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Review Article

Alzheimer Disease
Address correspondence to
Dr Liana G. Apostolova,
Indiana Alzheimers Disease
Center, 355 W 16th St, Suite
Liana G. Apostolova, MD, MS, FAAN 4700, Indianapolis, IN 46202,
lapostol@iu.edu.
Relationship Disclosure:
Dr Apostolova serves as senior
ABSTRACT associate editor of Alzheimers
Purpose of Review: This article discusses the recent advances in the diagnosis and & Dementia: Diagnosis,
Assessment & Disease
treatment of Alzheimer disease (AD). Monitoring and receives
Recent Findings: In recent years, significant advances have been made in the fields personal compensation for
of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most serving on the speakers bureau
of Eli Lilly and Company and
important recent advances in AD is our ability to visualize amyloid pathology in the GE Healthcare Worldwide.
living human brain. The newly revised criteria for diagnosis of AD dementia embrace Dr Apostolova receives grant
the use for biomarkers as supportive evidence for the underlying pathology. Guide- support from the Jim Easton
Consortium for Alzheimers
lines for the responsible use of amyloid positron emission tomography (PET) have Drug Discovery and Biomarker
been developed, and the clinical and economic implications of amyloid PET imaging Development and the National
are actively being explored. Institute on Aging.
Unlabeled Use of
Summary: Our improved understanding of the clinical onset, progression, neuroim- Products/Investigational
aging, pathologic features, genetics, and other risk factors for AD impacts the Use Disclosure:
approaches to clinical diagnosis and future therapeutic interventions. Dr Apostolova discusses the
unlabeled/investigational use
of antidepressant and
Continuum (Minneap Minn) 2016;22(2):419434. antipsychotic medications for
behavioral management as
well as antidementia therapy
in mild cognitive impairment.
INTRODUCTION United States.1 Although there is in- * 2016 American Academy
of Neurology.
Alzheimer disease (AD) is a neuro- creasing evidence that AD pathology
degenerative disorder featuring grad- starts depositing in the brain in midlife,
ually progressive cognitive and the first clinical symptoms usually occur
functional deficits as well as behavioral after the age of 65.2,3
changes and is associated with accu- AD prevalence is rapidly increasing
mulation of amyloid and tau deposi- in large part because the proportion
tions in the brain. Cognitive symptoms of people 65 years and older is grow-
of AD most commonly include deficits ing faster than any other age sector
in short-term memory, executive and of the population worldwide. Between
visuospatial dysfunction, and praxis. 1997 and 2050, the elderly popula-
Several rarer variants of AD with relative tion, defined as subjects 65 years of
preservation of memory have been age and older, will increase from 63 to
recognized. Clinical assessment, includ- 137 million in the Americas, from 18
ing cognitive testing, remains critical to 38 million in Africa, from 113 to
for the diagnosis and staging of AD, 170 million in Europe, and from 172
although recent advances in amyloid to 435 million in Asia.4 One nationally
imaging and genetics show great representative US data set, the Aging,
promise for facilitating early and Demographics, and Memory Study
presymptomatic diagnosis of AD and (ADAMS), estimated that in the
its discrimination from other neuro- United States, 14% of people 71 years
degenerative disorders. and older have dementia. AD demen-
tia accounted for 70% of the dementia
EPIDEMIOLOGY cases across the age spectrum in this
AD is the most common neurode- cohort.5 In a subsequent publication,
generative disorder and the sixth the ADAMS investigators reported that
most common cause of death in the an additional 22% (or 5.4 million

