CLINICAL REVIEW

Guidelines for the Management of Cognitive
and Behavioral Problems in Dementia
Carl H. Sadowsky, MD, and James E. Galvin, MD, MPH

Family physicians play a crucial role in the management and ongoing care of patients with Alzheimer
disease (AD). This article reviews the effects of nonpharmacologic and pharmacologic interventions on
the functional abilities and behavior of patients with dementia and how these can be implemented into
clinical practice. Nonpharmacologic interventions are recommended as the initial strategy for managing
problematic behaviors. Strategies for improving behavior include ensuring that the patient’s environ-
ment is safe, calm, and predictable; removing environmental stressors; and identifying and avoiding
situations that agitate or frighten the patient. Simple interventions include redirecting and refocusing
the patient, increasing social interaction, establishing regular sleep habits, eliminating sources of con-
flict and frustration, and establishing rewards for successes. The effectiveness of long-term behavioral
management is largely dependent on the caregiver; as such, it is important to assess the role and needs
of the caregiver.

Because currently available therapies cannot reverse the pathologic processes of AD, the primary
objective of pharmacotherapy is to preserve cognitive and functional ability, minimize behavioral dis-
turbances, and slow disease progression. Cholinesterase inhibitors represent first-line therapy for pa-
tients with mild to moderate AD, whereas a glutamate N-methyl D-aspartate antagonist is used in the
treatment of moderate to severe AD. Looking forward, there are a number of therapies in development
aimed at modifying the disease course; these include amyloid-lowering drugs, �-based and neuropro-
tective approaches, acetylcholine agonists, and mitochondrial inhibitors. ( J Am Board Fam Med 2012;
25:350 –366.)

Keywords: Dementia, Guidelines, Managed Care, Pharmacologic Therapy

The Role of the Family Physician in Treating
Dementia
Primary care is the point of first medical contact for
people with dementia and hence the cornerstone of

ensuring early detection, timely intervention, and
effective ongoing management.1 Inadequate detec-
tion and poor management have been reported
globally,2,3 leading to people with dementia and
their families being denied optimal pharmacologic4

and psychosocial intervention.5 Alzheimer disease
(AD), the most common cause of dementia world-
wide, is a complex disorder that warrants a multi-
dimensional approach with regular monitoring of
the patient for increasing cognitive, functional, and
behavioral challenges. Management consists of
both pharmacologic and nonpharmacologic inter-
ventions as well as referrals to social service agen-
cies and support resources, such as the Alzheimer’s
Association (www.alz.org). The family physician

This article was externally peer reviewed.
Submitted 5 August 2010; revised 14 October 2011; ac-

cepted 14 November 2011.
From the Division of Neurology, Nova Southeastern

University, Fort Lauderdale, FL (CHS); Premiere Research
Institute, Palm Beach Neurology, West Palm Beach, FL
(CHS); and Center of Excellence for Brain Aging, New York
University Langone School of Medicine, New York, NY
(JEG).

Funding: Administrative, editorial, and technical assis-
tance was funded by Novartis Pharmaceuticals Corporation.

Conflict of interest: none declared.
Disclosure: CHS has served as a consultant to Novartis

Pharmaceuticals Corporation; has served as a speaker for
Novartis Pharmaceuticals Corporation, Forest Pharmaceu-
ticals, and Accera; and has received honoraria from both
companies. JEG is a paid consultant for Pfizer, Eisai, No-
vartis Pharmaceuticals Corporation, Ortho-McNeil, and
Forest. Neither author received financial support for this
manuscript.

Corresponding author: Carl H. Sadowsky, MD, Medical
Director, Premiere Research Institute, Palm Beach Neurol-
ogy, 4631 Congress Ave Ste 200, West Palm Beach, FL
33407 (E-mail: CHsadow@aol.com).

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plays a key role in linking the family to community
resources and other health care and social service
providers who will help implement the overall care
plan.6,7 Physicians also play a key role in coordi-
nating the invaluable support network of nurse
practitioners, physician assistants, social workers,
and medical assistants. Moreover, the family phy-
sician can assist in maintaining the physical health
of patients with dementia, for example, assisting
with the evaluation and treatment of visual and
hearing defects, which are more common with ag-
ing. Such assistance can help directly and indirectly
in the management of dementia.

For the purpose of this review, an electronic search of
English-language articles (without time limits) was per-
formed using PubMed and MEDLINE. The primary
research parameters were Alzheimer’s disease, diagnosis,
therapy, treatment, and therapeutic. Original research ar-
ticles, reviews, and other articles of interest were re-
viewed, and the most important information was iden-
tified. This review provides a summary of these findings
as well as practical advice for the busy clinician.

Managing Cognitive, Memory, and
Functioning Problems
Goals of Therapy and Likely Outcomes
The management of a patient with AD is a complex
and evolving task because the natural history of AD is
one of progressive decline; patients’ cognitive, physi-
cal, and social functions gradually deteriorate.8 One
of the key aspects of optimal management of demen-
tia is realistic expectations for therapeutic outcomes,
including treatment effects and potential outcomes; it
is, therefore, imperative that the family physician is
aware of these issues and discusses them with both the
patient and caregiver.9 To be effective, interventions
for patients with dementia ideally will improve func-
tional status to a level that is detectable by caregivers
or health care providers.

In clinical trials, the Alzheimer’s Disease Assess-
ment Scale, Cognitive Subscale (ADAS-Cog), a 20-
minute, 11-item, 70-point scale that tests memory,
language, orientation, and praxis, is often used to
determine rate of cognitive decline. The total score
ranges from 0 to 70, with a high score indicating
greater impairment.10,11 Because of the progressive
nature of AD, there may be brief plateaus during the
illness; however, the decline is fairly consistent, tend-
ing to increase or accelerate as patients enter the
moderate stage.12 Therefore, any “improvement”

from an intervention for dementia must take this into
account. As such, “improvement” can be defined as a
reduction in rate of decline.8 For example, patients
with mild dementia experience an average rate of
decline of �5 ADAS-Cog points,8 and slowing this
decline by 2 to 3 ADAS-Cog points over a year could
mean a delay of up to 7 months in disease progres-
sion. In contrast, patients with moderate dementia
(ADAS-Cog score �15 but �55) experience an aver-
age decline in cognition of 7 to 11 ADAS-Cog points
(2– 4 Mini Mental State Examination [MMSE]
points) annually.13 Therefore, for people with mod-
erate dementia, slowing decline by 2 to 3 ADAS-Cog
points per year could mean a delay of 2 to 5 months
in disease progression. In general, cholinesterase in-
hibitors (ChEIs) do not delay ultimate progression of
AD by more than 6 to 7 months.

Nonpharmacologic Interventions
An increasing number of nonpharmacologic therapies
are now available for people with dementia, including
behavioral therapy, reality orientation, art therapy, mu-
sic therapy, complementary therapy, aromatherapy and
bright-light therapy, as well as cognitive behavioral ther-
apies. There are several areas of overlap between these
therapies and each approach is rarely used in isolation14;
it is therefore useful for clinicians to be familiar with
several of these approaches to enable a combination of
treatments to be tailored to individual requirements.15

Therapy is now directed toward person-centered forms
of care and greater attempts are made to understand the
individual’s experience of dementia and to employ strat-
egies to improve the person’s quality of life (QoL).15

Individualized nonpharmacologic interventions include
self-affirming exercises, such as reminiscence therapy,
and structured socialization, such as pet therapy and
viewing family videotapes.16 The efficacy of these inter-
ventions has been demonstrated in both small and larger
studies.17

Dietary Supplements
Several nutrient deficiencies are known to be risk
factors for AD. Evidence suggests that consumption
of fish with high fat content and marine omega-3
polyunsaturated fatty acid decreases the risk of cog-
nitive impairment and dementia.18 It is, therefore, not
unusual in clinical practice to encounter patients and
caregivers inquiring about dietary recommendations
for lowering the risk of dementia. However, to date,
there are no clinical trials to support a recommenda-
tion of dietary and supplemental omega-3 polyunsat-

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urated fatty acid for the sole purpose of preventing
cognitive impairment or dementia.18 Nevertheless, it
is not unwarranted to encourage adequate consump-
tion of fatty fish as part of general dietary recommen-
dations that may also confer benefits of reducing the
risk of stroke and heart disease.19

There has been recent attention regarding the
health benefits of curcumin (found in the commonly
used Asian spice, turmeric) in AD. In animal studies,
low-dose curcumin effectively disaggregates �-amy-
loid and prevents fibril and oligomer formation, sup-
porting the rationale for curcumin use in clinical trials
preventing or treating AD.20 Indeed, a phase II clin-
ical trial with patients with moderate to severe AD is
ongoing, designed to determine whether curcumin
can slow cognitive deterioration.21

Finally, recent studies from both the United
States and Europe have suggested that vitamin D
deficiency may be associated with increased odds of
cognitive impairment in older persons.22,23 Indeed,
results from a study in the United States in which
cognitive impairment was assessed using measures
of immediate and delayed verbal memory, orienta-
tion, and attention reported a link between vitamin
D deficiency and cognitive impairment in 3325
adults aged �65 years.22 The multivariate adjusted
odds ratios (95% confidence interval) of cognitive
impairment in patients who were vitamin D insuf-
ficient (�50 � 75 nmol/L), deficient (�25 � 50
nmol/L), and severely deficient (�25 nmol/L)
compared with those sufficient (�75 nmol/L) were
0.9 (0.6 –1.3), 1.4 (1.0 –2.1), and 3.9 (1.5–10.4), re-
spectively (P for linear trend � .02), suggesting that
vitamin D deficiency is associated with increased
odds of cognitive impairment among the elderly
population. Similar findings also have been re-
ported in a European study.23 Although further
exploration of a possible causal relationship be-
tween vitamin D deficiency and cognitive impair-
ment is warranted, these findings raise important
new possibilities for treatment and prevention of
cognitive decline in patients with AD.

