
significant reduction in the number of serotonin uptake sites
in the temporal regions of patients exhibiting depression
during life. These studies implicate both serotonin and nor-

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J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

epinephrine in the pathophysiology of mood changes in AD.
Additional research is necessary to further refine these observations and relate them to potential therapeutic interventions for patients with AD.
5.4. Apathy
Apathy is among the most common behavioral disturbances observed in patients with AD. It becomes apparent
early in the clinical course and progresses in concert with
declining cognitive function [42]. Petry and colleagues
[110,111], using an inventory originally developed to assess
patients with traumatic brain injury, documented that patients with AD become more passive with onset of the
illness. Similarly, application of a standard personality inventory to patients with AD showed reduced extroversion
[112,113]. Rubin and colleagues [114] used the personality
section of the Blessed Dementia Scale to document an
increase in passive behaviors in patients with AD. Studies
using the Neuropsychiatric Inventory [115] also have demonstrated increased apathy in AD victims [42,116].
Investigations using SPECT revealed that patients with
moderate or severe apathy had significantly reduced blood
flow in anterior temporal, orbito-frontal, anterior cingulate,
and dorsolateral prefrontal regions compared to patients
with no or mild apathy [117]. Patients with AD treated with
tacrine, a cholinesterase inhibitor, showed a significant reduction in apathy suggesting a cholinergic contribution to
the pathophysiology of apathy in AD [118].
Apathy has not been as thoroughly investigated as other
neuropsychiatric symptoms and the neuropathologic and
neurochemical correlates of this common behavioral manifestation of AD remain to be defined.

6. Behavioral genetics of Alzheimer’s disease
Exploration of the behavioral genetics of AD is in its
infancy. There has been limited attention to phenotypic
differences in sporadic and autosomal dominant familial
AD. In one study, Lahtovirta et al. [119] found no differences in either cognitive deficits or neuropsychiatric symptoms in patients with sporadic and familial AD.
The influence of the E-4 allele on cognition and behavior
has been studied more extensively. The presence of the E-4
allele may result in more severe impairments of language
comprehension and learning in AD [120]. Although a few
studies have found relationships between neuropsychiatric
symptoms and the presence of the E-4 genotype [121], most
investigators have failed to show any association between
the presence of the E-4 allele and a variety of behavioral
changes and neuropsychiatric symptoms [98 –100,102,103,
122–128].
Other genetic variations may affect behavior in AD patients. Relationships have been found between the 5-HT2A
receptor polymorphism 102 T/C and the 5-HT2c receptor

polymorphism Cys23Ser and a variety of types of behavioral disturbances in AD patients [129]. Polymorphisms of
the serotonin transporter promoter gene have been associated with anxiety disorders [130,131] and have not yet been
explored in relationship to psychopathology in AD. Some of
the issues in behavioral genetics can be addressed using
transgenic models of AD (below).

7. Functional imaging assessment of transmitter
system activity
Much can be learned from applying neuroimaging techniques to study cognitive and behavioral heterogeneity in
AD. Positron emission tomography and SPECT have been
used to assess the integrity of neuro-transmitter systems in
normal control subjects and in patients with a variety of
neurologic and psychiatric illnesses [132–134]. Properties
of pharmacological agents can be assessed by labeling the
agent itself and studying its anatomic distribution in the
brain of normals compared to subjects with disease states or
determining the effects of labeled drugs on radioligand
binding of transmitters to their receptors [135,136].
Functional imaging also can reveal disturbances in neurotransmitter function in patients with AD that may contribute to the observed cognitive and behavioral heterogeneity.
Single photon emission computed tomography using 123I-IBZM shows reduced striatal dopamine receptors in AD
[137] and PET studies using C11-flumazenil demonstrate
abnormalities in benzodiazepine receptors. Studies of AD
and DLB using a marker of striatal dopamine transporter
density showed greater impairment of dopamine transporter
function in DLB than AD [138]. Table 1 provides a partial
list of ligands available for exploration of transmitter systems in the human brain using PET.
Pharmacologic activity also can be assessed with functional neuroimaging. Studies with FDG PET reveal diminished glucose utilization in the frontal occipital, and anterior
cingulate cortices after administration of haloperidol, [139]
and patients receiving carbamazepine have reduced frontal,
parietal, temporal, and caudate metabolism compared to
unmedicated subjects [140]. Imaging techniques also can be
used to explore the behavioral differences among AD patients with similar levels of dementia (Fig. 2).
Positron emission tomography also has been used to
measure dopamine D2 receptor occupancy following treatment with haloperidol and cortical 5-HT2A receptor occupancy following treatment with conventional and novel antipsychotic agents [141,142] in nondemented patients.
Similarly, pharmacologic activation of cerebral cortex has
been assessed with measures of 0 –15 PET following administration of methylphenidate hydrochloride. Activation
of anterior limbic and paralimbic structures in normal human subjects was demonstrated [143]. The effects of antidementia psychotropic agents on brain metabolism, perfu-

