EDUCATIONAL REVIEW

Primary Psychiatry. 2008;15(2):66-76

The Black Book of Alzheimer’s Disease,

Part 1
Jeffrey L. Cummings, MD

INTRODUCTION
This educational review article is the first of a two-part
adaptation of a clinical handbook that is useful in the diag-
nosis and treatment of Alzheimer’s disease and other demen-
tias (The Black Book of Alzheimer’s Disease, J.L. Cummings,
MD, 2008, publication pending). The classification of
dementia, the expansion of diagnostic approaches to include
more mild syndromes such as mild cognitive impairment
(MCI), and the rapid evolution of new therapies make
it difficult to remain informed about all critical progress
relevant to Alzheimer’s disease and related conditions. The
article provides information needed to manage patients
using contemporary advances in diagnosis and manage-
ment. It will be updated annually in the form of a Black
Book to insure that it remains current.
This article is not intended as a comprehensive reference.
It provides critical information only. In addition, it provides
references and Web sites where more information can be
found on each topic presented. Constructed for the clinician
(primary care practitioner, neurologist, or psychiatrist) who
needs rapid access to updated information, this article also
contains information valuable to families (eg, Web sites) that
the practitioner can provide in the course of discussions about
Alzheimer’s disease and dementia.
Useful ratings scales and standardized assessments are
described. Reference and resource sections complete the article.
FOCUS POINTS
• Alzheimer’s disease is the most common cause of dementia in
the elderly.
• Alzheimer’s disease and dementia are affected by genetics,
neuropathology, and pathophysiology.
• The evaluation of the patient presenting for assessment
of cognitive impairment includes clinical, laboratory, and
imaging aspects.
• Clinical scales and inventories help to assess the presence of
dementia.
• Warning signs of Alzheimer’s disease may help family members
decide if an evaluation is warranted.
The presentations and discussions have been kept deliberately
short, as the purpose is not to serve as a textbook but to provide
information critical to patient care embedded in enough con-
text to make management decisions coherent and logical.
EPIDEMIOLOGY OF ALZHEIMER’S
DISEASE AND DEMENTIA
Alzheimer’s disease is the most common cause of demen-
tia in the elderly, accounting for 60% to 75% of cases. The
frequency of dementia doubles every 5 years, increasing from

Dr. Cummings is the Augustus S. Rose Professor of Neurology, professor of psychiatry and biobehavioral sciences, director of the Mary S. Easton Center for Alzheimer Research at the University of California,
Los Angeles (UCLA), and director of the Deane F. Johnson Center for Neurotherapeutics at the David Geffen School of Medicine at UCLA.
Disclosures: Dr. Cummings has served as a consultant for Acadia, Adamas, Astellas, Avanir, CoMentis, Eisai, EnVivo, Janssen, Forest, Lundbeck, Medivation, Merck, Merz, Myriad, Neurochem, Novartis, Ono,
Pfizer, Prana, Sanofi-Aventis and Takeda. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory. Dr. Cummings has been supported by a National Institute on Aging Alzheimer Disease Center
grant (P50 AG 10157), an Alzheimer’s Disease Research Center of California grant, the Sidell-Kagan Foundation, and the August Rose Chair of the University of California.
Acknowledgements: Dr. Cummings thanks his colleagues at the UCLA Alzheimer Disease Center and the patients and caregivers who have given meaning to his commitment to find more effective treatments
for Alzheimer’s Disease. He also thanks his wife Kate (Xue) Cummings (Zhong) without whose enthusiasm, love, and support this project would have been impossible.
Please direct all correspondence to: Jeffrey L. Cummings, MD, Alzheimer Disease Center, 10911 Weybrun Ave, #200, Los Angeles, CA 90095-7226; Tel: 310-794-3665; Fax: 310-794-3148;
E-mail: jcummings@mednet.ucla.edu.

Primary Psychiatry 66 February 2008

 The Black Book of Alzheimer’s Disease, Part 1

affecting 1% of individuals 60–64 years of age; to 2% of those
65–69 years of age; 4% of individuals 70–74 years of age; 8%
of those 75–79 years of age; 16% of those 80–84 years of
age; and 35% to 45% of those >85 years of age (Figure 1).1
Most of these dementia patients have Alzheimer’s disease
(Figure 2). An estimated 3.5–4.5 million Americans and 25
million worldwide have dementia.2 By 2040, these figures are
expected to rise to 9.2 million (North America) and 81.1 mil-
lion (global).2 The number of Alzheimer’s disease victims will
have a striking impact on the global economy. The estimated
cost of caring for dementia patients in 2003 was $156 billion3
and these costs will rise to staggeringly large numbers as the
world population ages.
Risk and protective factors for Alzheimer’s disease have
been identified through epidemiologic and case-controlled
studies (Tables 1 and 2). A Mediterranean type-diet, dietary
antioxidants, statins, and exercise are among the factors
associated with reduced risk of Alzheimer’s disease, while
low education levels, head injury, diabetes, and hypertension
increase the risk of Alzheimer’s disease.4-9
Discussion of these risk and protective factors with rela-
tives of Alzheimer’s disease patients interested in informa-
tion about reducing their risk for Alzheimer’s disease is war-
ranted. Lifestyle changes in midlife may have the greatest
impact on the eventual development of Alzheimer’s disease.
It is uncertain if factors that reduce the risk of Alzheimer’s
disease will also decrease the progression of MCI to
Alzheimer’s disease, or of the progression of established
Alzheimer’s disease.