Medical Foods
Medical foods as a class of intervention alternatives
are not well known to most clinicians but are a
growing area. Medical foods are a special category
of US Food and Drug Administration (FDA)–regu-
lated agents intended to provide specific nutritional
requirements for patients with certain diseases;
they can, therefore, provide an additional supple-

ment in a comprehensive therapeutic regimen for
patients with AD. Products being marketed cur-
rently or developed in the United States for the
management of dementia include Caprylic triglyc-
eride (Axona, Accera, Inc., Broomfield, CO) and
Souvenaid (Nutricia Advanced Medical Nutrition,
Schiphol, The Netherlands).

Axona has been developed for the clinical dietary
management of the metabolic processes associated
with mild to moderate AD. It is a formulation of
caprylic triglyceride, a medium-chain triglyceride
that is metabolized to ketone bodies, predomi-
nantly �-hydroxybutyrate, a common metabolic sub-
strate that is produced normally by the body for
neurons in starvation states where glucose is less avail-
able.24 A double-blind crossover study conducted in
patients with AD or mild cognitive impairment dem-
onstrated that Axona therapy was associated with sig-
nificant improvements in ADAS-Cog; however, the
effect was seen only in patients who were not carriers
of apolipoprotein E ε4.24 Similar results were re-
ported in a 90-day, randomized, placebo-controlled
study in patients with mild to moderate AD.25 Sig-
nificant gastrointestinal side effects have been associ-
ated with Axona, and slow titration of the product is
being recommended.

Souvenaid (food) combines omega-3 fatty acids,
choline, uridine monophosphate, and a mixture of
antioxidants and B vitamins.26 In a randomized,
controlled trial involving more than 200 patients
with mild AD, Souvenaid was well tolerated and
improved memory compared with placebo.27

Pharmacologic Interventions
There are currently no means of reversing the
pathologic processes of AD. Currently available
medications do not halt the underlying degenera-
tive process but can slow disease progression and
therefore delay symptomatic decline.28 The specific
goals of therapy are to preserve cognitive and func-
tional ability, minimize behavioral disturbances,
and slow disease progression with maintenance of
patients’ and caregivers’ QoL.29 Nevertheless, re-
alistic expectations of treatment outcomes are
needed because the impact for most patients is
likely to be modest and temporary, with not every
patient responding to treatment. The main benefit
of pharmacotherapy is an attenuation of decline
over time rather than an improvement in cognitive
or behavioral symptoms. It is important to discuss
this point with patients and their families, who may

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expect improvement rather than relative stability.30

Failure to do so often will result in patient and
family dissatisfaction with prescribed therapies and
the risk of discontinuation. Beneficial response to a
ChEI (ie, delayed deterioration of cognitive or be-
havioral problems) can be determined from the
physician’s global assessment of the patient, the
primary caregiver’s report, a neuropsychologic as-
sessment or mental status questionnaire, or evi-
dence of behavioral or functional changes.7

Four drugs are commonly used for treating AD:
3 ChEIs approved for mild to moderate disease, one
of which also is approved for severe AD, and a glu-
tamate N-methyl D-aspartate (NMDA) antagonist
approved for moderate to severe disease (Table 1).30

Mild to Moderate Disease
Since the introduction of the first ChEI in 1997,
most clinicians would consider these agents to be
first-line pharmacotherapy for mild to moderate
AD.11 Four ChEIs are currently available: tacrine
(Cognex, Shionogi, Inc., Atlanta, GA); donepezil
(Aricept, Eisai Co, Ltd., Woodcliff Lake, NJ); riv-
astigmine (Exelon, Novartis Pharmaceuticals Corp.,
East Hanover, NJ); and galantamine (Reminyl, Or-
tho-McNeil Neurologics, Titusville, NJ). Tacrine is
not commonly used because of a poor tolerability
profile and low oral bioavailability, and it is, there-
fore, excluded from this discussion.31 ChEIs raise
acetylcholine levels in the brain by inhibiting ace-
tylcholinesterase.6 Despite minor variations in their
mode of action there is no evidence to suggest any
difference in efficacy between the 3 commonly used
ChEIs.11 Likewise, the tolerability profile is similar
between the ChEIs for the oral formulations. How-
ever, the 10-cm2 rivastigmine patch has shown ef-
ficacy similar to oral rivastigmine formulations, but
with approximately two-thirds fewer reports of
nausea and vomiting, with adverse event (AE) rates
similar to those of placebo32 (Table 1). AD often is
accompanied and worsened by malnutrition, and
weight loss is a frequent complication of AD, oc-
curring in approximately 40% of patients at all
stages.33 Donepezil, rivastigmine, and galantamine
cause a broad spectrum of AEs, of which nausea,
vomiting, diarrhea, and weight loss are the most
common.34,35

There continues to be debate regarding the ex-
tent of the benefits achieved with ChEIs. Although
some assert that the most that can be achieved with
ChEIs is symptom modification,11 others consider

these agents to have disease-modifying effects.36 In
one study, after discontinuation of therapy, riv-
astigmine-treated patients showed less deteriora-
tion in cognitive function compared with placebo-
treated patients, suggesting an effect on disease
progression.37 In another study, donepezil treat-
ment slowed progression of hippocampal atrophy
compared with untreated patients, suggesting a
neuroprotective effect of donepezil in AD.38 How-
ever, these early observations require confirmation,
and, at present, the ChEIs generally are considered
symptomatic medications.

A systematic analysis of double-blind, placebo-
controlled trials of ChEIs demonstrated treatment
effects ranging from a 1.4- to 3.9-point improve-
ment at 6 months and 1 year, in the midrange of the
70-point ADAS-Cog scale.11 In clinical trials, a
change of 4 points is considered clinically signifi-
cant for patients with mild to moderate demen-
tia.39,40 As such, the symptomatic improvements
observed are modest and of debatable clinical sig-
nificance, despite being statistically significant.35 In
a meta-analysis of 16 double-blind, placebo-con-
trolled trials of ChEIs composed of almost 8000
patients, the numbers needed to treat for one ad-
ditional patient to benefit were 7 for stabilization or
better, 12 for minimal improvement or better, and
42 for marked improvement.41 Although the num-
bers needed to treat seem favorable, uncertainty
remains regarding the clinical relevance of these
outcomes and the duration of the apparent benefit
because the majority of trials reviewed were of less
than 26 weeks’ duration.

In addition to their effects on cognition, these
agents also have demonstrated beneficial effects on
measures of behavior, activities of daily living
(ADLs), and global patient function. A recent
meta-analysis that analyzed clinical results from 29
randomized, placebo-controlled trials of patients
with mild to moderate AD found that ChEI ther-
apy was associated with significant modest benefits
in terms of neuropsychiatric and functional out-
comes.42 Current guidelines acknowledge that pre-
venting or delaying further loss of ADL function is
an important goal of AD therapy43 and that the
benefits of ChEIs may be diminished when treat-
ment is delayed.28 Significant preservation of ADL
function has been observed with donepezil, galan-
tamine, and rivastigmine compared with placebo.29

ChEIs also have been shown to reduce AD care-
giver burden: in patients with moderate to severe

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AD, donepezil treatment for 24 weeks significantly
reduced caregiver time spent assisting patients with
basic and instrumental ADLs (�52 minutes/day;
P � .005).44 A small study has demonstrated that
rivastigmine treatment reduces caregiver time
spent assisting with ADLs (up to 690 hours over 2
years).45 Longer periods of treatment with ChEIs
also decrease the risk for nursing home place-
ment.46,47 A retrospective analysis of a large US
medical claims database showed that over a 27-
month follow-up period, more patients who were
not treated with ChEIs were placed in nursing
homes (11.0%) than were those who received ei-
ther rivastigmine (3.7%) or donepezil (4.4%).47

These studies suggest that ChEIs enable patients to
live longer in community settings with associated
personal, social, and economic benefits.29

Memantine (Namenda, Forest Pharmaceuticals,
St. Louis, MO) is sometimes used to treat patients
with less severe disease, despite its use in early AD
not being supported by the FDA. Although me-
mantine has been reported to improve cognition,
global status, and behavior in patients with mild to
moderate AD,48 its mechanism of action would sug-
gest that it does not have a place in early AD. Me-
mantine is not a ChEI; it is a low- to moderate-
affinity, noncompetitive (channel blocking), NMDA-
receptor antagonist that seems to block pathologic
neural toxicity associated with prolonged glutamate
release.49 Blockade of NMDA receptors by meman-
tine could confer disease-modifying activity in AD by
inhibiting the “weak” NMDA receptor– dependent
excitotoxicity that contributes to the neuronal loss
underlying the progression of dementia.49 As such,
memantine is not effective until weakened neurons
become vulnerable to glutamate-induced excitotoxic-
ity, and therefore it cannot substitute for ChEIs be-
cause of its inability to enhance cholinergic neu-
rotransmission required for memory and learning.49

Moderate to Severe Disease
Memantine is approved for the treatment of mod-
erate to severe AD on the basis of a study in which
patients with moderate to severe AD who received
20 mg memantine monotherapy showed less decline
in cognition and function while maintaining good
tolerability after 6 months compared with those who
received placebo.50 The ChEI donepezil also recently
has been approved for use in severe AD.