J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861
Table 1
Ligands uses positron emission tomography to study receptors in the
human CNS [Kumar, 1997 #160; Maziere, 1986 #159; Phelps, 1985
#158; Sedvall, 1986 #157]
Neuroreceptor

Labeled drug

Opiate

C-11 carfentanil
C-11 diprenorphine
F-18 acetylcyclofoxy
C-11 buprenorphine
C-11 etorphine
C-11 N-methylmorphine
C-11 morphine
C-11 heroin
C-11 raclopride
C-11 spiperone
C-11 pimozide
C-11 dopa
Br-76 bromo SCH 23390
C-11 SCH 23390
C-11 chlorpromazine
Br-76 spiperone
C-11 methyl spiperone
F-18 spiperone
F-18 haloperidol
F-18 dopa
C-11 ketanserin
C-11 methyketanserin
C-11 methylbenperidol
F-18 Flouroethylketanserin
C-11 methylbromo LSD
C-11 N-methylspiperone
Br-76 spiperone
F-18 methylspiperone
F-18 ethylspiperone
F-18 spiperone
C-11 dexetimide
F-18 flourodexetimide
C-11 QNB*
C-11 scopolomine
C-11 imipramine
C-11 Ro 15-1788
C-11 suriclone
C-11 diazepam
C-11 flunitrazepam
C-11 PK 11-195
C-11 flourodiazepam
C-11 pyrilamine
C-11 doxepin
C-11 propranodol
C-11 practolol
C-11 norepinephrine

Dopamine D2

Dopamine D1

Serotonin (5-HT2)

Muscarinic

Benzodiazepine

Histamine H-1
Adrenergic

* QNB Ϫ methylqueininuclidiybenzalate.

sion, or transmitter functions can be assessed with
functional imaging [144].
Together these studies show that PET and SPECT can be
used to characterize metabolic changes in AD, distinguish
AD from other dementing disorders, determine the effect of
drugs on cerebral metabolism and perfusion, assess the
impact of drugs on receptor occupancy, and potentially
predict treatment responsiveness. More extensive applica-

853

tion of these techniques to AD may facilitate drug development and treatment response prediction.
Neural networks can be activated by specific behavioral
tasks and these tasks may serve as probes of cognitive and
behavior heterogeneity in AD. Tasks such as directed attention, patterned flash stimuli, procedural learning, episodic
memory and word processing all activate task-specific neural-networks [145–150]. Response to these activation procedures is altered in AD and may be affected by drugs used
for cognitive enhancement or control of behavioral disturbances in AD. Activation studies may provide another avenue for exploration of cognitive, behavioral heterogeneity,
and treatment response in AD.

8. Experimental models of cognitive and behavioral
changes in Alzheimer’s disease
Animal models of AD can provide insight into the neurobiological bases and pathogenic mechanisms of cognitive
and behavioral changes in AD patients. Studies have focused primarily on the pathologic changes of the animals
with only limited attention to the cognitive changes and
almost no investigation of changes in behaviors analogous
to the neuropsychiatric symptoms commonly observed in
AD. Monitoring of behavioral changes in animal models
could both provide insight into the neurobiology of these
behavioral changes and help validate the felicity of the
model to AD since these changes are present in a majority
of AD patients.
Table 2 provides an overview of the principal AD models. The relationship between aging and AD made study of
aged animals an important first step. Aged non-human primates have been investigated on a variety of learning and
memory tasks, and aged rodents have been shown to have
memory impairment on tasks such as the Morris Water
Maze and Passive Avoidance tests. The senescence-accelerated mouse (SAM) exhibits age-related deficits in learning
and memory [144,151–153]. Aged rats have deficits in Water Maze and Radial Arm Maze performance.
In concert with recognition of the importance of the
cholinergic deficit in AD, early models of the disease concentrated on surgical or chemical lesions of the basal forebrain. These experiments involved primarily rats and nonhuman primates and demonstrated deficits in attention and
memory [150 –156]. The effect of nerve growth factor
(NGF) on cognition of aged rats has been assessed by
intraventricular infusion of NGF and assessment using Delayed Alternation, Morris Water Maze, and sensory motor
tasks [160].
Transection of the fornix results in degeneration of cholinergic cells in the basal forebrain. This observation has
provided a model for assessment of cholinoprotective effects of compounds potentially useful in the treatment of
AD. Nerve growth factor has been most thoroughly assessed
in this setting and has shown effects in rats [161–164] and