TABLE 1
FIGURE 1 ALZHEIMER’S DISEASE: RISK FACTORS
ALZHEIMER’S DISEASE DOUBLES IN FREQUENCY EVERY 5 Age
YEARS AFTER 60 YEARS OF AGE
Female gender
35
ApoE-4 genotype
30
Family history of dementia
Percent Affected (%)

25
Hypercholesterolemia
20
Hyper-homocysteinemia
15
Diabetes
10
Head injury
5
Psychological stress
0
60 65 70 75 80 85+ Hypertension
Age (years)
Smoking
Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008. Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008.

FIGURE 2 TABLE 2
FREQUENCY OF DEMENTIA TYPES (AUTOPSY SERIES) ALZHEIMER’S DISEASE: PROTECTIVE FACTORS
6% Education
11% AD Active cognitive involvement/leisure activity
3% AD+CVD Physical activity/exercise
5% 49%
DLB
Diet with high antioxidant content
PD with Dem
5% • Omega-3 fatty acids
MIX • Vitamins E, C
VaD
21% Dietry vitamins
Other • B6, B12, folate
Alcohol (modest use)
AD=Alzheimer’s disease; CVD= cardiovascular disease; DLB=dementia with Lewy bodies; Statins
PD=Parkinson’s disease; Dem=dementia; MIX=Alzheimer’s disease and cerebrovascular
disease; VaD=vascular dementia. Nonsteroidal anti-inflammatory agents
Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008. Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008.

Primary Psychiatry 67 February 2008

 J. Cummings

GENETICS, NEUROPATHOLOGY, AND Alzheimer’s disease is often complicated by other neuropatho-

PATHOPHYSIOLOGY OF ALZHEIMER’S
DISEASE
Genetics
Alzheimer’s disease is inherited as an autosomal dominant
disorder in a small number of cases (3% to 5%) of the total
number of Alzheimer’s disease patients. Most of the auto-
somal dominant forms of Alzheimer’s disease have an early
onset dementia syndrome with symptoms appearing in the
fifth and sixth decades of life. Mutations causing Alzheimer’s
disease have been identified on chromosome 21 in the amy-
loid precursor protein (APP) and in the genes encoding pre-
senilin 1 (chromosome 14) and preselinin 2 (chromosome
1), respectively.10 The presenilins form part of the γ-secre-
tase enzyme complex responsible for metabolizing APP to
amyloid β protein. Triplication of the APP gene in trisomy
Down syndrome is also associated with Alzheimer’s disease
and all long-surviving individuals with Down syndrome
develop Alzheimer’s disease-type brain pathology. Presenilin
1 mutations are the most common of the mutations causing
early onset Alzheimer’s disease, and testing for this mutation
is commercially available.
Polymorphisms of genes occurring in the population
may increase the risk of developing Alzheimer’s disease.
Apolipoprotein e4, encoded on chromosome 19, is the
most well-established risk gene for Alzheimer’s disease.10
Clinical testing for e4 in asymptomatic individuals is not
recommended since it does not provide definitive predic-
tive information. There is increasing evidence of a role for a
SORL1 polymorphism (chromosome 11) as a risk factor for
Alzheimer’s disease.11
logic processes when patient brains are studied at autopsy.13
These studies demonstrate that comorbid conditions commonly
coexist with Alzheimer’s disease at least by the time patients reach
advanced stages of their disease (Figures 3–6; Table 3).
Pathophysiology
The β-amyloid peptide is derived from the APP through
sequential proteolysis by β-secretase and γ-secretase.
Monomeric peptides aggregate into increasing complex
assemblies of oligomers, protofribrils, and fibrils, and are
eventually deposited as insoluble plaques.14 It is the oligomer-
ic intermediate species of amyloid to which neurotoxicity is
attributed.15 β-amyloid initiates a cascade of events leading to
synaptic dysfunction, neurodegeneration and neuron death.16
The elements of the cascade include oxidation, inflamma-
tion, excitotoxicty, and tau hyperphosphorylation leading to
neurofibrillary tangle formation.
FIGURE 3
PROGRESSIVE BRAIN ATROPHY IN THE COURSE OF
ALZHEIMER’S DISEASE AS SHOWN BY MAGNETIC
RESONANCE IMAGING CORTICAL THICKNESS MAPPING*
MRI-based cortical thickness maps of normal elderly (left), patients with MCI (middle),
and AD (right). There is progress brain atrophy from normal to MCI to AD.
*Images courtesy of L. Apostolova, University of California, Los Angeles.
MRI=magnetic resonance imaging; MCI=mild cognitive impairment; AD=Alzheimer’s disease.
Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008.

Neuropathology
FIGURE 4
There is progressive atrophy of the brain in Alzheimer’s AMYLOID PLAQUES, NEUROFIBRILLARY TANGLES AND
disease with loss of cerebral substance in temporal, parietal, NEURON DEATH ARE THE MAIN PATHOLOGICAL CHANGES
and frontal regions. Primary motor and sensory cortices IN THE BRAIN IN ALZHEIMER’S DISEASE
are relatively spared. The primary histopathologic lesions
of Alzheimer’s disease are amyloid plaques, neurofibrillary
tangles, and neuronal loss.12 Mature plaques consist of a
central amyloid core with surrounding degenerating neu-
rons affected by the toxic effect of the β-amyloid protein.
Proliferating astrocytes and activated microglia are present
in the plaque. Neurofibrillary tangles consist of hyperphos- Amyloid plaques in the cortex Neurofibrillary tangle in hippocam-
(Aß42 immunostain) pal neuron (tau immunostain)
phorylated tau protein that has assumed a double helical
Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008.
filament conformation.12