Recently, donepezil 23 mg/day has been ap-
proved for the treatment of moderate to severe AD.

Results from a 24-week, randomized, double-blind
study reported that donepezil 23 mg/day was asso-
ciated with greater benefits in cognition (as assessed
by the Severe Impairment Battery) compared with
donepezil 10 mg/day, although the between-treat-
ment difference in the Clinician’s Interview-Based
Impression of Change plus Caregiver Input Scale
was not significant. The most commonly reported
side effects with donepezil 23 mg/day were nausea
vomiting, and diarrhea, which occurred at a higher
incidence than with donepezil 10 mg/day.51

Combination therapy of a ChEI and memantine
is rational from a pharmacologic perspective be-
cause the agents have different mechanisms of ac-
tion. In a randomized controlled trial, patients with
moderate to severe AD who were already receiving
donepezil derived significant benefit from the ad-
dition of memantine in terms of cognition, ADLs,
global outcome, and behavior.52 There are also
economic benefits associated with the addition of
memantine to donepezil treatment for patients
with advanced AD. A recent study demonstrated
improvement in clinical outcomes plus cost savings
associated with the use of memantine.53 In a study
by Tariot et al,52 the incidence of nausea was sub-
stantially lower in patients receiving memantine
add-on therapy compared with those receiving
donepezil monotherapy. The safety and tolerability
of combining rivastigmine capsule and memantine
also has been studied in a 26-week, prospective,
open-label study of patients with moderate AD.54

The combination was found to be both tolerable
and safe, with a reduced incidence of gastrointesti-
nal-related AEs compared with those documented
in the US prescribing information for rivastigmine,
suggesting that this beneficial effect of memantine
may be applicable across ChEIs.54

Adjuncts to Pharmacotherapy for Improving
Cognitive Function
A recent study has demonstrated that ChEI-treated
patients with early AD who received psychosocial
support plus cognitive-motor intervention (CMI)
had additional mood and cognitive benefits over
those experienced by ChEI-treated patients who
received psychosocial support alone. The CMI
consisted of a 1-year structured program of 103
sessions, including reality orientation techniques,
cognitive exercises, training of ADLs, and psy-
chomotor exercises. Cognitive exercises were de-
signed to stimulate memory, attention, language,

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visuospatial abilities, calculation, and frontal/exec-
utive functions. The ADL training was related to
the particular cognitive function stimulated at each
session (eg, money handling was trained after cal-
culation exercises). The results showed that pa-
tients in the CMI group maintained cognitive sta-
tus at 6 months, whereas patients in the control
group had significantly declined by that time. In
addition, more patients who received CMI main-
tained or improved their affective status after 1 year
(CMI group, 75%; control group, 47%).55

Treatment Guidelines
In 2006, a panel of leading experts published rec-
ommendations for best practice in the treatment
and management of AD. These recommendations
were developed in an effort to address issues sur-
rounding early diagnosis, treatment, and care man-
agement of AD, as well as societal and managed-
care implications.56 An algorithm was created to
assist providers with the appropriate utilization of

therapy and care management (Figure 1). This al-
gorithm recommends initiating ChEI therapy in
patients with mild AD and using combination ther-
apy with a ChEI and memantine for patients who
progress from mild to moderate AD. Alternatively,
global guidelines recommend that patients who
continue on the drug should be reviewed every 6
months by MMSE score and global, functional, and
behavioral assessment.9 Treatment should be con-
tinued only while the patient’s MMSE score re-
mains �10 points and their global, functional, and
behavioral condition indicates that the drug is hav-
ing a worthwhile effect. In patients with moderate
to severe AD (MMSE score �12), treatment with
memantine can be considered, alone or in combi-
nation with a ChEI.9

Managing Mood Disorders and Behavior
Problems
Traditionally, cognitive function has been the main
focus of interest in treatment and research of peo-

Figure 1. Treatment and management of Alzheimer disease. *Memory complaint may be raised by family or
caregiver. All patients aged >75 years should be screened regardless of clinical presentation. †Cholinesterase
inhibitors (ChEIs) are included for mild to moderate Alzheimer disease, excluding donepezil, which is indicated
for mild, moderate, and severe Alzheimer disease. ‡Possible causes include medical comorbidities, the effects of
other drugs, behavioral disturbances, or delirium. §Memantine is indicated for the treatment of moderate to
severe Alzheimer disease. (This treatment algorithm is derived from recommendations published in Ref. 56.
Reproduced with permission from RG Stefanacci. Reinforcing the value of combination therapy to treat moderate
to severe alzheimer’s disease. Phys Week 2009;26(9). © 2009 Physician’s Weekly, LLC.)

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ple with dementia. It is becoming increasingly rec-
ognized, however, that noncognitive symptoms are
those that are most disturbing to families and care-
givers and may seriously impact not only the pa-
tient’s well-being, but also the family’s, caregivers’,
and providers’ approaches to managing the pa-
tient.15 The most common symptoms are agitation,
aggression, mood disorders/behavioral disturbance,
apathy, depression, psychosis and hallucinations,
with sexual disinhibition, elation/euphoria, appetite
and eating disturbances, and abnormal vocaliza-
tions occurring less frequently.15,57 These have
been grouped together under the umbrella term
behavioral and psychological symptoms of dementia by
the International Psychogeriatric Association.58 As
the disease progresses, these symptoms become
predominant problems59 and impose an enormous
toll, both emotionally and financially.17 They are
also a common reason for institutionalization of
people with dementia and they increase the burden
and stress of caregivers.55,57,60

Nonpharmacologic Interventions
Nonpharmacologic interventions are recom-
mended as the most appropriate initial strategy for
managing inappropriate behaviors in dementia be-
cause (1) they address the psychosocial/environ-
mental underlying reason for the behavior, and (2)
they avoid the limitations of pharmacologic inter-
ventions, namely, adverse side effects, drug– drug
interactions, and limited efficacy.15,17,61 Increased
involvement of caregivers often has a secondary
benefit of providing overburdened caregivers with
an opportunity to receive support, information, and
skills. Furthermore, environmental factors (eg, con-
fusing or noisy surroundings) or interpersonal factors
(eg, arguing with the patient) are often the primary
triggers of behavior problems. Attention to these fac-
tors through nonpharmacologic approaches can be
effective in alleviating or preventing behavioral prob-
lems in individuals with dementia and should be con-
sidered first.6,59,61 A recent consensus statement rec-
ommended that all treatment approaches start with
rigorous attempts to identify any reversible causes
of these behaviors and alleviate these factors16 by
modifying the physical and interpersonal environ-
ments.62,63 Common triggers of agitation and ag-
gression include pain, fecal impaction, medical ill-
ness, boredom, loneliness, depression, and social
and environmental stressors. Unfortunately, in
practice, pharmacologic approaches involving neu-

roleptic or other sedative medication are often used
as the first-line treatment, despite the modest evi-
dence of efficacy from clinical trials in which high
placebo response rates frequently are seen.15,64

Patients with AD function best in an environ-
ment that is safe, calm, and predictable, and their
caregivers require ongoing support and education
to develop realistic expectations throughout the
course of the illness.30 Caregivers can be taught
strategies to reduce agitation and anxiety in pa-
tients with dementia.65 One such strategy utilizes
the 3 Rs approach (repeat, reassure, and redirect),
whereby the caregiver repeats an instruction or
answer to a question as needed and redirects the
patient to another activity to divert attention from a
problematic situation. A predictable routine also is
important and may avert certain behavioral problems.
For example, scheduled toileting or prompted void-
ing can reduce urinary incontinence.6 Training pro-
grams for family caregivers of people with demen-
tia, such as Savvy Caregiver, Staff Training in
Assisted-Living Residences Caregivers, and Re-
sources for Enhancing Alzheimer’s Caregiver
Health, have resulted in decreased agitation among
people with dementia who live at home and re-
duced feelings of burden and depression among
family caregivers.66 – 69

Nonpharmacologic interventions can be as simple
as redirecting and refocusing the patient, increasing
social interaction, initiating enjoyable activities, estab-
lishing regular sleep habits, eliminating sources of
conflict and frustration (eg, activities that the pa-
tient can no longer undertake), and establishing
rewards for successes, however small (Table 2).61

The principles of person-centered care, which aims
to treat people as unique individuals with their own
personality and preferences, are essential in the
nonpharmacologic management of individuals with
AD.17 For example, a person’s religious back-
ground may influence his or her behavior. Patients
of certain faiths may become agitated during inti-
mate situations, such as bathing or dressing, when
in the presence of caregivers who are of the oppo-
site sex; a caregiver of the same sex may lead to
improvement in behavior. The removal of any trig-
gers of behavioral problems or the provision of
comforting stimulation, such as the patient’s favor-
ite music, also may be beneficial.70

The use of behavioral interventions in dementia
is hindered by the fact that the patient’s cognitive
functioning is declining progressively. As such, the

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effects of interventions must be monitored contin-
ually and adjustments made over time in response
to new behaviors that may emerge.62 In patients
with disruptive and hard-to-treat behavioral prob-
lems, referral to a behavioral specialist such as a
geriatric psychiatrist should be considered.

