International Psychogeriatrics: page 1 of 27 C ?International Psychogeriatric Association 2010
Management of behavioral problems in Alzheimer’s disease
Serge Gauthier,1Jeffrey Cummings,2Clive Ballard,3Henry Brodaty,4
George Grossberg,5Philippe Robert6and Constantine Lyketsos7
1Alzheimer’s Disease and Related Disorders Unit at the McGill Center for Studies in Aging, Douglas Mental Health University Institute, Montreal, Canada
2Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, Los Angeles, California, U.S.A.
3Age Related Diseases, King’s College London, London, U.K.
4Primary Dementia Collaborative Research Centre, School of Psychiatry, University of New South Wales, Sydney, Australia
5Department of Neurology and Psychiatry, St Louis University School of Medicine, St Louis, Missouri, U.S.A.
6Centre M´ emoire de Ressources et de Recherche (Memory Centre for Care and Research), CHU de Nice, Hˆ opital Pasteur, Nice, France
7Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, Maryland, U.S.A.
Alzheimer’s disease (AD) is a complex progressive brain degenerative disorder that has effects on multiple
cerebral systems. In addition to cognitive and functional decline, diverse behavioral changes manifest with
increasing severity over time, presenting significant management challenges for caregivers and health care
professionals. Almost all patients with AD are affected by neuropsychiatric symptoms at some point during
their illness; in some cases, symptoms occur prior to diagnosis of the dementia syndrome. Further, behavioral
factors have been identified, which may have their origins in particular neurobiological processes, and
respond to particular management strategies. Improved clarification of causes, triggers, and presentation
of neuropsychiatric symptoms will guide both research and clinical decision-making. Measurement of
neuropsychiatric symptoms in AD is most commonly by means of the Neuropsychiatric Inventory; its
utility and future development are discussed, as are the limitations and difficulties encountered when
quantifying behavioral responses in clinical trials. Evidence from clinical trials of both non-pharmacological
and pharmacological treatments, and from neurobiological studies, provides a range of management options
that can be tailored to individual needs. We suggest that non-pharmacological interventions (including
psychosocial/psychological counseling, interpersonal management and environmental management) should
be attempted first, followed by the least harmful medication for the shortest time possible. Pharmacological
treatment options, such as antipsychotics, antidepressants, anticonvulsants, cholinesterase inhibitors and
memantine, need careful consideration of the benefits and limitations of each drug class.
behavior, Alzheimer’s, measurement, treatment, non-pharmacologic, pharmacologic
The following review is a result of discussions
that occurred during an “Expert Round Table
Meeting: Management of Behavioral Problems
in Alzheimer’s Disease” held in Hong Kong on
27 February, 2008. The meeting was convened
by Serge Gauthier and Jeffrey Cummings to
evaluate the current gaps in our knowledge
concerning the management of behavioral and
psychological symptoms associated with dementia.
Correspondence should be addressed to: Serge Gauthier, Director of the
Alzheimer’s Disease and Related Disorders Unit at the McGill Center for
Studies in Aging, Douglas Mental Health University Institute, Montreal,
Canada. Phone: +1 514 766 2010; Fax: +1 514 888 4050. Email:
email@example.com. Received 10 Aug 2009; revision requested 5 Oct
2009; revised version received 2 Nov 2009; accepted 6 Nov 2009.
Henry Brodaty, George Grossberg, Constantine
Lyketsos, and Philippe Robert. The meeting
was sponsored by Forest Laboratories Inc, H.
Lundbeck A/S, and Merz Pharma, and immediately
preceded the Hong Kong/Springfield Symposium
on Advances in Alzheimer’s Disease Treatment.
Since these initial discussions, the literature has
been further studied and the first article by this
group has been published, on the specific topic
of the management of agitation and aggression in
Alzheimer’s disease (AD) (Ballard et al., 2009a).
The current review reflects a group consensus on
neuropsychiatric symptoms (NPS), with emphasis
on a clinical approach to the individual behavioral
symptoms, using the best available information.
Issues surrounding the measurement of NPS are
identified and suggestions on how to resolve
them are proposed. The purpose of the review
S. Gauthier et al.
is to look at the “bigger picture” rather than
individual studies. Therefore, we have not cited
every study that has been conducted on NPS
but rather have aimed to maintain a balance
in the evaluation among the many approaches
currently available. Our discussions were aimed at
the sub-acute and long-term management of NPS;
management of acute psychiatric inpatient care was
not discussed. Although both the recommendations
and comments made and the literature cited in
the body of this review are aimed primarily at
AD, they may also be useful in the consideration
of non-AD dementias. In this review, the term
psychological symptoms of dementia” (BPSD),
and “psychotropic drugs” include antipsychotics,
cholinesterase inhibitors and memantine.