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Alzheimer Disease

KEY POINTS
h Alzheimer disease Americans) 71 years or older have cog- to the clinical diagnosis and staging of
prevalence is nitive impairment in the absence of patients with AD.
rapidly increasing. overt dementia.6
Although age is the greatest risk Cognitive Decline
h Although age is the
greatest risk factor for
factor for the development of AD, in Memory impairment is the most per-
the development of and of itself, old age is not sufficient vasive feature of AD. Although non-
Alzheimer disease, old to cause AD. Other major risk factors memory cognitive deficits (eg, aphasia,
age is not sufficient, in include the presence of one or more executive dysfunction, apathy, or per-
and of itself, to cause apolipoprotein gene E4 alleles (APOE4), sonality change) can manifest early and
Alzheimer disease. low educational and occupational at- even be the presenting feature, in
h Memory impairment tainment, family history of AD, moder- general, memory decline is considered
is the most pervasive ate or severe traumatic brain injuries, the leading symptom. Early in the
feature of and cardiovascular risk factors. disease course, recent episodic mem-
Alzheimer disease. Gender modulates the prevalence ories are most affected, while memo-
of AD. Nearly two-thirds of all patients ries from the distant past are usually
diagnosed with AD are women.7 Ac- spared. As the disease progresses, all
cording to ADAMS, 16% of women, but aspects of episodic memory become
only 11% of men, live with dementia affected. In contrast to episodic mem-
after 71 years of age.5 While it is true ory, working memory and semantic
that women live longer than men, this memory are preserved until later in the
alone does not explain the discrepancy. disease course.
Genetic, hormonal, and societal factors Language disturbance, especially
(eg, lower education and occupational word-finding difficulties, is a com-
attainment among women currently in mon early symptom in AD but is
their 70s and 80s compared to men) generally mild. Subtle decline in visuo-
likely play a significant role as well. spatial skills likewise occurs in the
Racial disparities in AD prevalence mild dementia stages and progresses
have also been reported. Older African throughout the course of the disease.
Americans and Hispanics have a higher Executive dysfunction, on the other
prevalence of AD relative to older hand, begins even earlierVin the
Caucasians in part because of lower predementia stagesVand, similar to all
education levels and higher preva- other cognitive domains, worsens over
lence of cardiovascular comorbid- the disease course.
ities,8Y10 although other genetic and
societal factors likely play a role as well. Neuropsychiatric Symptoms
Patients with AD exhibit a variety of
CLINICAL PRESENTATION neuropsychiatric symptoms. Behavioral
Recognition of the clinical features and symptoms, once manifest, tend to
presenting symptoms of AD remains worsen over the course of the disease;
essential for the diagnosis and manage- however, these symptoms often fluctu-
ment of patients, even as biomarker ate and are not consistently present at
tests such as amyloid positron emis- each visit. Attention to these treatable
sion tomography (PET) imaging that components of excess morbidity is im-
detect the underlying neuropathology portant as they have a profound im-
of AD are increasingly available for pact on caregiver burden and are the
patient care. Ascertainment of symp- leading cause of institutionalization.11
toms of cognitive decline, behavioral The earliest AD-associated neuro-
symptoms, functional decline, and cog- psychiatric symptoms are apathy, anx-
nitive testing remain the cornerstones iety, and irritability. The latter two
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KEY POINTS
symptoms are often provoked in situ- ATYPICAL ALZHEIMER DISEASE h Neuropsychiatric
ations that the patient finds challeng- VARIANTS comorbidities often
ing. Mild to moderate depressive In addition to the classic AD presen- present the most
symptoms are also frequently present tation, several less common AD variants pressing therapeutic
early on. Disturbances of appetite and should be recognized, which include needs due to the
sleep, disinhibition, and alterations in frontal variant of AD, posterior cortical psychological and
perception (hallucinations) or thought atrophy, and logopenic variant primary physical strain they
(delusions) commonly occur in the progressive aphasia due to AD. place on the family and
later stages of dementia. In addition to caregivers of patients
Frontal variant of AD is character-
the classic neuropsychiatric behaviors, with Alzheimer disease.
ized by substantial behavioral or per-
anosognosia (ie, lack of insight) often sonality changes that are out of h Several less common
manifests early on and poses another proportion to the observed short-term Alzheimer disease
difficult management problem. variants should be
memory loss. These patients are often
Of all AD neuropsychiatric comor- recognized, which
profoundly impatient, irritable, impul-
include frontal variant
bidities, irritability, agitation, sundown- sive, and disinhibited. On formal test- of Alzheimer disease,
ing, psychosis, and diminished insight ing, they invariably show significant posterior cortical atrophy,
often present the most pressing thera- executive disturbances.12 and logopenic variant
peutic needs due to the psychological Posterior cortical atrophy presents primary progressive
and physical strain they place on the with visuospatial dysfunction often aphasia due to
family and caregivers. in the form of partial or full Balint Alzheimer disease.
syndrome (simultanagnosia, ocular
Neurologic Examination apraxia, and ocular ataxia), partial or
Outside of the mental status examina- full Gerstmann syndrome (acalculia,
tion, findings on the neurologic exam- agraphia, right/left disorientation, and
ination are often normal in patients finger agnosia), apperceptive visual
with AD. Parkinsonian symptoms can agnosia, and environmental disorienta-
emerge in the later stages, but if tion. Patients often develop construc-
these symptoms are present early in tional, dressing, and ideomotor apraxia
the course of the disease (eg, within early on in the presence of relatively
1 year of onset of cognitive problems) preserved memory and insight.
and especially when accompanied by Finally, the occasional patient with
cognitive fluctuations and early-onset AD may also present with early pro-
psychosis, a diagnosis of dementia gressive language involvement, most
with Lewy bodies should be consid- often in the form of logopenic aphasia
ered. Later in the disease course, with pronounced anomic deficits and
pathologic reflexes such as grasp, impaired repetition but preserved
root, and suck reflexes may be found. grammar and syntax.
Patients become increasingly impaired
in the moderate and severe stages and DIAGNOSTIC CRITERIA
are ultimately mute, incontinent, and Currently, the diagnostic standard for
bedridden at the end stages of disease. dementia is the Diagnostic and Sta-
At this stage, multiple complications tistical Manual of Mental Disorders,
arise such as risk of aspiration with Fifth Edition (DSM-5).13 DSM-5 recog-
unsafe swallowing, malnutrition, im- nizes two cognitive syndromes: major
mobility with associated risks for bed- neurocognitive impairment and mild
sores, deep venous thrombosis, and neurocognitive impairment. The diag-
infections. Often, these complications nosis of major neurocognitive im-
are the direct cause of death in patients pairment requires objective cognitive
with AD. decline that is severe enough to
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Alzheimer Disease