Primary Psychiatry 68 February 2008

 The Black Book of Alzheimer’s Disease, Part 1

ASSESSMENT OF COGNITIVE IMPAIRMENT assessments such as the Mini-Mental State Examination

(MMSE)17 or the Montreal Cognitive Assessment (MoCA)18
and unstructured hypothesis-driven assessments based on
Clinical Assessment findings that emerge in the course of the examination. The
The evaluation of the patient presenting for assessment of mental status examination should assess five basic cognitive
cognitive impairment includes clinical, laboratory, and imag- domains, including attention, memory, language, visuospatial
ing aspects. The history of present illness, medical history, function, and executive function.
review of systems, social history, family history, and current Results of the cognitive assessment are integrated with
medications should be discussed with the patients and cor- physical examination (ie, cardiac auscultation, carotid and
roborated by a caregiver or other knowledgeable informant. peripheral pulse palpation, head and neck examination) and
Caregiver mood and stress should be noted and evaluated. the neurologic examination (ie, cranial nerves, motor func-
The mental status examination is an essential part of the tion, sensory function, coordination, muscle stretch reflexes,
assessment of cognition and typically includes standardized primitive reflexes, gait, station). A preliminary diagnostic
formulation emerges and allows selection of appropriate labo-
ratory tests and neuroimaging. Standardized mental status
FIGURE 5 examinations are described below.
FORMATION OF OGLIOMERIC AMYLOID AND PLAQUES
FROM APP Laboratory Tests
APP
Aβ The American Academy of Neurology (AAN) guidelines19
β-secretase γ-secretase suggest that the routine laboratory assessment of cognitively
(intramembranous)
impaired patients include basic laboratory studies of complete
Aβ blood count, electrolytes, blood sugar, liver function tests,
and blood urea nitrogen as well as thyroid stimulating hor-
Aggregation of Aβ Neurotoxicity and mone and serum B12 level (Table 4).19-21 Additional tests may
into oligomers cell death
be sought to clarify the clinical assessment. Lumbar puncture
and examination of the cerebrospinal fluid is not a routine
Formation of
neuritic plaques
part of the evaluation for cognitive impairment but can be
very helpful in assisting diagnosis in some cases (Table 5).
APP=amyloid precursor protein; Aβ=amyloid beta.
Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008. TABLE 3
STAGES OF ALZHEIMER’S DISEASE
FIGURE 6 Executive
NEUROTOXIC CASCADE INITIATED BY AMYLOID β PROTEIN Stage Memory Language V-S Skills Function ADL
Aggregation of Aβ
Aβ into oligomers MCI Amnesia Normal Normal Minimally No impair-
affected ment
Mild Amnesia Decreased Mildly Mildly IADL
verbal flu- abnormal abnormal affected
ency
Oxidative Loss of Excitotoxicity Moderate Amnesia Anomia; Moderately Moderately ADL
injury synapses (excessive plus decreased abnormal abnormal affected
glutamate)
remote comp.
Neurofibrillary memory
Neuritic plaques tangles
impair-
ment
Severe Absent Aphasia Severely Untestable Totally
Transmitter deficits
abnormal dependent
Nerve cell death V-S=visuospatial; ADL=activities of daily living; IADL=instrumental activities of daily living; MCI=mild
Aβ=amyloid beta. cognitive impairment.

Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008. Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008.

Primary Psychiatry 69 February 2008

 J. Cummings

Neuroimaging Single photon emission computed tomography demonstrates

cerebral blood flow; patterns distinctive for Alzheimer’s disease
Brain imaging of patients with dementia is recommended
(bilateral parietal hypoperfusion), frontotemporal dementia
by the AAN19 and the European Federation of Neurological
(frontal and temporal hypoperfusion), and vascular dementia
Science.20 Computerized tomography or magnetic resonance
(multifocal hypoperfusion with multiple infarctions) can be
imaging (MRI) provide structural information to exclude
identified. Metabolic imaging with fluorodeoxyglucose posi-
brain tumors, subdural hematomas, and obstructive hydro-
tron emission tomography (PET) reveals distinctive metabolic
cephalus. Medial temporal atrophy can usually be discerned
profiles for different dementia syndromes21 (Figures 7–10).
on MRI of patients with Alzheimer’s disease or amnestic MCI.
PET imaging of amyloid with Pittsburgh Compound B22 or
Areas of high signal intensity are seen in the cerebral white
FDDNP23 is being studied but is not yet commercially avail-
matter on T2-weighted images in patients with small vessel
able. Amyloid in the brain is synonymous with the presence of
disease associated with hypertension or diabetes. Obtaining
Alzheimer’s disease; with PET imaging, the amyloid may be identi-
T1, T2, and fluid-attenuated inversion-recovery imaging
fied before the patient meets criteria for Alzheimer type dementia.
are the most useful in assessment of dementia syndromes.20
Magnetic resonance spectroscopy is a research instrument
whose potential for more routine use is under investigation.
CLINICAL SCALES AND INVENTORIES