Behavior in the context of Alzheimer’s disease
AD is a complex progressive degenerative brain
disorder that has effects on multiple cerebral
systems, giving rise to diverse clinical phenomena.
As the disease progresses, more and more brain
regions are affected, and intellectual impairment
advances. Cognitive deterioration, as well as
progressive impairment in activities of daily living,
leads to an increase in patient dependency. NPS
associated with AD tend to follow a trajectory
of increasing severity over time – a feature they
have in common with cognitive and functional
decline. However, greater variability is observed
in the pattern of behavioral changes and in their
evolution than is characteristic of the decline
in cognition and function. Furthermore, there is
inconsistent correlation between NPS and cognitive
decline as measured using the Mini-mental State
Examination (MMSE) (Craig et al., 2005), or
the cognition portion of the Alzheimer’s Disease
Assessment Scale (ADAS-Cog) (Cummings et al.,
2004a). Some individual NPS are more closely
correlated with cognitive decline than others.
Onyike et al. (2007), when examining prevalence
and associations of apathy in older adults, found
that apathy was evident in 3.1% of those with mild
cognitive impairment and in 17.3% of those with
dementia (Onyike et al., 2007). This association
The authors concluded that both the frequency
and severity of apathy is positively correlated with
the severity of cognitive impairment (Onyike et al.,
2007). A direct correlation of apathy with severity
was also reported in nursing home residents (Wu
et al., 2009). Irritability was also found to correlate
with cognitive decline (Craig et al., 2005).
NPS are present in all stages of AD, such
that almost all patients with AD will manifest
such symptoms, including personality alterations,
psychoses, mood changes, agitation, apathy and
aberrant motor behavior, at some point during the
course of the disease (Gauthier et al., 2002a). NPS
are as clinically relevant as cognitive and functional
impairment; importantly, they contribute to patient
and caregiver distress (Banerjee et al., 2006), and
may precipitate institutionalization (Lesser and
Hughes, 2006). As many as 80–97% of patients
with AD are affected by at least one NPS at
some point in their illness (Jost and Grossberg,
1996; Lyketsos et al., 2002; Steinberg et al., 2008).
Some of these symptoms, depression in particular,
may be present even before the cognitive decline
becomes evident (Jost and Grossberg, 1996), and
in the dementia prodromes, such as mild cognitive
impairment (MCI) and cognitive impairment no
dementia (CIND) (Lyketsos et al., 2002). Indeed,
the association of apathy and depressive symptoms
with mild cognitive impairment has been shown to
increase the likelihood of progression to dementia
of the Alzheimer type (Teng et al., 2007; Robert
et al., 2008a).
Prevalence of NPS in AD
NPS comprise a variety of features that evolve
over time. Figure 1 shows the evolution of
behavioral changes, in terms of Neuropsychiatric
Inventory (NPI) symptoms, as found in the
Cache County Study (five-year period prevalence;
Steinberg et al., 2008). Latent class and factor
analytic studies suggest the existence of several
(Frisoni et al., 1999; Lyketsos et al., 2001;
Moran et al., 2004). Frisoni et al. (1999) grouped
these into three syndromes: “psychotic” (agitation,
(anxiety, depression), and “frontal” (disinhibition,
three groupings: “no neuropsychiatric symptoms”,
“affective” and “psychotic” symptoms.
The most frequently occurring of the NPS are
apathy, depression, and anxiety (Robert et al., 2005;
Steinberg et al., 2008; Table 1). Apathy can be
present in all stages of the disease, but increases
in prevalence with severity of disease (Figure 2).
Apathy appears to be an independent syndrome,
whereas agitation may occur in combination with
many different symptoms. Senanarong et al. (2004)
found significant correlations between agitation and
all other NPI subscale scores, with the strongest
correlations existing with irritability, disinhibition,
delusions, and aberrant motor activity (p<0.001
in all cases) (Senanarong et al., 2004). Aberrant
Management of behavioral problems in AD: a review
Figure 1. Five-year prevalence of NPI symptoms (NPI >0) in the Cache County Study (Steinberg et al., 2008).