KEY POINTS
h The Diagnostic and interfere with activities of daily living ciation (AA).14Y16 Similarly to the DSM-5
Statistical Manual of and is not caused by delirium or criteria, the NIA-AA criteria for de-
Mental Disorders, Fifth another neurologic, medical, or psy- mentia of any cause no longer explicitly
Edition criteria no chiatric disorder. Patients with mild require memory impairment to be
longer require the neurocognitive impairment have present, but rather, for the diagnosis
presence of memory milder cognitive decline that does of dementia to be established, call for
impairment for the not yet deprive them of the ability to documentation of impairment in two
diagnosis of lead an independent lifestyle and cognitive domains or one cognitive
neurodegenerative perform complex daily activities such and one behavioral domain in addition
dementia to as managing finances or driving a car. to significant decline in day-to-day
be established.
It should be noted that the DSM-5 functioning (Table 3-2). For the first
h The National Institute introduces a major change in terms of time, the NIA-AA criteria for probable
on Aging and diagnostic criteria for cognitive disor- Alzheimer dementia as a subtype of
Alzheimers Association ders. The criteria no longer require the dementia recognized the diagnostic
criteria for probable
presence of memory impairment for utility of disease biomarkers that
Alzheimer dementia
the diagnosis of neurodegenerative de- have proven sensitivity, specificity,
recognize the
diagnostic utility of
mentia to be established, as was the and pathologic validity (Table 3-2).
disease biomarkers. case in all previous DSM editions. At the present time, two types of
DSM-5 thus recognizes that for some biomarkers meet these criteria. Two
dementing disorders such as vascular neurodegenerative biomarkersV
and frontotemporal dementia, for in- mesial temporal lobe atrophy on
stance, memory impairment is not an structural imaging (Figure 3-1) and
early symptom and may never mani- posterior predominant hypometabo-
fest (Table 3-1). lism with involvement of the posterior
Another set of diagnostic criteria cingulate gyrus on fluorodeoxyglu-
spanning all three major stages of AD cose positron emission tomography
(ie, the preclinical, the prodromal, and (FDG-PET) (Figure 3-2)Vhave already
the overt dementia stages) were recently received wide acceptance. However,
developed by the National Institute on neither of these are exclusively seen
Aging (NIA) and the Alzheimers Asso- in AD dementia. Hippocampal atrophy

TABLE 3-1 Summary of Diagnostic Criteria for Mild and Major


Neurocognitive Disordera

b Mild Neurocognitive Impairment


Cognitive decline one to two standard deviations from normal on formal
cognitive testing
Does not interfere with independence
Not due to delirium or other medical or psychiatric disorder
b Major Neurocognitive Impairment
Cognitive decline two standard deviations or more from normal on formal
cognitive testing
Interferes with independence
Not due to delirium or other medical or psychiatric disorder
a
Data from American Psychiatric Association.13