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J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

Table 2
Animal models of Alzheimer’s disease
Model

Species

Commonly used tests

Aged animals

Monkey
Rat

Passive avoidance
Morris water maze
Radial arm maze
Morris water maze
Passive avoidance
Delayed alternation
Morris water maze
Sensory-motor coordination
Passive avoidance
Spatial reversal
Object discrimination
Delayed nonmatched to sample task
Angle threshold discrimination task
Delayed response
Concurrent object discrimination
Spatial discrimination
Wire hanging
Inclined screen
Rod walking
Plank walking
Passive avoidance
Active avoidance
Shock sensitivity
Morris water maze
Radial arm maze
EEG

Mouse
Aged animals with NGF* infusion

Rat

Lesions of the basal forebrain (surgical, excitotoxic)

Monkey/baboon

Rat

Fimbria/fornix lesions followed by
NGF infusions
Amyloid infusion
APP** transgenics
Presenilin-1 transgenics
Apolipoprotein knockout

Rats
Monkeys
Rats
Mice

Morris water maze
Spatial reference memory
Spatial alternation

Mice

NGF* ϭ nerve growth factor.
APP** ϭ amyloid precursor protein.

non-human primates [165,166]. Few behavioral or cognitive
observations have been reported in the various species following fimbria and fornix transection.
Given the apparent central importance of amyloid deposition in the pathogenesis of AD, animal models of amyloid toxicity have been developed. Intraventricular infusion
of amyloid beta protein [167] mimics some of the pathological processes of AD; few behavioral observations with
this model have been reported.
Recognition of autosomal dominant cases of AD induced
by mutations of APP (chromosome 21), presenilin 1 (chromosome 14), or presenilin 2 (chromosome 1) allowed development of transgenic mouse models of AD [168]. These
animals exhibit some of the pathologic hallmarks of AD
including neuritic plaques although they have not evidenced
neurofibrillary tangles and have limited cell death. These
models facilitate investigation of the relationship of amyloid
deposition to other aspects of the pathology of AD including
inflammation, hormonal levels, trophic factor influences,
calcium metabolism, amino acid toxicity and apoptosis.
There has been limited behavioral testing of transgenic

mice, but impairments of memory have been reported on the
Morris Water Maze, Spatial Reference Memory, and YMaze Alternation Tasks [168].
The E-4 allele of apolipoprotein (ApoE-4) confers an
increased risk for AD and a decreased age of onset [169]. A
variety of transgenic and knock-out apolipoprotein models
have been developed. When the ApoE knockout mouse is
crossed with an AD transgenic mouse [170] there is dramatic reduction in amyloid beta protein deposition.
Review of the cognitive testing and behavioral measures
of the various available animal models of AD reveals the
impoverished state of these assessments and the need to
develop new evaluation technologies. Cognitive tasks analogous to the deficits observed in human AD need to be
developed for application to transgenic, knockout and other
models currently used to investigate AD pathogenesis. Tests
of language are obviously not applicable but assessment of
attention, memory, spatial orientation and executive function are feasible. Such tasks must be valid, reliable, and
consistent with the abnormalities observed in human disease
victims [171,172].

J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

855

Table 3
Disease-promoting and disease-ameliorating factors influencing the behavioral phenotype of Alzheimer’s disease
Level of influence

Disease-promoting factor

Disease-inhibiting factor

Behavioral

Premorbid psychopathology: aging

Regional involvement
Tissue/Cellular

Parietal, frontal and limbic cortex
Regional vulnerability; development of
neuritic plaques; calcium influx;
excitotoxicity; deficit in neurotropic factors

Molecular

Beta and gamma secretase processing of
APP*; generation of A␤-42 molecular
species; oxidative injury; inflammation;
apoptosis; hyperphosphorylation of tau
Deficits in acetylcholine, serotonin, and
norepinephrine
Estrogen deficiency in post-menopausal
woman
Family history of psychopathology;
Alzheimer’s disease inducing-mutations;
apolipoprotein E-4 genotype

Higher educational level: greater intellectual
integrity
Primary motor and sensory cortex
Robust synaptic connectivity: compensatory cellular
sprouting; limitation of amyloid deposition or
aggregation; calcium channel blocking; NMDA
receptor blockers; nerve growth factors
Alpha secretase processing of APP; antioxidant,
anti-inflammatory response; antiapoptotic
response; inhibition of tau phosphorylation

Biochemical
Hormonal
Genetic

Upregulation of transmitter production and
receptors
Estrogen administration in post-menopausal women
Apolipoprotein E-2 genotype

* APP ϭ amyloid precursor protein.
* NMDA ϭ N-methyl-D-aspartate.