Cognitive Behavioral Therapy
Over the past 10 years there has been an increasing
interest in applying therapeutic frameworks, such
as cognitive behavioral therapy (CBT), cognitive
stimulation therapy (CST), and interpersonal ther-
apy to dementia. These therapies are designed to
actively stimulate and engage people with demen-
tia; group therapy, such as that used for CST,
provides an optimal learning environment and the
social benefits of a group and aims to create an
environment in which people learn and strengthen
their existing resources. The principles of person-

centered care are essential when delivering CST
for individuals with dementia; as such, group mem-
bers often are assigned a role within the group
according to their interests and abilities. During
each themed session, there is a range of activities
available, which allows the facilitator to adapt the
level of difficulty of the activities depending on the
group’s cognitive capabilities, interests, and gender
mix; each individual can be provided with an activ-
ity suitable for him or her personally. Sessions for
CST include physical games, sound and word as-
sociation, and faces/scenes. Individuals are asked to
give their opinions rather than provide factual an-
swers, and multisensory stimulation is used when
possible. Teri and Gallagher-Thompson71 re-
ported positive findings from a clinical trial of CBT
with individuals with early AD, and individual and
group CBT also has been used with some favorable
results.15,72 A CBT perspective is appropriate for

Table 2. Nonpharmacologic Interventions for Reducing Behavioral Disturbances in Alzheimer Disease (AD)6,95

Symptom Response

Indecisiveness • Reduce choices
Disorientation • Provide the patient with a predictable routine (eg, exercise, meals, and bedtime

should be routine and punctual)
• Avoid relocation; if necessary bring familiar items
• Allow the patient to dress in his or her own clothing and keep possessions
• Use calendars, clocks, labels, and newspapers for orientation to time
• Use color-coded or graphic labels (eg, on closets, table service, drawers) as

cues for orientation in the home environment
Hallucinations • Do not be overly concerned if they are not distressing to the patient

• Consider antipsychotic agents where necessary, but fully inform family and
caregivers of the risks/benefits of these medications

Delusions • Redirect and distract the patient
• Consider using antipsychotic medications

Repetitiveness • Answer decisively, then distract
Lack of motivation • Ensure tasks are simple so that the patient can complete them; break up

complex tasks into smaller steps
• Before performing all procedures and activities, explain them to the patient in

simple language
Wandering (usually occurs later in the

disease, ie, moderate to severe AD)
• Register the patient in the Alzheimer’s Association Safe Return Program
• Secure the environment with complex handles
• Equip doors and gates with safety locks
• Inform neighbors

Agitation • Use distraction and redirection of activities to divert the patient from
problematic situations

• Reduce excess stimulation and outings to crowded places (overexposure to
environmental stimuli can lead to agitation and disorientation)

• Use lighting to reduce confusion and restlessness at night
• Avoid glare from windows and mirrors, noise from a television, and household

clutter
Accident-prone • Provide a safe environment (eg, no sharp-edged furniture, no slippery floors or

throw rugs, no obtrusive electrical cords)
• Install grab bars by the toilet and in the shower

Ensure that comorbid conditions are optimally treated
Consider using a day care program for patients with AD

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people with dementia because many of the behav-
ioral difficulties encountered emerge through one
or more of the following cognitive features: cogni-
tive misinterpretations, biases, distortions, errone-
ous problem-solving strategies, and communica-
tion difficulties. Put simply, many of the challenges
posed by people with dementia are caused by their
thinking style—the very thing that is addressed in
CBT. CBT, therefore, offers a framework within
which to understand the individual’s distressing ex-
periences, and this understanding allows the clini-
cian to target interventions more appropriately.15

Pharmacologic Interventions
Pharmacologic interventions are necessary when
nonpharmacologic strategies fail to reduce behav-
ioral symptoms sufficiently. Patients treated with
ChEIs, memantine, or both may also experience
behavioral benefits in terms of reduced severity of
existing behavioral disturbances and fewer new be-
havior symptoms29; usually agitation/aggression
and irritability show responsiveness to ChEIs, me-
mantine, or both, whereas depression, apathy, and
anxiety do not.

If behavioral disturbances persist despite the use
of ChEIs, memantine, or both, a psychotropic
agent may be necessary.6 In accordance with the
principles of geriatric psychiatry “start low and go
slow, but go,” the psychotropic agent should be
initiated in a low dosage and then increased slowly
until an adequate response occurs or side effects
emerge. After behavioral disturbances have been
controlled for 4 to 6 months, the dosage of the
psychotropic agent can be reduced periodically to
determine whether continued pharmacotherapy is
required. The choice of psychopharmacologic
agent is determined by specific target symptoms;
some behaviors, such as wandering and pacing, are
not amenable to drug therapy. Medications used to
treat behavioral disturbances and mood disorders
are summarized in Table 3.6

Atypical Antipsychotics
Atypical antipsychotic drugs have been commonly
used off-label in clinical practice for treatment of
serious, dementia-associated agitation and aggres-
sion, although they are not approved by the FDA
for such use. In addition, these agents have a black-
box warning of increased mortality among elderly
patients with dementia-related psychosis. A meta-
analysis assessed the evidence for increased mortal-

ity from atypical antipsychotic drug treatment for
people with dementia. Fifteen trials (9 unpub-
lished), generally 10 to 12 weeks in duration and
including 16 contrasts of atypical antipsychotic
drugs with placebo, met criteria for inclusion (arip-
iprazole [n � 3], olanzapine [n � 5], quetiapine
[n � 3], risperidone [n � 5]; one trial was counted
both as a risperidone trial and an olanzapine trial).
A total of 3353 patients were randomized to study
drug and 1757 were randomized to placebo. Results
demonstrated that atypical antipsychotics may be
associated with a 50% increased risk of death from
all causes, which is similar to older antipsychotics,
but there was no obvious difference in risk between
the 4 agents.73 In general, drugs may be used only
when nonpharmacologic approaches have failed to
control serious behavioral disruption adequately
within 5 to 7 days.16 Members of a recent consen-
sus conference, who are experts in the field of
geriatric mental health, reviewed the available evi-
dence regarding the safety and efficacy of antipsy-
chotic drugs. They concluded that problems in
clinical trial design may have contributed to the
negative results reported and suggested that future
studies be required to address the benefit–risk bal-
ance in this patient population.16 Nevertheless, the
well-known incidence of side effects, such as seda-
tion, falls, extrapyramidal signs, potential reduction
in well-being and QoL,14 and even possible accel-
eration of cognitive decline,15,74,75 mean that the
risk– benefit ratio must be considered carefully
when prescribing these drugs to a generally frail
population. If antipsychotics are indicated, then it
is recommended that they are used at the lowest
effective dose, with dosage reduced or treatment
discontinuation considered on a regular basis.59

Agitation
Agitation and psychosis are distressing and are
likely to overwhelm the caregiver’s ability to cope.
If behavioral and nonpharmacologic interventions
are inadequate, mild agitation can be managed with
low doses of medications, such as trazodone, car-
bamazepine, and valproate.59 Tricyclic antidepres-
sants and benzodiazepines generally are avoided in
this population.59 In patients with severe agitation
and aggression, a recent consensus conference con-
cluded that there is a need for an FDA-approved
indication for treating dementia-related symptoms
of severe and persistent or recurrent agitation and

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Table 3. Pharmacologic Treatment of Behavior and Mood Disorders

Antipsychotic drugs
Atypical antipsychotic agents

Recommended uses: control of problematic delusions, hallucinations, severe psychomotor agitation, and combativeness
General cautions: diminished risk of developing extrapyramidal symptoms and tardive dyskinesia compared with typical

antipsychotic agents
Warning: atypical antipsychotic agents can cause an increased risk of cerebrovascular events (including stroke) in elderly

patients with dementia-related psychosis
Risperidone (Risperdal) Initial dosage: 0.25 mg/day at bedtime;

maximum dosage: 2–3 mg/day,
usually twice daily in divided doses

Comments: current research supports use of
low dosages; extrapyramidal symptoms
may occur at 2 mg/day