TABLE 4 Brief Screening Tools

AAN LABORATORY TEST GUIDELINES 19-21
Mini-Mental State Examination
Recommended for all patients19 The MMSE17 is the most widely used brief mental status
CBC Anemia and blood dyscrasias screening instrument. It consists of 30 questions, comprised
Electrolytes Electrolyte imbalance contributing to confusion of 10 orientation items, three recall items, five reverse spell-
BUN Renal function; disorder can contribute to confusion
Blood sugar Diabetes; risk factor for Alzheimer’s disease TABLE 5
Liver function Liver function; disorder can contribute to confusion EVALUATION OF DEMENTIA
tests
Standard tests
Cholesterol Elevated cholesterol is a cardiovascular and
Alzheimer’s disease risk factor Cell count Elevated in infections and inflammation
Thyroid stimulat- Elevated in hypothyroidism Protein Elevated in many CNS disorders including infections,
ing hormone inflammation, and tumors
Serum B12 level Level reduced in B12 deficiency with dementia Glucose Reduced in most CNS infections
Contingent test obtained in specific clinical circumstances Contingent tests to be considered in specific clinical circumstances
Erythrocyte Elevated in inflammatory disorders IgG Elevated in MS (>12% of total protein)
sedimentation rate IgG index Elevated in MS (>1.7 is suggestive of multiple scle-
Homocysteine level Elevated level are risks for stroke and Alzheimer’s rosis)
disease Oligoclonal bands Present in MS
Testosterone level20 Low levels contribute to poor quality of live in male 14-3-3 protein Elevated in Creutzfeldt-Jakob disease can also be
patients with Alzheimer’s disease increased following stroke with infection and in para-
Apolipoprotein E E4 allele confers an increased risk for Alzheimer’s neoplastic disorders
genotype disease Amyloid β protein Low amyloid beta protein and high tau protein is char-
Presenilin 1 muta- Autosomal dominant form of Alzheimer’s disease; rare acteristic of Alzheimer’s disease
tion testing and limited to early onset familial cases Tau/phosphotau Low amyloid beta protein and high tau protein is char-
Plasma HIV viral HIV dementia protein acteristic of Alzheimer’s disease
titers, CD4+T cell Cytology Abnormal cells may be seen in CNS lymphoma and
count21 other tumors
AAN=American Academy of Neurology; CBC=complete blood count; BUN=blood urea nitrogen. CNS=central nervous system; MS=multiple sclerosis.
Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008. Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008.

Primary Psychiatry 70 February 2008


ing or serial subtraction items, three learning items, six oral
language items (naming, repetition, comprehension), one
reading item, one writing item, and one construction item.
The MMSE best assesses disorders with important language
and memory components such as Alzheimer’s disease. The
examination changes at a rate of approximately three points
per year in typical Alzheimer’s disease. The MMSE may be
abnormal in dementia, delirium, aphasia, or amnesia syn-
dromes. It is relatively insensitive to mild changes in well-
educated individuals and is insensitive to change in advanced
dementia. The MMSE lacks tests of executive function.
Mini-Cog
The Mini-Cog is a very brief assessment of memory and
drawing skills. It is comprised of three memory items and a
clock-drawing test (Figure 11). This very short assessment has
similar sensitivity in specificity to the MMSE.25
FIGURE 7
MAGNETIC RESONANCE IMAGING*
Magnetic resonance imaging shows (A) a normal hippocampus (arrow) in a healthy elderly
individual, (B) mild atrophy in mild cognitive impairment, and (C) marked atrophy in an
individual with Alzheimer type dementia.
*Images courtesy of L. Apostolova, University of California, Los Angeles.
Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008.
FIGURE 8
FLUORODEOXYGLUCOSE POSITRON EMISSION
TOMOGRAPHY—ALZHEIMER’S DISEASE
Normal elderly; the posterior cin-
gulate region (red area; left scan)
shows normal or high metabolism
Alzheimer’s disease; there is hypo-
metabolism in the posterior cingu-
late and in both parietal lobes
Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008.
Primary Psychiatry
The Black Book of Alzheimer’s Disease, Part 1
Montreal Cognitive Assessment
The MoCA is a 30-item test similar to the MMSE but
with less emphasis on language, memory, and orientation,
and greater emphasis on executive function.18 Executive items
included in the MoCA include Trails-B, clock drawing, word
list generation, a continuous performance task, and abstrac-
tion of similarities. The naming items are lower frequency
than those of MMSE and more likely to detect a mild ano-
mia. The five-word learning test may be more sensitive to
memory impairment than the three-word learning test of the
MMSE (See example at www.mocatest.org28).
Functional Activity Questionnaire
The Functional Activity Questionnaire measures instrumen-
tal activities of daily living such as using transportation, balanc-
ing a checkbook, and preparing a meal.9 It provides a means of
assessing mild impairment of higher level daily functions.
FIGURE 9
FLUORODEOXYGLUCOSE POSITRON EMISSION
TOMOGRAPHY—FRONTOTEMPORAL DEMENTIA AND
DEMENTIA WITH LEWY BODIES
Frontotemporal dementia; there is marked
hypometabolism of the frontal and ante-
rior temporal lobes
Dementia with Lewy bodies; the hypo-
metabolism extended into the occipital
lobes
Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008.
FIGURE 10
FDDNP PET IMAGING OF BRAIN AMYLOID*
FDDNP PET imaging of brain amyloid (yellow and red signal) in normal aging (right), mild
cognitive impairment (center), and Alzheimer’s disease (left).
*Image courtesy of G. Small, University of California, Los Angeles.
FDDNP=2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile;
PET=positron emission tomography; LT=lateral temporal; MT=medial temporal.
Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008.
71 February 2008
 J. Cummings

Neuropsychiatry Inventory–Questionnaire anxiety, depression, apathy, elation, disinhibition, irritabil-