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TABLE 3-2 Summary of Diagnostic Criteria for Dementia Syndrome
and Probable Alzheimer Disease from the National
Institute on Aging and the Alzheimers Associationa

b Dementia Syndrome
Objective cognitive or behavioral impairment in at least two of the following
Memory
Reasoning and handling complex tasks
Visuospatial abilities
Language functions
Personality, behavior, or comportment
Decline from previous level of functioning
Functional impairment
b Probable Alzheimer Disease Dementia
Criteria for dementia are met
Insidious onset
Gradual progression
Initial symptoms
Amnestic
Nonamnestic (language, executive)
No other neurologic, psychiatric, or general medical disorders of severity
that can interfere with cognition
Positive biomarkers (eg, CSF amyloid-" [A"]/tau, amyloid positron emission
tomography [PET], hippocampal atrophy on MRI) increase diagnostic certainty
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
a
Data from McKhann GM, et al, Alzheimer Dement.15 www.alzheimersanddementia.com/
article/S1552-5260(11)00101-4/fulltext.

occurs in normal aging,17,18 and both played an important role in the workup
hippocampal atrophy and FDG-PET of patients with dementia. The American
abnormalities occur in other demen- Academy of Neurology (AAN) guidelines
ting conditions.19,20 On the other hand, for the diagnostic evaluation of de-
amyloid proteinYbased biomarkers such mentia require physicians to obtain
as a low CSF level of "-amyloid or a a structural imaging scan in every pa-
positive amyloid PET scan have been tient with objective cognitive decline.23
shown to be highly sensitive and spe- This recommendation follows the re-
cific in their ability to detect amyloid view of the evidence presented in a
pathology in the brain.21,22 Class II study showing that 5% of all
patients with cognitive complaints har-
Current Role of Biomarkers in bored a causative nondegenerative
Alzheimer Disease Diagnosis lesion, such as a slow-growing brain
In addition to supporting clinical diag- neoplasm (most commonly of the fron-
nosis, biomarkers have historically tal lobes), subdural hematoma, or

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Alzheimer Disease

ter quantification of cerebral structures


and better discrimination of normal
from mildly affected patients with AD
than is possible with CT. Some of the
findings suggestive of AD pathology
include mesial temporal atrophy25Y27
and, in the more advanced stages, global
brain atrophy with pronounced ven-
tricular enlargement (Figure 3-1).28,29
Cortico-subcortical microhemorrhages
are often found on gradient echo
MRI sequences and are suggestive of
the presence of vascular amyloidosis
(Figure 3-3).
Functional brain imaging using
single-photon emission computed to-
mography (SPECT) and PET technol-
ogies can be used to identify AD-specific
patterns such as temporoparietal
hypoperfusion/hypometabolism in pa-
tients with AD (Figure 3-2). More re-
FIGURE 3-1 Coronal T1-weighted MRI slices with findings
suggestive of Alzheimer disease (AD) pathology cently, arterial spin-labeling MRI
show mesial temporal atrophy (A, B, arrows) sequences have been shown to capture
and, in the more advanced stages, global brain atrophy with
pronounced ventricular enlargement. perfusion abnormalities.30 Validation
studies of SPECT and PET have gen-
erally shown high sensitivity yet rela-
normal pressure hydrocephalus.24 In tively lower specificity, hence the
addition to identifying a potentially increased risk for false-positive diagno-
treatable lesion, a brain CT or MRI scan ses.31,32 Currently, FDG-PET and SPECT
can uncover ischemic changes that use is only covered by Medicare for
would prompt further workup and differentiating AD from frontotem-
potential initiation of therapy aiming poral dementia.
to reduce vascular risk factors or intro- The recent discovery and validation
duce behavioral modifications. MRI, of amyloid PET imaging has the poten-
with its improved resolution, allows bet- tial to change the approach to clinical

FIGURE 3-2 Temporal (thick arrows) and parietal (thin arrows) hypometabolism on
fluorodeoxyglucose positron emission tomography (FDG-PET) is often seen in
patients with Alzheimer disease dementia.

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KEY POINT
h Amyloid positron
emission tomography
imaging allows the
detection of moderate
to severe amyloid
deposition in the brain.