Olanzapine (Zyprexa) Initial dosage: 2.5 mg/day at bedtime;
maximum dosage: 10 mg/day,
usually twice daily in divided doses

Comments: generally well tolerated

Quetiapine (Seroquel) Initial dosage: 12.5 mg twice daily;
maximum dosage: 200 mg twice
daily

Comments: more sedating; beware of
transient orthostasis

Typical antipsychotic agents
Recommended uses: control of problematic delusions, hallucinations, severe psychomotor agitation, and combativeness;

second-line therapy for patients who cannot tolerate or who do not respond to atypical antipsychotic agents
General cautions: current research suggests that these drugs be avoided if possible because they are associated with

significant, often severe side effects involving the cholinergic, cardiovascular, and extrapyramidal systems; there is also an
inherent risk of irreversible tardive dyskinesia, which can develop in 50% of elderly patients after continuous use of typical
antipsychotic agents for 2 years

Warning: typical antipsychotic agents can cause an increased risk of cerebrovascular events (including stroke) in elderly
patients with dementia-related psychosis

Haloperidol (Haldol), fluphenazine
(Prolixin), thiothixene (Navane)

Dosage: varies by agent Comments: anticipated extrapyramidal
symptoms; if these symptoms occur,
decrease dosage or switch to another
agent; avoid use of benztropine
(Cogentin) or trihexyphenidyl (Artane)

Trifluoperazine (Stelazine),
molindone (Moban), perfenazine
(Trilafon), loxapine (Loxitane)

Dosage: varies by agent Comments: agents with “in-between” side-
effect profile

Mood-stabilizing (anti-agitation) drugs
Recommended uses: control of problematic delusions, hallucinations, severe psychomotor agitation, and combativeness; useful

alternatives to antipsychotic agents for control of severe agitated, repetitive, and combative behaviors
General cautions: see comments about specific agents
Trazodone (Desyrel) Initial dosage: 25 mg/day; maximum

dosage: 200 to 400 mg/day in
divided doses

Comments: use with caution in patients
with premature ventricular contractions

Carbamazepine (Tegretol) Initial dosage: 100 mg twice daily;
titrate to therapeutic blood level
(4–8 �g/mL)

Comments: monitor complete blood cell
count and liver enzyme levels regularly;
carbamazepine has problematic side
effects

Divalproex sodium (Depakote) Initial dosage: 125 mg twice daily;
titrate to therapeutic blood level
(40–90 �g/mL)

Comments: generally better tolerated than
other mood stabilizers; monitor liver
enzyme levels; monitor platelets,
prothrombin time, and partial
thromboplastin time as indicated

Anxiolytic drugs
Benzodiazepines

Recommended uses: management of insomnia, anxiety and agitation
General cautions: regular use can lead to tolerance, addiction, depression and cognitive impairment; paradoxic agitations

occurs in about 10% of patients treated with benzodiazepines; infrequent, low doses of agents with a short half-life are
least problematic

Lorazepam (Ativan), oxazepam
(Serax), temazepam (Restoril),
zolpidem (Ambien), triazolam
(Halcion)

Dosage: varies by agent See general cautions

Continued

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Table 3. Continued

Nonbenzodiazepines
Buspirone (BuSpar) Initial dosage: 5 mg twice daily;

maximum dosage: 20 mg 3 times
daily

Comments: useful only in patients with
mild to moderate agitation; may take 2 to
4 weeks to become effective

Antidepressant drugs
Recommended uses: see comments on specific agents
General cautions: selection of an antidepressant is usually based on previous treatment response, tolerance and the advantage of

potential side effects (eg, sedation vs activation); a full therapeutic trial requires 4–8 weeks; as a rule, dosage is increased
using increments of initial dose every 5–7 days until therapeutic benefits or significant side effects become apparent; after 9
months, dosage reduction is used to reassess the need to medicate; discontinuing an antidepressant over 10–14 days limits
withdrawal symptoms.

Note: patients with depression and psychosis require concomitant antipsychotic medications.
Tricyclic antidepressant agents

Desipramine (Norpramin) Initial dosage: 10–25 mg in the
morning; maximum dosage: 150 mg
in the morning

Comments: tends to be activating (eg,
reduces apathy); lower risk for
cardiotoxic, hypotensive and
anticholinergic effects; may cause
tachycardia; blood levels may be helpful

Nortriptyline (Pamelor) Initial dosage: 10 mg at bedtime;
anticipated dosage range: 10–40 mg/
day (given twice daily)

Comments: tolerance profile is similar to
that of desipramine, but nortriptyline
tends to be more sedating; may be useful
in patients with agitated depression and
insomnia; therapeutic blood level
“window” of 50–150 ng/mL (190–570
nmol/L)

Heterocyclic and noncyclic antidepressant agents
Nefazodone (Serzone) Initial dosage: 50 mg twice daily;

maximum dosage: 150–300 mg twice
daily

Comments: effective, especially in patients
with associated anxiety; reduced dose of
coadministered alprazolam (Xanax) or
triazolam by 50%; monitor for
hepatotoxicity

Buproprion (Wellbutrin) Initial dosage: 37.5 mg every morning,
then increase by 37.5 mg every 3
days; maximum dosage: 150 mg
twice daily

Comments: activating; possible rapid
improvement of energy level; should not
be used in agitated patients and those
with seizure disorders; to minimize risk of
insomnia, give second dose before 3pm

Mirtazapine (Remeron) Initial dosage: 7.5 mg at bedtime;
maximum dosage: 30 mg at bedtime

Comments: potent and well tolerated;
promotes sleep, appetite, and weight gain

SSRIs
Recommended uses: may prolong half-life of other drugs by inhibiting various cytochrome P450 isoenzymes
General cautions: typical side effects include sweating, tremors, nervousness, insomnia or somnolence, dizziness, and various

gastrointestinal and sexual disturbances
Fluoxetine (Prozac) Initial dosage: 10 mg every other

morning; maximum dosage: 20 mg
every morning

Comments: activating, very long half-life;
side effects may not manifest for a few
weeks

Paroxetine (Paxil) Initial dosage: 10 mg/day; maximum
dosage: 40 mg/day (morning or
evening)

Comments: less activating but more
anticholinergic than other SSRIs

Sertraline (Zoloft) Initial dosage: 25–50 mg/day;
maximum dosage: 200 mg/day
(morning or evening)

Comments: well tolerated; compared with
other SSRIs, sertraline has less effect on
metabolism of other medications

Citalopram (Celexa) Initial dosage: 10 mg/day; maximum
dosage: 40 mg/day

Comments: well tolerated; some patients
experience nausea and sleep disturbances

Fluvoxamine (Luvox) Initial dosage: 50 mg twice daily;
maximum dosage: 150 mg twice
daily

Comments: exercise caution when using
fluvoxamine with alprazolam or triazolam

Reproduced with permission from Cummings JL, et al. Am Fam Physician 2002; 65:2525 to 2534. © 2002 American Academy of
Family Physicians.6

SSRI, selective serotonin reuptake inhibitor.

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aggression, even in the absence of psychosis.16 Se-
lective serotonin reuptake inhibitors seem to have
efficacy for treatment of agitation in patients with
AD. Studies have demonstrated benefits for agita-
tion with citalopram compared with placebo76 and
similar efficacy compared with risperidone.77

Apathy
Apathy as a distinct psychiatric syndrome is an
evolving concept but generally has been defined as
poor initiation, impaired persistence, indifference,
reduced emotional response, and low social en-
gagement.78 Although once believed to be just a
symptom of depression, apathy is characterized pri-
marily as a loss of motivation and reduced emo-
tional reactivity, as opposed to depression, which is
a mood disturbance.79 Based on a limited but in-
creasing body of evidence, methylphenidate seems
to have some efficacy for the treatment of apathy in
older adults with AD.80

Depression
Depression is common in older adults, including
those with AD, and often is undiagnosed and un-
treated. The efficacy of antidepressants in patients
with AD who also suffer depression has been dem-
onstrated in clinical trial; the most useful medica-
tions are those with minimal anticholinergic side
effects. Selective serotonin reuptake inhibitors,
such as citalopram (Celexa, Forest Laboratories,
Inc.) and sertraline (Zoloft, Pfizer, New York, NY),
seem to be effective and have fewer side effects
compared with other antidepressants; as such, they
are considered the agents of choice for the treat-
ment of depression in patients with dementia, al-
though direct head-to-head studies have yet to be
undertaken.7,81

The Needs of the Caregiver
Caregivers can become exhausted and frustrated;
suffer depression, anxiety, and health problems;
and be at increased risk of death.2,9 Ideally, care-
givers would receive assistance in caregiving, peri-
odic assessment of their own health and welfare,
support from family and friends, and respite care.
One study has reported that the most consistently
effective method of caregiver treatment interven-
tions is to teach caregivers how to change or modify
their interaction with the patient.30