The Neuropsychiatry Inventory-Questionnaire (NPI- ity, abberrant motor behavior, agitation, sleep abnormali-
Q)30 is the brief version of the Neuropsychiatric Inventory.31 ties, and appetite disturbances. The associated NPI-Q also
The NPI-Q can be completed by a caregiver and provides allows the caregiver to indicate their level of distress with
information regarding 12 common behavioral changes and each behavior (Figure 12).
behavioral syndromes, including hallucinations, delusions, Other commonly used assessments of neuropsychiatric
symptoms and behavioral abnormalities in patients with
Alzheimer’s disease and other dementias include the Cohen-
FIGURE 11
Mansfield Agitation Inventory,32 the Behavioral Pathology in
MINI-COG SCORING ALGORITHM Alzheimer’s Disease rating scale,33 and the Cornell Scale for
MINI-COG
MINI-COG Depression in Dementia.34
Neuropsychological Measures
Formal neuropsychological assessment allows standardized
3-Item Recall
Recall == 00
R
3-Item Recall
Recall ==
R
Recall==33
3-Item Re
Recall
comprehensive evaluation of cognitive deficits and cognitive
1 or
o 2
strength compared to age- and education-matched controls.
IMPAIRED
IMPAIRED NOT IMPAIRED
NOT IMPAIRED Psychological testing is particularly useful when questions
arise in regard to distinguishing normal aging from early
cognitive abnormalities and MCI.
Clock
Clock Drawing
Drawing
wi Abnormal Clock
Clock Drawing
Drawing Normal
i Normal
Neuropsychological testing can generate an intelligence
quotient as well as assessments of memory and learning, lan-
IMPAIRED
IMPAIRED NOTIMPAIRED
NOT IMPAIRED guage, visuospatial and constructional skills, executive func-
tion, and psychomotor speed.
Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008.

FIGURE 12
NEUROPSYCHIATRIC INVENTORY QUESTIONNAIRE (NPI-Q)
Please answer the following questions based on changes that have occurred since the patient first began to experience memory problems
Circle “Yes” only if the symptom(s) has been present in the last month. Otherwise, circle “No”. For each item marked “Yes”:
a) Rate the SEVERITY of the symptom (how it affects the patient):
1 = Mild (noticeable, but not a significant change)
2 = Moderate (significant, but not a dramatic change)
3 = Severe (very marked or prominent, a dramatic change)
b) Rate the DISTRESS you experience due to that symptom (how it affects you):
0 = Not distressing at all
1 = Minimal (slightly distressing, not a problem to cope with)
2 = Mild (not very distressing, generally easy to cope with)
3 = Moderate (fairly distressing, not always easy to cope with)
4 = Severe (very distressing, difficult to cope with)
5 = Extreme or Very Severe (extremely distressing, unable to cope with)

Please answer each question carefully. Ask for assistance if you have any questions.
Delusions Does the patient have false beliefs, such as thinking that others are stealing from him/her or planning to harm him/her in
some way?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Hallucinations Does the patient have hallucinations such as false visions or voices?
Does he or she seem to hear or see things that are not present?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
(cont. on next page)

Primary Psychiatry 72 February 2008

 The Black Book of Alzheimer’s Disease, Part 1

FIGURE 12 (cont. from page 72)

NEUROPSYCHIATRIC INVENTORY QUESTIONNAIRE (NPI-Q)
Agitation/Aggression Is the patient resistive to help from others at times, or hard to handle?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Depression/Dysphoria Does the patient seem sad or say that he /she is depressed?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Anxiety Does the patient become upset when separated from you? Does he/she have any other signs of nervousness such as short-
ness of breath, sighing, being unable to relax, or feeling excessively tense?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Elation/Euphoria Does the patient appear to feel too good or act excessively happy?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Apathy/Indifference Does the patient seem less interested in his/her usual activities or in the activities and plans of others?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Disinhibition Does the patient seem to act impulsively, for example, talking to strangers as if he/she knows them, or saying things that
may hurt people’s feelings?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Irritability/Lability Is the patient impatient and cranky? Does he/she have difficulty coping with delays or waiting for planned activities?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Motor Disturbance Does the patient engage in repetitive activities such as pacing around the house, handling buttons, wrapping string, or doing
other things repeatedly?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Nighttime Behaviors Does the patient awaken you during the night, rise too early in the morning, or take excessive naps during the day?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5
Appetite/Eating Has the patient lost or gained weight, or had a change in the type of food he/she likes?
Yes No SEVERITY: 1 2 3 DISTRESS: 0 1 2 3 4 5

NPI-Q SUMMARY
No Total (Severity) Caregiver Distress
Delusions 0 1 2 3 1 2 3 4 5
Hallucinations 0 1 2 3 1 2 3 4 5
Agitation/Aggression 0 1 2 3 1 2 3 4 5
Dysphoria/Depression 0 1 2 3 1 2 3 4 5
Anxiety 0 1 2 3 1 2 3 4 5
Euphoria/Elation 0 1 2 3 1 2 3 4 5
Apathy/Indifference 0 1 2 3 1 2 3 4 5
Disinhibition 0 1 2 3 1 2 3 4 5
Irritability/Lability 0 1 2 3 1 2 3 4 5
Aberrant Motor 0 1 2 3 1 2 3 4 5
Nighttime Behavior 0 1 2 3 1 2 3 4 5
Appetite/Eating 0 1 2 3 1 2 3 4 5
Total

Cummings JL. Primary Psychiatry

Psychiatry. Vol 15, No 2. 2008.