FIGURE 3-3 Cortico-subcortical microhemorrhages are often found on gradient echo MRI
sequences and are suggestive of the presence of vascular amyloidosis.

diagnosis of AD. This type of imaging which recommend employing amyloid


allows the detection of moderate to PET imaging in three specific clinical
severe amyloid deposition in the scenarios: (1) patients with amnestic
brain (Figure 3-4). Despite its well- mild cognitive impairment (ie, mild
documented sensitivity and specific- neurocognitive disorder), (2) patients
ity,22 this technology has not yet in the dementia stages with suspected
entered routine clinical practice, in atypical AD or etiologically mixed pre-
part because insurance companies do sentation, and (3) those with early
not provide coverage for it. The major disease onset (younger than 65 years
drawbacks among insurance carriers
are: (1) the unproven economic benefit
of using this relatively expensive PET
technology for diagnostic purposes
while disease-modifying therapies are
lacking and (2) the potential risk for it
to be used in cognitively normal in-
dividuals. Clearly, the latter scenario
(ie, detecting AD in the latent stages in
the form of asymptomatic brain amy-
loidosis) could inflict an insurmount-
able psychological burden given the
absence of effective therapeutic ap-
proaches to delay disease onset or
modify its course. In response to these Amyloid positron emission tomography
FIGURE 3-4
concerns, a group of imaging and de- (PET) imaging allows the detection of amyloid
pathology of the brain. A negative scan (A)
mentia experts convened to establish shows only nonspecific white matter binding and indicates
a set of recommendations of which no to sparse amyloid plaque deposition, while a positive
amyloid PET scan (B) shows significant uptake in multiple
patients should be imaged. These cortical areas and indicates the presence of moderate to
suggestions are the Appropriate Use severe amyloid pathology.
Criteria for amyloid PET imaging,33,34