There has been essentially no effort devoted to measuring spontaneous behavioral changes in models of AD analogous to the apathy, agitation, anxiety, irritability, psychosis
or depression evident in humans with the disease. Delusions
cannot be studied in animal models; behavior analogous to
amphetamine-induced psychosis-like behavior in animals,
however, could be assessed [173,174]. Similarly, studies of
animal models of depression [173,175] provide a repertoire
of tools potentially applicable to assessment of depression
in animal models of AD. Animals with anxiety could serve
as a source of behavioral markers of anxiety in AD models
[176]. Quantitation of apathy in animal models of AD is
essential since this spontaneous reduction in behavior could
confound assessments of attention, memory and other cognitive capacities. Likewise, agitation could be measured in
animal models of AD. In addition to providing models for
observing behavioral changes in animals, experimental
causes of psychopathology (e.g. amphetamines, social deprivation) can be applied to transgenic animals to determine
their vulnerability to provocative stimuli and the effects of
psychotropic agents in modifying these responses.
Strain differences in spontaneous and drug-induced behaviors are known for different mouse and rat species and
thus the strain of the host mouse of the transgene must be
considered when assessing transgenic-related behavioral
changes [174]. In addition, the age of the animal at the time
of testing as well as the gender of the animal also must be
included in the interpretation of behavioral observations.
The validity of transgenic models of AD will eventually
depend on convergent evidence from studies of the pathology of the transgenic animals, performance on cognitive
tasks, spontaneous behavioral changes analogous to those of
human AD, and response to therapeutic interventions. Electrophysiological studies (both intracellular and full brain,

such as evoked responses) and structural and functional
imaging of experimental models may further amplify their
utility as simulacra of AD. Aging, lesion and genetic models
are all likely to contribute information important to our
understanding of AD and none is likely to represent a
completely isomorphic model that is fully predictive of the
pathogenesis, course, and treatment of human AD.
Table 3 summarizes putative disease-promoting and disease-inhibiting factors whose dynamic interplay result in the
final phenotype manifest in the AD patient. Animal models
will play a critical role in further defining the events and
processes underlying the final phenotypic expression.

9. Assessment of psychotropic effects of drugs in
animal models of Alzheimer’s disease
Alzheimer’s disease research is mission-oriented and focused on the development of treatments that will prevent,
defer the onset, slow the progress, or improve the cognitive
and behavioral symptoms of AD. Animal models may have
a role in assessing disease-modifying, mechanism-based,
and symptomatic interventions. Disease-modifying treatments are those that ameliorate the central pathogenic
events such as amyloid production, accumulation, or aggregation; inflammation; tau hyperphosphorylation and formation of neurofibrillary tangles; and apoptosis. Mechanismbased treatment are those based as a known pathologic
alteration in the brain (such as the cholinergic deficit) but
are not necessarily disease-modifying. Symptomatic therapies modify brain functions whose relationship to the disease state is uncertain. Assessment of drugs beneficial in
these domains can be explored in tissue culture and animal
models of AD.