Table 1. Frequency (percent) of NPS in community care samples evaluated with the NPI in three European
Hallucinations 13.1 7.8
Agitation 28.6 44.3
Aberrant motor behavior34.729.8
NPS = neuropsychiatric symptoms; NPI = Neuropsychiatric Inventory; MAASBED = Maastricht Study of Behavior in Dementia;
REAL = R´ eseaux Alzheimer Franc ¸ais; EADC = European Alzheimer Disease Consortium; MMSE = Mini-mental State Examination.
∗Overall mean taking into account the relative contribution of the size (n) of each study.
Source: Robert et al. (2005).
motor behavior (wandering, pacing, rummaging,
purposeless hyperactivity) is observable in more
than one-quarter of patients with dementia (Aalten
et al., 2007), and falls into the behavioral category
of “hyperactivity”, which also comprises agitation,
disinhibition and irritability (Aalten et al., 2007).
Agitation and aggression are among the most
troublesome of the NPS for caregivers and,
along with depression and psychosis, are leading
predictors of institutionalization (Yaffe et al., 2002;
Gauthier et al., 2008; Gaugler et al., 2009)
Within care facilities, 40–60% of AD patients have
aggression and agitation (Margallo-Lana et al.,
2001; Ballard and Howard, 2006).
Irritability is common and can be troublesome to
the caregiver; it occurs with a prevalence of ∼40%
of patients with mild and moderate AD, increasing
to ∼50% of patients in the more severe stages of the
disease (Cummings and Back, 1998; Robert et al.,
Psychotic disorders (delusions and hallucina-
tions) can affect 27–45% of AD patients (Leroi
S. Gauthier et al.
Figure 2. NPI symptoms in AD, by MMSE groupings (mild, moderate, severe) (Craig et al., 2005).
et al., 2003; Jost and Grossberg, 1996), and has
been associated with accelerated cognitive decline,
earlier institutionalization, and caregiver burnout
(Drevets and Rubin 1989; Yaffe et al., 2002; Lesser
and Hughes, 2006). Delusions most often present
in the form of beliefs of theft and infidelity, and
hallucinations (most often visual) are usually visions
of people from the past, or of intruders. Prospective
studies show that hallucinations often resolve over
a few months, but delusions and agitation are more
persistent (Ballard and Howard, 2006).
The prevalence of depression in AD patients, as
estimated in both population and clinical studies,
is between 20% (Lyketsos et al., 2000; 2003)
and 50% (Lyketsos and Olin, 2002). Regular
screening for depression in AD is recommended:
preliminary studies suggest that antidepressant
treatment instigated on the basis of screening for
the condition improves outcomes for patients (in
terms of depression symptom scores) (Cohen et al.,
2003), and may decrease the strain on the caregiver.
Sleep problems, which are estimated to occur
in 25–54% of AD patients (Chen et al., 2000;
Hart et al., 2003; Moran et al., 2005), can
impact greatly on the quality of sleep of caregivers.
It is well established that sleep disturbance,
and the accompanying caregiver stress, are very
common precipitants of institutionalization in
dementia (Vitiello and Borson, 2001). Although the
management of sleep problems is not specifically
the report published by Deschenes and McCurry
to be a significant predictor of sleep disturbance
(p=0.009) (Moran et al., 2005).
Other behavioral symptoms include personality
changes, where a person’s premorbid personality
may be accentuated, attenuated or, in some cases,
may be the complete opposite of the premorbid
character (Archer et al., 2007; Talassi et al., 2007).
Alterations in sexual behavior may also occur
Significance of NPS in AD
There is a growing interest in NPS since these
symptoms are present from the early stages
of the disease, constitute a marker of disease
progression, and strongly determine the patient’s
daily function and the clinician’s management
choices, e.g. the use of psychotropic medication.
An even more salient reason is that NPS are
a major contributor to suffering and quality of
life for both patients and caregivers (Banerjee
et al., 2006), leading to caregiver burnout and
institutionalization of patients with AD (Lesser and
Hughes, 2006; Gaugler et al., 2000). Caregiver
distress is significantly correlated with behavior,
as reflected by the Neuropsychiatric Inventory
Management of behavioral problems in AD: a review
Caregiver Distress Scale (total NPI-D score), and is
unrelated to the patients’ place of residence (Craig
et al., 2005).