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Alzheimer Disease

KEY POINTS
h Amyloid positron of age). At present, the impact of in the brain tissue begins early in the
emission tomography amyloid PET imaging on clinical prac- disease course and is associated with
scans are only tice and health outcomes is not yet decline in CSF A".35 CSF total and
appropriate if the scan known. Given the lack of disease- phosphorylated tau levels rise in AD
results are expected to modifying drugs for AD, the rationale secondary to neurodegeneration of
alter clinical management. for the use of amyloid PET imaging in tau-containing neurons.36Y39 CSF tau
h The APOE4 genotype clinical practice includes: (1) helping changes occur later in the disease
should be considered a the practitioner to select appropriate course and are associated with cognitive
risk factor that is neither treatments and avoid unnecessary in- decline.40Y43 CSF A" and tau mea-
sufficient nor necessary terventions and to aid in accurate surements are covered by most insur-
for Alzheimer disease diagnosis, (2) improving diagnostic ac- ance companies in the United States
development. curacy, (3) advising patients and fami- as part of the workup for AD. Despite
lies on the clinical course and prognosis, this, they are not routinely used due
and (4) educating patients and families to relative invasiveness of the lumbar
on community services and resources puncture procedure and the risk for
for medical, financial, and legal plan- side effects such as back discomfort,
ing.34 Case 3-1 and Case 3-2 describe headache, and, in rare cases, iatrogenic
exemplary scenarios. meningitis. However, CSF A" and tau
The Appropriate Use Criteria also testing can be quite useful in diag-
define the inappropriate uses of amy- nostically challenging cases as well as
loid PET imaging. Patients who should in those with early disease onset or an
not be scanned include those lacking unusual clinical course. CSF A" level is
objective cognitive decline. Scanning highly correlated with the presence
solely on the basis of family history or of amyloid deposition in the cor-
APOE4 status was likewise determined tex. 44 Thus, CSF A" levels can be
to be inappropriate. Furthermore, amy- used in lieu of an amyloid PET scan
loid PET scans cannot be used for de- as a reliable proxy measure of the
termining dementia severity, as this is presence of brain amyloidosis.
not feasible with this technology.
Another important suggestion of the GENETICS OF ALZHEIMER
Appropriate Use Criteria for amyloid PET DISEASE
imaging is the recommendation that Although the APOE4 gene variant is
the responsibility for determining pa- the most established genetic risk fac-
tients eligibility (ie, appropriateness for tor for sporadic AD, screening for
imaging) should lie with medical pro- APOE4 is not recommended on a rou-
fessionals with significant expertise in tine basis. While it has been estimated
evaluating and treating patients with that one copy of this genetic variant
dementia (defined as 25% or greater increases the odds for developing
proportion of clinical practice devoted AD threefold and two copies increase
to cognitive disorders of the elderly).33 the odds 15-fold,45 a large multicenter
Last but not least, the committee rec- study demonstrated that the presence
ommended that amyloid PET scans of the APOE4 allele increased the
are only appropriate if the scan results positive predictive value of diagnos-
are expected to alter clinical manage- ing AD by only 4% over diagnoses made
ment (see Case 3-1 and Case 3-2 on clinical grounds alone (from 90%
for examples). to 94%).46 The APOE4 genotype should
CSF amyloid-" (A") and tau protein be considered a risk factor that is
levels are the most established AD fluid neither sufficient nor necessary for dis-
biomarkers. Pathologic A" deposition ease development.
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Case 3-1
A 78-year-old man with 12 years of education presented to the memory
disorder clinic reporting progressive memory difficulties for the past 1 to
2 years. His memory deficits were most noticeable when he recalled recent
events as opposed to events from the distant past. He had on two occasions
experienced mild spatial confusion when walking his dog but, in both
instances, he was eventually able to find his way. He had no problems with
attention, language skills, or judgment. He operated all appliances at home
and safely drove a car. His family noticed mild anxiety in challenging
situations and questioned whether he was a little depressed, as he had
become quieter. The patient had no significant comorbidities and no family
history of dementia. He had been prescribed memantine 10 mg once a
day by an outside physician.
The patients cognitive evaluation revealed a Mini-Mental State
Examination (MMSE) score of 25 out of 30, poor recollection of recent events,
lower than expected performance on category fluency (number of animals
produced in 1 minute), poor encoding and retention of verbal and
nonverbal information, mild anxiety, and minimal depression. His attention,
visuospatial skills, and abstract thinking were preserved. Formal
neuropsychological testing confirmed the above deficits and further
clarified his memory profile as most consistent with retrieval memory
loss, as he showed significant improvement on cued recall (ie, the
recognition portion of the memory tests). Review of an outside MRI
revealed age-appropriate atrophy.
The patient was given a diagnosis of mild neurocognitive disorder by
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5)13 criteria (ie, mild cognitive impairment), most likely due to a
neurodegenerative etiology. Although the leading consideration was
Alzheimer disease (AD), the observed significant improvement on cued
recall, suggestive of retrieval rather than encoding deficits, was considered
atypical. An amyloid positron emission tomography (PET) scan was ordered
and revealed diffuse amyloid tracer uptake in the cerebral cortical gray
matter with complete loss of the gray-white matter differentiation
consistent with the presence of moderate to severe amyloid pathology.
A diagnosis of mild neurocognitive disorder due to AD was made.
The patient was prescribed donepezil. He experienced significant
gastrointestinal side effects as the dose was increased from 5 mg/d to
10 mg/d. A slower escalation regimen (introducing an additional titration
step of 7.5 mg/d for 1 month before introducing 10 mg/d) was effective. Two
years later, his MMSE score had declined to 19 out of 30. His family reported
difficulties with managing finances, shopping, navigation, and cooking.
Comment. This patient presented with atypical amnestic mild cognitive
impairment that met Appropriate Use Criteria33,34 for amyloid PET imaging.
The diagnostic uncertainty stemmed from the patients pronounced memory
retrieval deficit. The amyloid PET scan was beneficial in assisting the
physicians therapeutic decisions and counseling the patient and family.

More recently, several large genome- 20 risk/protective genetic variants.47 Rel-


wide association studies have uncov- ative to APOE4, these variants explain
ered and successfully replicated another only a small fraction of the genetic

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Alzheimer Disease

KEY POINT
h The search for other
gene variants that may
Case 3-2
A 59-year-old woman with 12 years of education presented to the memory
affect risk of Alzheimer
disorder clinic because of memory difficulties for the past 1 to 2 years. Her
disease is ongoing.
husband reported that for the past few months they had the same conversation
multiple times a day. She misplaced items more often. Her recall of distant
memories and visuospatial function were preserved. She was also becoming
more distractible. She managed their household without a problem and
safely operated a motor vehicle. On a few occurrences, she reportedly paid
some bills twice while being on time with the rest. She was still able to
manage her appointments and medications with occasional reminders.
She had become quieter in social situations and more reluctant to go out.
She was no longer interested in volunteering at their church.
On bedside cognitive testing the patient scored 22 out of 30 on the
Mini-Mental State Examination (MMSE). She showed relatively preserved
encoding, impaired delayed recall, and endorsed multiple false-positive
items on recognition testing. Her language and visuospatial skills were
preserved. She made a few errors on frontal executive tasks. On formal
neuropsychological testing, additional deficits in category fluency and
nonverbal memory were noted.
The patients MRI revealed mild global atrophy with medial temporal lobe
predominance and hippocampal atrophy. An amyloid PET scan was performed
and showed diffusely increased tracer uptake throughout the cortical cerebral
gray matter with loss of the normal gray-white matter contrast consistent with
the presence of moderate to severe amyloid pathology. A diagnosis of mild
neurocognitive disorder (ie, mild cognitive impairment) due to early-onset AD
was made. The patient was started on donepezil.
Comment. This patient presented with early-onset prodromal AD. The
patient met the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5)13 criteria for mild neurocognitive disorder (ie, mild cognitive
impairment) and met the Appropriate Use Criteria for amyloid PET imaging
by virtue of early disease onset. The amyloid PET scan was considered
beneficial in assisting the physicians therapeutic decisions and counseling
of the patient.