Primary Psychiatry 73 February 2008

 J. Cummings
Clinical Trials
Clinical trial instrumentation overlaps with tools used in
clinical practice but many of the outcome measures used in
clinical trials are too time and labor intensive to be used in
routine clinical practice.
The Food and Drug Administration requires that an
agent produce a statistically significant advantage over pla-
cebo on a cognitive outcome and a global or functional out-
come to be approved as an antidementia agent. Secondary
outcomes commonly included in clinical trials assess behav-
ioral changes and alterations in activities of daily living.
Pharmacoeconomics, caregiver burden, and quality of life
are assessed in some trials (Figure 13).
Cognition
The cognitive assessment most commonly used in clini-
cal trials is the Alzheimer’s disease Scale cognitive portion
(ADAS-Cog).35 This instrument assesses memory, language,
and praxis; higher scores indicate greater impairment.
The ADAS-Cog is used to assess patients with mild-to-
moderate dementia. Clinical trials including patients with
moderate-to-severe dementia are assessed with a Severe
Impairment Battery.36
The Neuropsychological Test Battery has been used as
an outcome measure in some clinical trials of patients with
mild-to-moderate Alzheimer’s disease. The instrument has a
memory and executive function factor, is reliable and sensi-
tive to change, and may be particularly useful for patients
with mild degrees of cognitive impairment.37
FIGURE 13
ASSESSMENT TYPICALLY USED IN CLINICAL TRIALS
Alzheimer’s Disease
Mild-moderate: ADAS-Cog
Cognition
Moderate-severe: SIB
Function/Activities ADCS ADL Scale
Of Daily Living Disability Assessment for Dementia
Behavior Neuropsychiatric Inventory
Clinical Global Impression of Change
Global/Overview
Clinician Interview Based Impression of Change
ADAS-Cog=Alzheimer’s Disease Assessment Scale, Cognitive Portion; SIB=severe impair-
ment battery; ADCS=Alzheimer’s Disease Cooperative Study; ADL=activities of daily living.
Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008.
Primary Psychiatry
Global Assessments
Global assessments that may be used in clinical trials
include the Clinical Interview-based Impression of Change
scale37 or the Clinical Global Impression of Change scale.38
These global assessments provide a summary evaluation that
includes cognition, function, and behavior. The Clinical
Dementia Rating scale39 is sometimes used as a global out-
come, particularly in longer clinical trials.
Activities of Daily Living
Activities of Daily Living (ADL) are an important outcome
in clinical trials and are usually assessed as a secondary out-
come measure. Commonly used assessments of ADL include
the Alzheimer’s Disease Cooperative Study, ADL Inventory,40
or Disability Assessment for Dementia scale.41
Behavior
The Neuropsychiatric Inventory29 is the behavioral mea-
sure most widely used as an outcome in clinical trials involv-
ing dementia patients.
Parkinsonism
Parkinsonism is assessed in many studies of patients with
Parkinson’s disease or dementia with Lewy bodies. The
Unified Parkinsonism Disease Rating Scale42 is the instru-
ment most commonly incorporated into clinical trials where
parkinsonism was an important outcome.
10 WARNING SIGNS OF ALZHEIMER’S
DISEASE
Families may be uncertain and concerned if a loved one has
the symptoms of Alzheimer’s disease. The warning signs may
help them decide if an evaluation is warranted; the presence
of any of these symptoms should lead to medical referral.
Memory Loss
Forgetting recently learned information is one of the most
common early signs of dementia. A person begins to forget more
often and is unable to recall the information later. However, for-
getting names or appointments occasionally is normal.
Difficulty Performing Familiar Tasks
People with dementia often find it hard to plan or
complete everyday tasks. Individuals may lose track of the
steps involved in preparing a meal, placing a telephone
call or playing a game. However, occasionally forgetting
why one came into a room or what one planned to say
is normal.
74 February 2008
 The Black Book of Alzheimer’s Disease, Part 1

Problems with Language usual, or not wanting to perform usual activities. However, it is
normal to sometimes feel weary of work or social obligations.
People with Alzheimer’s disease often forget simple words or
substitute unusual words, making their speech or writing hard to
understand. For exmple, they may be unable to find the tooth-
brush and instead ask for “that thing for my mouth.” However,
CAREGIVER AND PROFESSIONAL
sometimes having trouble finding the right word is normal. RESOURCES
Contact information for caregiver and professional resources
Disorientation to Time and Place can be found in Tables 6 and 7.
People with Alzheimer’s disease can become lost in their own
neighborhood, forget where they are and how they got there, TABLE 6
and not know how to get back home. However, it is normal to
CONTACT INFORMATION: FAMILIES 43-59
forget the day of the week or where one was going.
Alzheimer’s Association www.alz.org
Poor or Decreased Judgment Alzheimer’s Disease International (ADI) www.alz.co.uk
Alzheimer’s Foundation of America www.alzfdn.org
Those with Alzheimer’s disease may dress inappropriately,
wearing several layers on a warm day or little clothing in the American Stroke Association www.strokeassociation.org
cold. They may show poor judgment, like giving away large Brain Injury Association www.biausa.org
sums of money to telemarketers. However, making a question- Clinical Trials www.clinicaltrials.gov
able or debatable decision from time to time is normal. Deane F. Johnson Center for www.jcnt.org
Neurotherapeutics at UCLA
Problems with Abstract Thinking Frontotemporal Dementia Association www.FTD-Picks.org
Leeza Gibbons Memory Foundation www.memoryfoundation.org
Someone with Alzheimer’s disease may have unusual dif-
ficulty performing complex mental tasks, like forgetting what Lewy Body Dementia Association www.lewybodydementia.org
numbers are for and how they should be used. However, it is National Institute on Aging, Alzheimer www.nia.nih.gov/alzheimers
Disease Education and Referral Center
normal to find it challenging to balance a checkbook. (ADEAR)
National Parkinson Foundation www.parkinson.org
Misplacing Objects
National Stroke Association www.stroke.org
A person with Alzheimer’s disease may put objects in unusual Parkinson’s Disease Foundation www.pdf.org
places, such as an iron in the freezer or a wristwatch in the sugar
Progressive Supranuclear Palsy (Europe) www.pspeur.org
bowl. However, misplacing keys or a wallet temporarily is normal.
Society for Progressive Supranuclear Palsy www.psp.org
UCLA Alzheimer Disease Center www.adc.ucla.edu
Changes in Mood or Behavior
UCLA=University of California, Los Angeles.
Someone with Alzheimer’s disease may show rapid mood
swings, from calm to tears to anger, for no apparent reason. Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008.