Factors contributing to NPS
A complex interaction of biological, psychoso-
cial/psychological, and environmental factors con-
tributes to the development and presence of NPS in
From a biological perspective, progression in brain
pathology is associated with the emergence of NPS
over the course of AD, although there have been
relatively few studies directly correlating behavior
and pathologic changes.
Psychosis has been associated with an increase
in neocortical neurofibrillary tangles (Farber et al.,
2000), and agitation in AD has been associated with
a greater burden of neurofibrillary tangles in the
orbitofrontal cortex (Tekin et al., 2001). Apathy in
AD is related to decreased perfusion and metabolic
activity, as well as increased neurofibrillary tangle
burden, in the anterior cingulate region (Migneco
et al., 2001; Marshall et al., 2006). These
associations reinforce findings from several studies
demonstrating an association between apathy in
AD and deficits in medial frontal integrity (e.g.
Apostolova et al., 2007; Marshall et al., 2007).
AD with depression is associated with more
plaques and tangles than are found in patients
not exhibiting mood changes earlier in life (Rapp
et al., 2006). Furthermore, depression in AD
is correlated with frontal and prefrontal hypo-
metabolism (Hirono et al., 1998; Holthoff et al.,
2005), and concomitant cerebrovascular disease
(Treiber et al., 2008). Decreased activity of the
suprachiasmatic nucleus (circadian pacemaker or
body clock) may be responsible for the circadian
breakdown in the sleep–wake cycle, leading to the
sleep problems commonly seen in AD (Wu et al.,
2006). Additionally, genetic factors may account
for some of the neuropsychiatric heterogeneity
associated with AD. Some studies have found
relationships between the apolipoprotein E-ε4
genotype and delusions and agitation (van der
Flier et al., 2007); others have been unable to
demonstrate genetic associations (Craig et al.,
2004), or an association between psychosis in
AD and a personal or family history of psychosis
(Kotrla et al., 1995; Craig et al., 2004). There is
some evidence that risk of depression in AD is
significantly increased in the presence of a positive
family history of depression, particularly if a first-
degree relative is affected (Pearlson et al., 1990;
Strauss and Ogrocki, 1996; Lyketsos et al., 1996);
however, this finding has not been consistently
replicated (Butt and Strauss, 2001), and in one
particular study this positive association was true
only in female patients with AD (Lyketsos et al.,
Additionally, AD is accompanied by changes in
several neurotransmitter systems in the brain. The
two most studied systems involve glutamate and
acetylcholine. Glutamate receptors are involved in
the central neuronal mechanisms responsible for
the cognitive processes of memory and learning. In
AD, glutamate release and uptake are dysfunctional
and this may contribute to the cognitive and
behavioral changes observed in AD (M¨ uller et al.,
1995). Acetylcholine is another important neuro-
acetylcholine are substantially reduced, as are the
levels of choline acetyltransferase (ChAT) and
acetylcholinesterase (AChE) – the two enzymes
which regulate acetylcholine function (Perry et al.,
1977; Francis et al., 1999; Rinne et al., 2003).
Increases in muscarinic cholinergic M2 receptors
have been identified in patients with psychosis (Lai
et al., 2001).
noradrenergic (noradrenaline) (Gsell et al., 2004),
dopaminergic, and serotoninergic systems in AD,
possibly contributing to the mood changes, e.g.
depression (serotonin and noradrenaline) (Raskind
and Peskind, 1994); movement disorders, e.g.
restlessness and wandering (dopamine) (Gsell et al.,
2004); and behavioral changes, e.g. aggression
(serotonin) (Zarros et al., 2005), seen in AD.
It has been proposed that 5-HT2A
polymorphisms are associated with risk of psychosis
and aggression. In particular, the 5-HT2Areceptor
102T/C polymorphism was found to be positively
delusions (p=0.045) in AD patients (Assal et al.,
2004). Further, an association between 5-HT6
receptor/ChAT ratio in frontal and temporal cortex
and aggression in AD has been reported (Garcia-
Alloza et al., 2007).
NPS may be an expression of unmet psychological
needs, such as those associated with thirst, hunger,
pain, distress, feelings of abandonment, or fear of
endangerment. Several psycho-social models have
been proposed to explain these behaviors. The
Unmet Needs Model proposes that people with
dementia are unable to articulate their needs and
therefore react to adverse situations with behaviors
that may be disturbing to others (Algase et al.,
1996; Cohen-Mansfield, 2000). For example, an