Mittelman and colleagues82 have demonstrated
the effectiveness of long-term behavioral interven-
tions for caregivers. Caregivers of patients with AD
often suffer from depression, and optimizing long-
term social support (individual and family counsel-
ing, the continuous availability of ad hoc counsel-
ing, and support group participation) can have a
significant impact on depression in caregivers.82

The same authors subsequently demonstrated that
a program of counseling and support substantially
increased the time spousal caregivers were able to
care for AD patients at home. Patients whose
spouses received the intervention experienced a
28% reduction in the rate of nursing home place-
ment compared with usual care controls, with a
difference in time to placement of 557 days. Im-
provements in caregivers’ satisfaction with social
support, response to patient behavior problems,
and symptoms of depression collectively accounted
for 61% of the intervention’s beneficial impact on
placement.83,84 Furthermore, these benefits were
greatest in patients who had only mild dementia,
when nursing home placement is generally least
appropriate.83,84

In the event that insufficient resources are avail-
able to provide for and protect both patient and
caregiver, nursing home placement needs to be
considered.2 The progressive nature of dementia
also must be emphasized, such that in the event of
nursing home placement the caregiver does not
consider it to be a failure on their part.2 Discussing
the benefits and disadvantages of institutional care
with caregivers is often challenging. Although con-
sideration of the patient’s previously expressed
wishes is essential, caregivers often feel constrained
by comments made years earlier and believe that
the patient would not accept long-term care. It can
be helpful to remind caregivers that earlier com-
ments were made without a full appreciation of the
current circumstances and that expectations almost
always change with chronic illnesses.70

Future Therapies
ChEIs and memantine are symptomatic therapies
that help maintain neuronal function but do not
have a significant impact on the underlying disease
process. Their benefits are mild, and treatments
that modify the disease course are urgently
needed.30,39 AD is the destruction of brain that
cannot be regenerated, and any effective treatment

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needs to start before much brain is destroyed.
There recently has been intense research interest in
characterizing the earliest stages of AD that pre-
cede the crossing of the dementia threshold, de-
fined by functional disability.85 Such preclinical
disease detection may allow earlier therapeutic in-
tervention before critical numbers of neurons are
lost.

AD currently is thought to be a complex, mul-
tifactorial syndrome, unlikely to arise from a single
causal factor; instead, a number of related biologic
alterations are thought to contribute to its patho-
genesis. In light of this, drug combinations that can
act at different levels of the neurotoxic cascade offer
new avenues toward curing AD and other neuro-
degenerative diseases.86 Effective treatment will re-
quire attacking multiple targets.87 At present, key
therapeutic approaches include reduction of brain
amyloid levels,30,88,89 prevention of � hyperphospho-
rylation into intraneuronal neurofibrillary tan-
gles,30,89 and stimulation of muscarinic acetylcholine
receptors,90,91 although novel therapies increasingly
are targeted to preserving energy metabolism in the
mitochondria.92–94

Conclusion
Family physicians play a crucial role in the care of
patients with AD in terms of early detection, timely
intervention, and effective ongoing management.
Optimal management involves a multidimensional
approach to treatment that includes the physician,
geriatric care managers, social services, and the
patient’s family. The treatment of AD consists of
both pharmacologic and nonpharmacologic inter-
ventions.

Nonpharmacologic interventions are recom-
mended as the most appropriate initial strategy for
managing problematic behaviors. Patients with AD
function best in an environment that is safe, calm,
and predictable. Interventions for improving be-
havior include reduction of environmental stressors
and strategies to reduce the agitation and anxiety of
the patient. These interventions can be as simple as
redirecting and refocusing the patient, increasing
social interaction, establishing regular sleep habits,
eliminating sources of conflict and frustration, and
establishing rewards for successes, however small.
The role and needs of the caregiver are important,
and the effectiveness of long-term behavioral inter-
ventions for caregivers has been demonstrated.

In the absence of means to reverse the patho-
logic processes of AD, the primary objectives of
pharmacologic interventions are to preserve cogni-
tive and functional ability, minimize behavioral dis-
turbances, and slow disease progression. At present,
four drugs are widely used to treat AD: 3 ChEIs,
which are first-line treatment for patients with mild
to moderate AD, and an NMDA antagonist ap-
proved for treatment of moderate to severe AD.

The authors would like to thank Frances Gambling for her
editorial assistance with the manuscript. Administrative, edito-
rial, and technical assistance was funded by Novartis Pharma-
ceuticals Corporation.

References
1. Downs M, Turner S, Bryans M, et al. Effectiveness

of educational interventions in improving detection
and management of dementia in primary care: clus-
ter randomised controlled study. BMJ 2006;332:
692– 6.

2. van Hout H, Vernooij-Dassen M, Bakker K, Blom
M, Grol R. General practitioners on dementia: tasks,
practices and obstacles. Patient Educ Couns 2000;
39:219 –25.

3. Knopman D, Donohue JA, Gutterman EM. Patterns
of care in the early stages of Alzheimer’s disease:
impediments to timely diagnosis. J Am Geriatr Soc
2000;48:300 – 4.

4. Bullock R. New drugs for Alzheimer’s disease and
other dementias. Br J Psychiatry 2002;180:135–9.

5. Woods RT, Moniz-Cook E, Iliffe S, et al. Dementia:
issues in early recognition and intervention in pri-
mary care. J R Soc Med 2003;96:320 – 4.

6. Cummings JL, Frank JC, Cherry D, et al. Guidelines
for managing Alzheimer’s disease: part II. Treat-
ment. Am Fam Physician 2002;65:2525–34.

7. Cummings JL, Frank JC, Cherry D, et al. Guidelines
for managing Alzheimer’s disease: part I. Assess-
ment. Am Fam Physician 2002;65:2263–72.

8. Boustani M, Peterson B, Hanson L, Harris R, Lohr
KN. Screening for dementia in primary care: a sum-
mary of the evidence for the U.S. Preventive Services
Task Force. Ann Intern Med 2003;138:927–37.

9. Waldemar G, Dubois B, Emre M, et al. Recommenda-
tions for the diagnosis and management of Alzheimer’s
disease and other disorders associated with dementia:
EFNS guideline. Eur J Neurol 2007;14:e1–26.

10. Rosen WG, Mohs RC, Davis KL. A new rating scale
for Alzheimer’s disease. Am J Psychiatry 1984;141:
1356 – 64.

11. Birks J. Cholinesterase inhibitors for Alzheimer’s
disease. Cochrane Database Syst Rev 2006;(1):
CD005593.

12. National Institute of Clinical Excellence. Dementia:
supporting people with dementia and their carers in

doi: 10.3122/jabfm.2012.03.100183 Guidelines for the Management of Dementia 363

 o
n

 5
 A

p
ril 2

0
2
1

 b
y g

u
e
st. P

ro
te

cte
d
 b

y co
p
yrig

h
t.

h
ttp

://w
w

w
.ja

b
fm

.o
rg

/
J A

m
 B

o
a

rd
 F

a
m

 M
e

d
: first p

u
b

lish
e

d
 a

s 1
0

.3
1

2
2

/ja
b

fm
.2

0
1

2
.0

3
.1

0
0
1
8
3
 o

n
 8

 M
a
y 2

0
1
2
. D

o
w

n
lo

a
d
e
d
 fro

m
 

http://www.jabfm.org/


health and social care. 2006. November 2006, amended
March 2011. Available from: http://www.nice.org.uk/
nicemedia/live/10998/30318/30318.pdf. Accessed 29
March 2012.

13. Salmon DP, Thal LJ, Butters N, Heindel WC. Lon-
gitudinal evaluation of dementia of the Alzheimer
type: a comparison of 3 standardized mental status
examinations. Neurology 1990;40:1225–30.

14. Ballard CG, O’Brien J, James I. Dementia: manage-
ment of behavioral and psychological symptoms. Ox-
ford: Oxford University Press; 2001.

15. Douglas S, James I, Ballard C. Non-pharmacological
interventions in dementia. Adv Psychiatric Treat-
ment 2004;10:171–9.

16. Salzman C, Jeste DV, Meyer RE, et al. Elderly
patients with dementia-related symptoms of severe
agitation and aggression: consensus statement on
treatment options, clinical trials methodology, and
policy. J Clin Psychiatry 2008;69:889 –98.

17. Cohen-Mansfield J. Nonpharmacologic interven-
tions for inappropriate behaviors in dementia: a re-
view, summary, and critique. Am J Geriatr Psychia-
try 2001;9:361– 81.

18. Lim WS, Gammack JK, Van Niekerk J, Dangour
AD. Omega 3 fatty acid for the prevention of de-
mentia. Cochrane Database Syst Rev 2006;(1):
CD005379.

19. Friedland RP. Fish consumption and the risk of
Alzheimer disease: is it time to make dietary recom-
mendations? Arch Neurol 2003;60:923– 4.

20. Yang F, Lim GP, Begum AN, et al. Curcumin in-
hibits formation of amyloid beta oligomers and fi-
brils, binds plaques, and reduces amyloid in vivo.
J Biol Chem 2005;280:5892–901.