heritability of sporadic AD where each do not.48 Genetic makeup is not the


risk variant conveys a relative risk of only risk; shared environmental and
1.1 to 1.3.47 The vast majority of these lifestyle factors likely also play a role.
risk variants take part in processes im- Several rare autosomal dominant
plicated in the pathogenesis of AD such variants of AD have been described.
as amyloid metabolism, inflammation, The first symptoms usually affect in-
oxidative stress, and energy metabo- dividuals in their 30s and 40s. These
lism. The search for other gene variants families show multiple affected individ-
that may affect risk of AD is ongoing. uals across generations. These autoso-
Family history of sporadic AD is a mal dominant AD variants have been
well-established risk factor. Individuals traced to genetic mutations in the amy-
who have a first-degree relative diag- loid precursor protein (APP), presenilin
nosed with AD are more likely to 1 (PSEN1), and presenilin 2 (PSEN2)
develop the disease than those who genes. Mutations in all three genes

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KEY POINTS
increase the levels of "-amyloid. Early- to receive diagnostic and prognostic h Amyloid deposition
onset autosomal dominant AD accounts counseling as well as appropriate is thought to begin
for less than 2% of all AD cases. medications in an optimized regimen. 20 years prior to
Patients coexisting behavioral and development of
ALZHEIMER DISEASE non-neurologic conditions need to be clinical symptoms.
PATHOLOGY optimally managed. Vital importance h Vital importance should
AD is thought to result from over- should be placed on coordinating care be placed on
production and impaired clearance of coordinating care
among physicians, nurse practitioners,
"-amyloid. Downstream events are tau and social workers, and instituting
among physicians,
hyperphosphorylation and neuronal nurse practitioners, and
appropriate oversight and safety pre- social workers, and
toxicity. The primary pathologic features cautions when patients have functional instituting appropriate
of AD are brain atrophy from regional impairment and poor judgment. It is oversight and safety
neuronal and synaptic loss, extracellu- important to encourage patients to par- precautions when
lar "-amyloid deposition in the form patients have functional
ticipate in social activities, adult day care
of neuritic plaques, and intraneuronal impairment and
centers and exercise programs, as well
tau protein deposition in the form of poor judgment.
as to encourage both patients and care-
intraneuronal neurofibrillary tangles. h Treatment with
givers to take part in support groups.
"-Amyloid also deposits in the cerebral acetylcholinesterase
blood vessels. Cerebral amyloid angio- Acetylcholinesterase Inhibitors inhibitors should be
pathy ranges in severity from small considered in patients
Two classes of medications have been with mild to moderate
amounts of amyloid to major deposits approved for AD: the acetylcholines- Alzheimer disease per
that distort the artery architecture and terase inhibitors (AChEIs) and the the American Academy
cause cortical microinfarcts, microaneu- N-methyl- D -aspartate (NMDA) recep- of Neurology practice
rysms, and cerebral microhemorrhages tor antagonist memantine. Treatment guidelines for dementia.
or macrohemorrhages (multiple micro- with AChEIs should be considered in
hemorhages in the occipital lobes of a patients with mild to moderate AD per
patient with AD are shown in Figure 3-3). the AAN practice guidelines for demen-
Amyloid deposition is thought to tia.51 Three agents are currently ap-
begin 20 years prior to development proved and marketed in the United
of clinical symptoms.2 Longitudinal States: donepezil, rivastigmine, and
studies of cognitively normal individ- galantamine. All three have been shown
uals who are amyloid-positive are to be effective in double-blind placebo-
presently ongoing and are focusing on controlled trials, showing some benefit
ascertainment of the risk for future de- on cognitive measures including mem-
velopment of dementia among these ory and concentration as well as global
individuals. Neurofibrillary tangles are and functional outcome measures;
not exclusive to AD and can be found however, their therapeutic cognitive
in other conditions, such as dementia and functional effects seem to be mod-
pugilistica and chronic traumatic enceph- est in size and purely symptomatic.
alopathy, prion disease, and in normal Gastrointestinal side effects, more
aging. Neurofibrillary tangle burden and commonly seen during the dose esca-
neuronal loss show a robust association lation phase of treatment, occur with
with global cognitive impairment.49,50 all three agents. Bradycardia and heart
block may occur, especially in patients
TREATMENT with underlying cardiac conduction
The clinical management of patients deficits or in those individuals taking
with AD dementia should accomplish medications that cause PR interval
several important tasks. Patients need prolongation such as beta-blockers. If