However, it is normal to occasionally feel sad or moody.

TABLE 7
Changes in Personality CONTACT INFORMATION: PROFESSIONALS 28,48,60-62
The personalities of people with dementia can change dra- American Academy of Neurology www.aan.com
matically. They may become extremely confused, suspicious, Alzheimer Research Forum www.alzforum.org
fearful or dependent on a family member. However, people’s Clinical Trials www.clinicaltrials.gov
personalities do change somewhat with age.
Food and Drug Administration www.fda.gov (includes informa-
tion on drug interactions and other
Loss of Initiative useful prescribing information)

A person with Alzheimer’s disease may become very passive, Montreal Cognitive Assessment www.mocatest.org
sitting in front of the television for hours, sleeping more than Cummings JL. Primary Psychiatry
Psychiatry. Vol 15, No 2. 2008.

Primary Psychiatry 75 February 2008

 J. Cummings
CONCLUSION
Alzheimer’s disease research is forging ahead rapidly
toward new therapies and the possibility of disease-modify-
ing interventions. The second part of this review will appear
in the March 2008 issue and will focus on diagnostic crite-
ria for dementia and related disorders as well as treatment
options for these disorders. PP
REFERENCES
1. Jorm AF. Cross-national comparisons of the occurrence of Alzheimer’s and vascular dementia. Eur
Arch Psychiatry Clin Neurosci
Neurosci. 1991;240(4-5):218-222.
2. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study.
Lancet. 2005;366(9503):2112-2117.
Lancet
3. Wimo A, Jonsson L, Winblad B. An estimate of the worldwide prevalence and direct costs of
dementia in 2003. Dement Geriatri Cogn Disorders. 2006;21(3):175-181.
4. Abbott RD, White LR, Ross GW, Masaki KH, Curb JD, Petrovitch H. Walking and dementia in physi-
cally capable elderly men. JAMA. 2004;292(12):1447-1453.
5. Crispy M, Carlson LA, Winblad B. Statins in the prevention and treatment of Alzheimer disease.
Alzheimer Dis Assoc Disor
Disor. 2002;16:131-136.
6. Honig LS, Kukull W, Mayeux R. Atherosclerosis and AD: analysis of data from the US National
Alzheimer’s Coordinating Center. Neurology
Neurology. 2005;64(3):494-500.
7. Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R. Relation of diabetes to mild cognitive
impairment. Arch Neurol
Neurol. 2007;64(4):570-575.
8. Scarmeas N, Stern Y, Mayeux R, Luchsinger JA. Mediterranean diet, Alzheimer disease, and vascu-
lar mediation. Arch Neurol
Neurol. 2006;63(12):1709-1717.
9. Zandi PP, Anthony JC, Khachaturian AS, et al. Reduced risk of Alzheimer disease in users of
antioxidant vitamin supplements: the Cache County study. Arch Neurol
Neurol. 2004;61(1):82-88.
10. Thomas P, Fenech M. A review of genome mutation and Alzheimer’s disease. Mutagenesis.
2007;22(1):15-33.
11. Rogaeva E, Meng Y, Lee JH, et al. The neuronal sortrilin-related receptor SORL1 is genetically
associated with Alzheimer disease. Nat Genet
Genet. 2007;39(2):168-177.
12. Esiri MM, Lee VM-Y, Trojanowski JQ, eds. The Neuropathology of Dementia. New York, NY:
Cambridge University Press; 2004.
13. Jellinger KA, Attems J. Neuropathological evaluation of mixed dementia. J Neurol Sci
Sci. 2007;257(1-
2):80-87.
14. Dominic MW, Selko DJ. Aß oligomers–a decade of discovery. J Neurochem. 2007;101:1172-1184.
15. Hardy J. A hundred years of Alzheimer’s disease research. Neuron. 2006;52:3-13.
16. Cummings JL. Alzheimer’s disease. New Engl J Med Med. 2004;351(1):56-67.
17. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”. A practical method for grading cogni-
tive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
18. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment (MoCA): A brief
screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699.
19. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an
evidence-based review). Report of the Quality Standards Subcommittee of the American Academy
of Neurology. Neurology
Neurology. 2001;56(9):1143-1153.
20. Lu PH, Masterman DA, Mulnard R, et al. Effects of testosterone on cognition and mood in male
patients with mild Alzheimer disease and healthy elderly men. Arch Neurol
Neurol. 2006; 63:(2)177-185.
21. American Academy of Neurology AIDS Task Force. Nomenclature and research case definitions for
neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a
Working Group of the American Academy of Neurology
Neurology. 1998;41:778-785.
22. Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of
Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol
Neurol.
2007;14(1):e1-e26.
23. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of demen-
tia. JAMA. 2001;286(17):2120-2127.
24. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with
Pittsburgh Compound-B. Ann Neurol
Neurol. 2004;55(3):306-319.
Primary Psychiatry
25. Small G, Kepe V, Ercoli L, et al. PET of brain amyloid and tau in mild cognitive impairment. New
Engl J Med