21. Poncha F. Efficacy and safety of curcumin formulation
in Alzheimer’s disease. ClinicalTrials.gov identifier:
NCT01001637. 15 October 2009, updated 23 October
2009. Available from: http://clinicaltrials.gov/ct2/show/
NCT01001637?term�NCT01001637&rank�1. Ac-
cessed 15 March 2012.

22. Llewellyn DJ, Lang IA, Langa KM, Melzer D. Vi-
tamin D and cognitive impairment in the elderly
U.S. population. J Gerontol A Biol Sci Med Sci
66:59 – 65.

23. Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D
and risk of cognitive decline in elderly persons. Arch
Intern Med 170:1135– 41.

24. Reger MA, Henderson ST, Hale C, et al. Effects of
beta-hydroxybutyrate on cognition in memory-im-
paired adults. Neurobiol Aging 2004;25:311– 4.

25. Accera. Axona description. Available from: http://
www.about-axona.com/wordpress/wp-content/
uploads/prescribinginformation.pdf. Accessed 29
March 2012.

26. Nutricia. The Science Behind Souvenaid®. Available
from: http://souvenaid.nutricia.com/the-science-behind-
souvenaid.html. Accessed 29 March 2012.

27. Scheltens P, Verhey FRJ, Olde Rikkert MGM, Kam-
phuis PJGH, Wilkinson D, Kurz A. The efficacy of
a medical food (Souvenaid) in Alzheimer’s disease:
results from the first trial and design of future trials.
Alzheimers Dement 2009;5(Suppl):258 –9.

28. Farlow MR, Cummings JL. Effective pharmacologic
management of Alzheimer’s disease. Am J Med 2007;
120:388 –97.

29. Geldmacher DS. Treatment guidelines for Alzhei-
mer’s disease: redefining perceptions in primary
care. Prim Care Companion J Clin Psychiatry 2007;
9:113–21.

30. Salloway S, Correia S. Alzheimer disease: time to
improve its diagnosis and treatment. Cleve Clin
J Med 2009;76:49 –58.

31. Birks J, Grimley Evans J, Iakovidou V, Tsolaki M,
Holt FE. Rivastigmine for Alzheimer’s disease. Co-
chrane Database Syst Rev 2009;(2):CD001191.

32. Winblad B, Grossberg G, Frolich L, et al. IDEAL: a
6-month, double-blind, placebo-controlled study of
the first skin patch for Alzheimer disease. Neurology
2007;69:S14 –22.

33. Guerin O, Andrieu S, Schneider SM, et al. Different
modes of weight loss in Alzheimer disease: a pro-
spective study of 395 patients. Am J Clin Nutr 2005;
82:435– 41.

34. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt
HP, van den Bussche H. Cholinesterase inhibitors
for patients with Alzheimer’s disease: systematic re-
view of randomised clinical trials. BMJ 2005;331:
321–7.

35. Qaseem A, Snow V, Cross JT Jr, et al. Current
pharmacologic treatment of dementia: a clinical
practice guideline from the American College of
Physicians and the American Academy of Family
Physicians. Ann Intern Med 2008;148:370 – 8.

36. Cummings JL. Searching for methods to detect, pre-
vent, and treat Alzheimer’s disease. Am J Psychiatry
2005;162:645–7.

37. Farlow M, Potkin S, Koumaras B, Veach J, Mirski D.
Analysis of outcome in retrieved dropout patients in
a rivastigmine vs placebo, 26-week. Alzheimer dis-
ease trial. Arch Neurol 2003;60:843– 8.

38. Hashimoto M, Kazui H, Matsumoto K, Nakano Y,
Yasuda M, Mori E. Does donepezil treatment slow
the progression of hippocampal atrophy in patients
with Alzheimer’s disease? Am J Psychiatry 2005;162:
676 – 82.

39. Raina P, Santaguida P, Ismaila A, et al. Effectiveness
of cholinesterase inhibitors and memantine for treat-
ing dementia: evidence review for a clinical practice
guideline. Ann Intern Med 2008;148:379 –97.

40. Doraiswamy PM, Kaiser L, Bieber F, Garman RL.
The Alzheimer’s Disease Assessment Scale: evalua-
tion of psychometric properties and patterns of cog-
nitive decline in multicenter clinical trials of mild to
moderate Alzheimer’s disease. Alzheimer Dis Assoc
Disord 2001;15:174 – 83.

364 JABFM May–June 2012 Vol. 25 No. 3 http://www.jabfm.org

 o
n

 5
 A

p
ril 2

0
2
1

 b
y g

u
e
st. P

ro
te

cte
d
 b

y co
p
yrig

h
t.

h
ttp

://w
w

w
.ja

b
fm

.o
rg

/
J A

m
 B

o
a

rd
 F

a
m

 M
e

d
: first p

u
b

lish
e

d
 a

s 1
0

.3
1

2
2

/ja
b

fm
.2

0
1

2
.0

3
.1

0
0
1
8
3
 o

n
 8

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a
y 2

0
1
2
. D

o
w

n
lo

a
d
e
d
 fro

m
 

http://www.jabfm.org/


41. Lanctot KL, Herrmann N, Yau KK, et al. Efficacy
and safety of cholinesterase inhibitors in Alzheimer’s
disease: a meta-analysis. CMAJ 2003;169:557– 64.

42. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy
of cholinesterase inhibitors in the treatment of neu-
ropsychiatric symptoms and functional impairment
in Alzheimer disease: a meta-analysis. JAMA 2003;
289:210 – 6.

43. Doody RS, Stevens JC, Beck C, et al. Practice pa-
rameter: management of dementia (an evidence-
based review). Report of the Quality Standards Sub-
committee of the American Academy of Neurology.
Neurology 2001;56:1154 – 66.

44. Feldman H, Gauthier S, Hecker J, et al. Efficacy of
donepezil on maintenance of activities of daily living
in patients with moderate to severe Alzheimer’s dis-
ease and the effect on caregiver burden. J Am Geriatr
Soc 2003;51:737– 44.

45. Marin D, Amaya K, Casciano R, et al. Impact of
rivastigmine on costs and on time spent in caregiving
for families of patients with Alzheimer’s disease. Int
Psychogeriatr 2003;15:385–98.

46. Lopez OL, Becker JT, Saxton J, Sweet RA, Klunk
W, DeKosky ST. Alteration of a clinically meaning-
ful outcome in the natural history of Alzheimer’s
disease by cholinesterase inhibition. J Am Geriatr
Soc 2005;53:83–7.

47. Beusterien KM, Thomas SK, Gause D, Kimel M,
Arcona S, Mirski D. Impact of rivastigmine use on
the risk of nursing home placement in a US sample.
CNS Drugs 2004;18:1143– 8.

48. Peskind ER, Potkin SG, Pomara N, et al. Meman-
tine treatment in mild to moderate Alzheimer dis-
ease: a 24-week randomized, controlled trial. Am J
Geriatr Psychiatry 2006;14:704 –15.

49. Rogawski MA, Wenk GL. The neuropharmacolog-
ical basis for the use of memantine in the treatment
of Alzheimer’s disease. CNS Drug Rev 2003;9:275–
308.

50. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S,
Mobius HJ. Memantine in moderate-to-severe Alz-
heimer’s disease. N Engl J Med 2003;348:1333– 41.

51. Farlow MR, Salloway S, Tariot PN, et al. Effective-
ness and tolerability of high-dose (23 mg/d) versus
standard-dose (10 mg/d) donepezil in moderate to
severe Alzheimer’s disease: a 24-week, randomized,
double-blind study. Clin Ther;32:1234 –51.

52. Tariot PN, Farlow MR, Grossberg GT, Graham
SM, McDonald S, Gergel I. Memantine treatment in
patients with moderate to severe Alzheimer disease
already receiving donepezil: a randomized controlled
trial. JAMA 2004;291:317–24.

53. Weycker D, Taneja C, Edelsberg J, et al. Cost-
effectiveness of memantine in moderate-to-severe
Alzheimer’s disease patients receiving donepezil.
Curr Med Res Opin 2007;23:1187–97.

54. Olin JT, Bhatnagar V, Reyes P, Koumaras B, Meng
X, Brannan S. Safety and tolerability of rivastigmine

capsule with memantine in patients with probable
Alzheimer’s disease: a 26-week, open-label, prospec-
tive trial (study ENA713B US32). Int J Geriatr Psy-
chiatry 25:419 –26.

55. Olazaran J, Muniz R, Reisberg B, et al. Benefits of
cognitive-motor intervention in MCI and mild to
moderate Alzheimer disease. Neurology 2004;63:
2348 –53.

56. Fillit HM, Doody RS, Binaso K, et al. Recommen-
dations for best practices in the treatment of Alzhei-
mer’s disease in managed care. Am J Geriatr Phar-
macother 2006;4(Suppl 1):S9 –S24; quiz S5–S8.

57. deSouza L, Sarazin M, Goetz C, Dubois B. Clinical
investigations in primary care. Front Neurol Neuro-
sci 2009;24:1–11.