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Alzheimer Disease

KEY POINTS
h Memantine is US Food one agent causes intolerable side ef- support or refute use of memantine in
and Drug Administration fects, another AChEI should be tried. moderate to severe AD.59
approved for the
moderate to Glutamate Receptor Medications for Behavioral
severe stages of Modulators Symptoms
Alzheimer disease. Memantine is a low to moderate affin- The first line of treatment for behav-
h The first line of ity NMDA receptor antagonist that is ioral symptoms of AD are nonpharma-
treatment for behavioral used as an add-on to ongoing AChEI cologic techniques. A quiet, familiar
and neuropsychiatric therapy. A recent meta-analysis of nine environment with labels on doors and
symptoms of Alzheimer trials with a combined sample size of sufficient lighting in all rooms is im-
disease are
2433 revealed that memantine had a portant to reduce disorientation. Ag-
nonpharmacologic
modalities. beneficial effect on cognition, behavior, gressive behavior should always be
activities of daily living, and global addressed with positive and clear
function.52 Memantine is approved by language to reassure and distract
the US Food and Drug Administration the patient.
(FDA) for the moderate to severe AD Depressive symptoms are treated
stages (Mini-Mental State Examination with selective serotonin reuptake in-
[MMSE] score of 5 to 15) in the United hibitors (SSRIs) due to their low pro-
States. The main side effects of con- pensity to cause anticholinergic effects.
fusion and dizziness occur only rarely. SSRIs may also ease anxiety, irritability,
The timing of initiation of cholines- or other nonspecific symptoms that
terase inhibitors and memantine ther- may accompany depression. The SSRI
apy is an area of some controversy.53
citalopram may be useful for agitation.
Cholinesterase inhibitors and meman-
Agitation or disruptive behavior
tine are frequently prescribed off-label
may require a neuroleptic for optimal
for mild cognitive impairment in the
therapeutic response. The newer
United States.54 Recent meta-analyses
atypical antipsychotic medications
have not demonstrated a benefit of
cholinesterase inhibitors in mild cogni- (quetiapine, risperidone, olanzapine)
tive impairment, although a benefit for are often used in low doses with
subgroups of patients remain unde- careful titration. Typical and atypical
termined.55,56 A separate meta-analysis antipsychotic agents, however, carry a
suggests there is not a benefit of black box warning label due to an
memantine in patients with mild AD.57 association with increased cardiovas-
While the 2001 AAN practice parame- cular morbidity and mortality (higher
ter for treatment of dementia is cur- for the typical compared to atypical
rently under revision, 2011 guidelines antipsychotics) and cerebrovascular
from the National Institute for Health adverse events in the elderly with
and Clinical Excellence now recommend dementia-related psychosis.60Y62 In
memantine as an option for managing addition, these medications have ad-
moderate AD for people who cannot ditional adverse effects: anticholiner-
take AChEIs and as an option for man- gic adverse events and orthostatic
aging severe AD.58 In contrast, Canadian and metabolic disturbances. Tradi-
Consensus guidelines on dementia from tional neuroleptics are more likely to
2013 state that, while combination ther- produce extrapyramidal symptoms,
apy of a cholinesterase inhibitor and which may worsen cognitive function.
memantine is rational and appears to All antipsychotics, typical as well as
be safe, there is insufficient evidence to atypical, when used in older adults with
430 www.ContinuumJournal.com April 2016

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dementia, are associated with risk for Aging (NIA R01 AG040770, NIA K02
death. This risk is quite comparable AG048240, and NIA P30 AG010133).
among atypical and typical antipsy-
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