856

J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

Symptomatic therapies may improve cognition or relieve
behavioral disturbances. Potential means of assessing the
cognitive effects of drugs such as cholinesterase inhibitors
or cholinergic receptor agonists in animal models of AD are
shown in Table 2 and discussed above.
Assessment of the effects of psychotropic compounds in
animal models of AD must await the development of approaches to evaluate behavioral disturbances in these models. Combinations of existing techniques for assessing effects of psychotropic drugs with animal models of AD may
provide insight into the potential utility of psychotropic
compounds in modifying behavioral disturbances in AD.
For example, antipsychotic compounds potentially useful in
the treatment of psychosis and agitation in AD could be
assessed in animals with spontaneous or induced psychosisrelated behavior. Control of hallucinogen-related behaviors;
amelioration of psychostimulant-related behavioral toxicity;
and determination of impact on sensorimotor gating (latent
inhibition, prepulse inhibition) are alternative models of
assessing antipsychotic activity [173,174]. Antipsychotic
activity can be assessed with in vivo electrophysiology
using recording electrodes placed in the A9 and A10 areas
of the midbrain (A9 is relevant to extrapyramidal symptoms
and A10 is relevant to antipsychotic effects), apomorphineinduced climbing, turning behavior in rats with unilateral
6-hydroxydopamine lesions of the nigrostriatial dopamine
pathway, catalepsy and conditioned avoidance responding.
Additional experimental models of behaviors relevant to
assessing the efficacy of anti-psychotic agents include the
effect on conditioned avoidance responding to adverse stimuli, induction of catalepsy, paw test (a measurement of
reaction time of extended forelimbs and hind limbs), selfstimulation paradigms, blocking selective attention, rodent
interaction tests, and assessment of the behavioral effects of
hippocampal damage.
The use of provocative stimuli known to induce depression-related behaviors in experimental animals also could
be applied to animal models of AD. The effects of antidepressants in these models may provide insight into the
potential utility of available and experimental anti-depressant medications in ameliorating depression-related symptoms in AD. The animal models used for assessment of
antidepressant activity include muricide, yohimbine lethality, amphetamine potentiation, kindling, circadian rhythm
readjustment, lesioning of the olfactory bulbs, differential
operant responding for low reinforcement, isolation-induced hyperactivity, reserpine-induced reduction of motor
activity, suppression of active responding induced by 5-hydroxytrypotophan, swim test immobility, clonidine withdrawal, tail suspension test, lesioning of the dorsomedial
amygdala in dogs, isolation and separation-induced depression in monkeys, exhaustion stress, chronic mild stress and
uncontrollable shock [171,172,175,176].
Table 4 provides a list of the tests used to measure
anti-psychotic and anti-depressant activity in experimental
models; some of these paradigms might be applicable to

Table 4
Animal models of depression and psychosis used to assess the efficacy
of antipsychotic and anti-depressant agents in animal models
Psychosis-related models
Inhibition of conditioned avoidance responding
Catalepsy test
Paw withdrawal test
Self-stimulation paradigms
Latent inhibition paradigms
Blocking paradigm
Prepulse inhibition of the startle reflex
Rodent interaction
Chronic amphetamine intoxication
Hippocampal damage
High ambient pressure
Depression-related models
Muricide
Yohimbine lethality
Amphetamine potentiation by anti-depressants
Kindling
Circadian rhythm readjustment to switching of light-dark periods
Lesioning of olfactory bulbs
Differential operant responding for low reinforcement
Isolation-induced hyperactivity
Reserpine-induced reduction of motor activity
Suppression of active responding induced by five hydroxytrypotophan
Swim test immobility
Clonidine withdrawal
Tail Suspension test
Neontal clomipramine
Exhaustion stress
Chronic mild stress
Uncontrollable shock (learned helplessness)
Prolonged restraint stress
Apomorphine antagonism

assessing the utility of psychotropic medications in ameliorating behavioral disturbances in animal models of AD.

10. Summary
This review of the cognitive and behavioral diversity of
AD provides a framework for a dialogue between basic and
clinical scientists regarding animal models and the human
form of AD. Basic science investigators may reveal causes
of selective regional vulnerability in neurons providing an
explanation for the cognition and behavioral heterogeneity
absent in AD. Advances in treatment — disease-modifying,
mechanism-based, and symptomatic — depend on advances
in basic science research, improvement of animal models of
AD, development of cognitive and behavioral measures
relevant to the disturbances observed in AD patients, and
testing of promising interventions in human clinical trials.
Identification of new agents, development of pertinent biologic measures of treatment response, and improvement in
outcomes assessments can be facilitated through the use of
animal models. The length of clinical trials might be shortened, the number of patients required to show an effect

J.L. Cummings / Neurobiology of Aging 21 (2000) 845– 861

reduced, and the potential synergistic effects of multiple
simultaneous interventions demonstrated when the requirements of AD therapies have been anticipated in animal
models. Functional neuroimaging and pharmacoimaging
contribute to understanding clinical heterogeneity in AD
and may aid in development of new therapeutic agents. The
recent emphasis on disease-modifying therapies must be
intensified, and the effects of cognitive and psychotropic
symptomatic interventions must be added to the testing
currently being pursued in models of AD. An enriched
dialogue between clinical and basic scientists promises to
address these issues and bring better treatments to AD
patients.

Acknowledgments
This project was supported by an Alzheimer’s Disease
Research Center grant (AG 16570) from the National Institute on Aging, an Alzheimer’s Disease Research Center of
California grant, and the Sidell-Kagan Foundation.

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