Med. 2006;355(25):2652-2663.
26. Gauthier S. Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet
Lancet. 2006;367(9518):1262-1270.
27. Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog as a screen for dementia: validation in a
population-Bbased sample. J Am Geriatr Soc. 2003;51(10):1451-1454.
28. Montreal Cognitive Assessment (MoCA). Available at: www.mocatest.org. Accessed January 14, 2008.
29. Pfeffer RI, Kurosaki TT, Harrah CH, Chance JM, Filos S. Measurement of functional activities in
older adults in the community. J Gerontol
Gerontol. 1982;37(3):323-329.
30. Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPIQ, a brief clinical form of the
Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosi
Neurosi. 2000;12(2):233-239.
31. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia.
Neurology. 1994;44(12):2308-2314.
Neurology
32. Koss E, Weiner M, Ernesto CH, et al. Assessing patterns of agitation in Alzheimer’s disease
patients with the Cohen-Mansfield Agitation Inventory. The Alzheimer’s Disease Cooperative Study.
Alzheimer Dis Assoc Disord
Disord. 1997;11(suppl 2):S45-S50.
33. Reisberg B, Borenstein J, Salob SP, Ferris SH, Franssen E, Georgotas A. Behavioral symptoms in
Alzheimer’s disease: phenomenology and treatment. J Clin Psychiatry
Psychiatry. 1987;48(suppl):9-15.
34. Alexopoulos GS, Abrams RC, Young RC, Shamoian CA. Cornell Scale for Depression in Dementia.
Biol Psychiatry
Psychiatry. 1988;23(3):271-284.
35. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry Psychiatry.
1984;141(11):1356-1364.
36. Schmitt FA, Ashford W, Ernesto C, et al. The severe impairment battery: concurrent validity and
the assessment of longitudinal change in alzheimer’s disease. Alzheimer Dis Assoc Disord Disord.
1997;11(suppl 2):S51-S56.
37. Knopman DS, Knapp MJ, Gracon SI, Davis CS. The Clinician Interview-Based Impression (CIBI): A
clinician’s global change rating scale in Alzheimer’s disease. Neurology
Neurology. 1994;44(12):2315-2321.
38. Schneider LS, Olin JT, Doody R, et al. Validity and reliability of the Alzheimer’s Disease Cooperative
Study-Clinical Global Impression of Change. The Alzheimer’s Disease Cooperative Study. Alzheimer
Dis Assoc Disord
Disord. 1997;11(suppl 2):S22-S32.
39. Hughes C, Berg L, Danziger W, Coben L, Martin R. A new clinical scale for the staging of dementia.
Br J Psychiatry
Psychiatry. 1982;140:566-572.
40. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical
trials in Alzheimer’s disease. Alzheimer Dis Assoc Disord
Disord. 1997;11:S33-S39.
41. Gelinas I, Gauthier L, McIntyre M, Gauthier S. Development of a functional measure for
persons with Alzheimer’s disease: the disability assessment of dementia. Am J Occup Ther Ther.
1999;53(5):471-481.
42. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. The Unified
Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord Disord.
2003;18(7):738-750.
43. Alzheimer’s Association. Available at: www.alz.org. Accessed January 14, 2008.
44. Alzheimer’s Disease International (ADI). Available at: www.alz.co.uk. Accessed January 14, 2008.
45. Alzheimer’s Foundation of America. Available at: www.alzfdn.org. Accessed January 14, 2008.
46. American Stroke Association. Available at: www.strokeassociation.org. Accessed January 14, 2008.
47. Brain Injury Association. Available at: www.biausa.org. Accessed January 14, 2008.
48. Clinical Trials. Available at: www.clinicaltrials.gov. Accessed January 14, 2008.
49. Deane F. Johnson Center for Neurotherapeutics at UCLA. Available at: www.jcnt.org. Accessed
January 14, 2008.
50. Frontotemporal Dementia Association. Available at: www.FTD-Picks.org. Accessed January 14, 2008.
51. Leeza Gibbons Memory Foundation. Available at: www.memoryfoundation.org. Accessed January 14, 2008.
52. Lewy Body Dementia Association. Available at: www.lewybodydementia.org. Accessed January 14, 2008.
53. National Institute on Aging, Alzheimer Disease Education and Referral Center (ADEAR). Available
at: www.nia.nih.gov/alzheimers. Accessed January 14, 2008.
54. National Parkinson Foundation. Available at: www.parkinson.org. Accessed January 14, 2008.
55. National Stroke Association. Available at: www.stroke.org. Accessed January 14, 2008.
56. Parkinson’s Disease Foundation. Available at: www.pdf.org. Accessed January 14, 2008.
57. Progressive Supranuclear Palsy (Europe). Available at: www.pspeur.org. Accessed January 14, 2008.
58. Society for Progressive Supranuclear Palsy. Available at: www.psp.org. Accessed January 14, 2008.
59. UCLA Alzheimer Disease Center. Available at: www.adc.ucla.edu. Accessed January 14, 2008.
60. American Academy of Neurology. Available at: www.aan.com. Accessed January 14, 2008.
61. Alzheimer Research Forum. Available at: www.alzforum.org. Accessed January 14, 2008.
62. Food and Drug Administration. Available at: www.fda.gov. Accessed January 14, 2008.
76 February 2008