58. Finkel SI, Costa e Silva J, Cohen G, Miller S, Sar-
torius N. Behavioral and psychological signs and
symptoms of dementia: a consensus statement on
current knowledge and implications for research and
treatment. Int Psychogeriatr 1996;3(8 Suppl):497–
500.

59. Christensen DD, Lin P. Practical treatment strate-
gies for patients with Alzheimer’s disease. J Fam
Pract 2007;56:S17–23.

60. Schultz R, Williamson GH. A 2-year longitudinal
study of depression among Alzheimer’s caregivers.
Psychol Aging 1991;6:569 –78.

61. Teri L, Logsdon RG, McCurry SM. Nonpharmaco-
logic treatment of behavioral disturbance in demen-
tia. Med Clin North Am 2002;86:641–56, viii.

62. Logsdon RG, McCurry SM, Teri L. Evidence-based
psychological treatments for disruptive behaviors in
individuals with dementia. Psychol Aging 2007;22:
28 –36.

63. Emerson E. Working with people with challenging
behavior. Chichester: John Wiley and Sons; 1998.

64. Ballard C, O’Brien J. Treating behavioural and psy-
chological signs in Alzheimer’s disease. BMJ 1999;
319:138 –9.

65. Haupt M, Karger A, Janner M. Improvement of
agitation and anxiety in demented patients after psy-
choeducative group intervention with their caregiv-
ers. Int J Geriatr Psychiatry 2000;15:1125–9.

66. Hepburn KW, Lewis M, Sherman CW, Tornatore
J. The savvy caregiver program: developing and test-
ing a transportable dementia family caregiver train-
ing program. Gerontologist 2003;43:908 –15.

67. Kovach CR, Taneli Y, Dohearty P, Schlidt AM,
Cashin S, Silva-Smith AL. Effect of the BACE in-
tervention on agitation of people with dementia.
Gerontologist 2004;44:797– 806.

68. Teri L, McCurry SM, Logsdon R, Gibbons LE.
Training community consultants to help family
members improve dementia care: a randomized con-
trolled trial. Gerontologist 2005;45:802–11.

69. Ostwald SK, Hepburn KW, Caron W, Burns T,
Mantell R. Reducing caregiver burden: a random-
ized psychoeducational intervention for caregivers of

doi: 10.3122/jabfm.2012.03.100183 Guidelines for the Management of Dementia 365

 o
n

 5
 A

p
ril 2

0
2
1

 b
y g

u
e
st. P

ro
te

cte
d
 b

y co
p
yrig

h
t.

h
ttp

://w
w

w
.ja

b
fm

.o
rg

/
J A

m
 B

o
a

rd
 F

a
m

 M
e

d
: first p

u
b

lish
e

d
 a

s 1
0

.3
1

2
2

/ja
b

fm
.2

0
1

2
.0

3
.1

0
0
1
8
3
 o

n
 8

 M
a
y 2

0
1
2
. D

o
w

n
lo

a
d
e
d
 fro

m
 

http://www.jabfm.org/


persons with dementia. Gerontologist 1999;39:299 –
309.

70. Herrmann N, Gauthier S. Diagnosis and treatment
of dementia: 6. Management of severe Alzheimer
disease. CMAJ 2008;179:1279 – 87.

71. Teri L, Gallagher-Thompson D. Cognitive-behav-
ioral interventions for treatment of depression in
Alzheimer’s patients. Gerontologist 1991;31:413– 6.

72. Kipling T, Bailey M, Charlesworth G. The feasibil-
ity of a cognitive behavioural therapy group for men
with a mild/moderate cognitive impairment. Behav
Cogn Psychother 1999;27:189 –93.

73. Schneider LS, Dagerman KS, Insel P. Risk of death
with atypical antipsychotic drug treatment for de-
mentia: meta-analysis of randomized placebo-con-
trolled trials. JAMA 2005;294:1934 – 43.

74. McShane R, Keene J, Gedling K, Fairburn C, Jacoby
R, Hope T. Do neuroleptic drugs hasten cognitive
decline in dementia? Prospective study with nec-
ropsy follow up. BMJ 1997;314:266 –70.

75. Schneider LS, Tariot PN, Dagerman KS, et al. Ef-
fectiveness of atypical antipsychotic drugs in patients
with Alzheimer’s disease. N Engl J Med 2006;355:
1525–38.

76. Pollock BG, Mulsant BH, Rosen J, et al. Compari-
son of citalopram, perphenazine, and placebo for the
acute treatment of psychosis and behavioral distur-
bances in hospitalized, demented patients. Am J Psy-
chiatry 2002;159:460 –5.

77. Pollock BG, Mulsant BH, Rosen J, et al. A double-
blind comparison of citalopram and risperidone for
the treatment of behavioral and psychotic symptoms
associated with dementia. Am J Geriatr Psychiatry
2007;15:942–52.

78. Landes AM, Sperry SD, Strauss ME, Geldmacher
DS. Apathy in Alzheimer’s disease. J Am Geriatr Soc
2001;49:1700 –7.

79. Boyle PA, Malloy PF. Treating apathy in Alzhei-
mer’s disease. Dement Geriatr Cogn Disord 2004;
17:91–9.

80. Dolder CR, Davis LN, McKinsey J. Use of psycho-
stimulants in patients with dementia. Ann Pharma-
cother 2010;44:1624 –32.

81. Lyketsos CG, Sheppard JM, Steele CD, et al. Ran-
domized, placebo-controlled, double-blind clinical
trial of sertraline in the treatment of depression com-
plicating Alzheimer’s disease: initial results from the
Depression in Alzheimer’s Disease study. Am J Psy-
chiatry 2000;157:1686 – 0.

82. Mittelman MS, Ferris SH, Shulman E, et al. A com-
prehensive support program: effect on depression in
spouse-caregivers of AD patients. Gerontologist
1995;35:792– 802.

83. Mittelman MS, Ferris SH, Shulman E, Steinberg G,
Levin B. A family intervention to delay nursing
home placement of patients with Alzheimer disease.
A randomized controlled trial. JAMA 1996;276:
1725–31.

84. Mittelman MS, Haley WE, Clay OJ, Roth DL. Im-
proving caregiver well-being delays nursing home
placement of patients with Alzheimer disease. Neu-
rology 2006;67:1592–9.

85. Dubois B, Picard G, Sarazin M. Early detection of
Alzheimer’s disease: new diagnostic criteria. Dia-
logues Clin Neurosci 2009;11:135–9.

86. Bolognesi ML, Rosini M, Andrisano V, et al. MTDL
design strategy in the context of Alzheimer’s disease:
from lipocrine to memoquin and beyond. Curr
Pharm Des 2009;15:601–13.

87. Duara R, Barker W, Loewenstein D, Bain L. The
basis for disease-modifying treatments for Alzhei-
mer’s disease: the Sixth Annual Mild Cognitive Im-
pairment Symposium. Alzheimers Dement 2009;5:
66 –74.

88. Bates KA, Verdile G, Li QX, et al. Clearance mech-
anisms of Alzheimer’s amyloid-beta peptide: impli-
cations for therapeutic design and diagnostic tests.
Mol Psychiatry 2009;14:469 – 86.

89. Tarawneh R, Holtzman DM. Critical issues for suc-
cessful immunotherapy in Alzheimer’s disease: de-
velopment of biomarkers and methods for early de-
tection and intervention. CNS Neurol Disord Drug
Targets 2009;8:144 –59.

90. Caccamo A, Fisher A, LaFerla FM. M1 agonists as a
potential disease-modifying therapy for Alzheimer’s
disease. Curr Alzheimer Res 2009;6:112–7.

91. Conn PJ, Jones CK, Lindsley CW. Subtype-selective
allosteric modulators of muscarinic receptors for the
treatment of CNS disorders. Trends Pharmacol Sci
2009;30:148 –55.

92. Lermontova NN, Redkozubov AE, Shevtsova EF,
Serkova TP, Kireeva EG, Bachurin SO. Dimebon
and tacrine inhibit neurotoxic action of beta-amyloid
in culture and block L-type Ca(2�) channels. Bull
Exp Biol Med 2001;132:1079 – 83.

93. Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug
GF, Sablin SO. Mitochondria as a target for neuro-
toxins and neuroprotective agents. Ann N Y Acad
Sci. 2003;993:334 – 44.

94. Doody RS, Gavrilova SI, Sano M, et al. Effect of
dimebon on cognition, activities of daily living, be-
haviour, and global function in patients with mild-
to-moderate Alzheimer’s disease: a randomised, dou-
ble-blind, placebo-controlled study. Lancet 2008;
372:207–15.

95. Leifer BP. Alzheimer’s disease: seeing the signs
early. J Am Acad Nurse Pract 2009;21:588 –95.

366 JABFM May–June 2012 Vol. 25 No. 3 http://www.jabfm.org

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u
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st. P

ro
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cte
d
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y co
p
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h
t.

h
ttp

://w
w

w
.ja

b
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.o
rg

/
J A

m
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o
a

rd
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a
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: first p

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e

d
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a
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