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Chapter 13

Clinical Assessment of
Alzheimer’s Disease
Emily C. Edmonds, David P. Salmon, and Mark W. Bondi
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Alzheimer’s disease (AD) is an age-related degenera- Because increasing age is the main risk factor for
tive brain disorder that causes a decline in cognitive the development of AD, an aging society means that
skills and affects one’s ability to perform everyday there will be a dramatic increase in the number of
activities. It is the most common cause of demen- individuals with AD. By 2050, the estimated number
tia, accounting for 60%–80% of dementia cases of people with AD in the United States is expected to
(Alzheimer’s Association, 2016). An estimated be almost 14 million, nearly triple the current num-
5.4 million Americans are currently living with AD, ber (Hebert, Weuve, Scherr, & Evans, 2013). As the
the vast majority of whom are age 65 years or older. number of individuals being diagnosed increases,
A breakdown of prevalence rate in older adults caregiver burden and health care costs associated
shows that one in nine people age 65 and older with dementia care will also rise at alarming rates.
has AD (11%), and this increases to about one in Thus, AD is one of the most important public health
three people among those age 85 and older (32%; concerns in the United States. Accurate clinical
Alzheimer’s Association, 2016). According to the diagnosis of AD dementia and earlier identification
Centers for Disease Control and Prevention (2016), of AD in its prodromal phase are critical for future
AD is the sixth leading cause of death in the United efforts designed to prevent disease onset and to
States. This may underestimate the mortality of AD, modify the course of the disease.
however, as James et al. (2014) have shown that the In this chapter, we first review the updated
proportion of older adults who die of AD is much diagnostic criteria for dementia due to AD. Next,
higher than current estimates. This is because the we present the pattern of neuropsychological
official cause of death listed on a death certificate is deficits and functional changes that allows one to
often an acute complication related to AD dementia clinically differentiate the early stages of AD from
(e.g., fatal pneumonia) rather than AD itself as the normal aging and other causes of dementia. Finally,
underlying cause. Once these cases are taken into we discuss prodromal AD (i.e., mild cognitive
account, the data suggest that AD may actually impairment [MCI] and “preclinical” AD), including
be the third leading cause of death in the United current diagnostic criteria and limitations. We con-
States after heart disease and cancer (James et al., clude by summarizing and providing directions for
2014). future research.
In the coming years and decades, there will be
substantial growth in the population of older adults
DIAGNOSTIC CRITERIA FOR ALZHEIMER’S
in the United States, largely due to aging of the baby
DISEASE
boom generation. It is projected that individuals
age 65 and older will make up more than 20% of Diagnostic criteria for dementia and AD have been
the population by 2030 (Colby & Ortman, 2014). updated by two separate workgroups: the National

http://dx.doi.org/10.1037/0000076-013
APA Handbook of Dementia, G. E. Smith (Editor-in-Chief)
249
Copyright © 2018 by the American Psychological Association. All rights reserved.
Edmonds, Salmon, and Bondi

Institute on Aging–Alzheimer’s Association (NIA–AA) When these conditions are not met, the diagnosis
workgroup (McKhann et al., 2011) and the Ameri- is specified as “possible” AD (American Psychiatric
can Psychiatric Association workgroup for the fifth Association, 2013).
edition of the Diagnostic and Statistical Manual of The NIA–AA (McKhann et al., 2011) criteria
Mental Disorders (DSM–5; American Psychiatric for AD largely overlap with those of the DSM–5,
Association, 2013). The DSM–5 refers to dementia but there are several differences worth noting. The
as a syndrome of acquired cognitive impairment NIA–AA criteria require cognitive decline in a mini-
due to brain dysfunction that is severe enough to mum of two cognitive domains for a diagnosis of
interfere with everyday activities. Dementia is sub- dementia (based on any cause, not specific to AD),
sumed in the DSM–5 under the diagnosis of major whereas a DSM–5 diagnosis of major NCD (due to
neurocognitive disorder (NCD). Four criteria for any cause) requires cognitive decline in only one
major NCD are described (American Psychiatric cognitive domain. Only when specifying that major
Association, 2013). First, there must be evidence NCD is due to AD does DSM–5 require at least two
Copyright American Psychological Association. Not for further distribution.

of significant decline from a previous level of per- domains to be impaired. Although this may seem to
formance in one or more cognitive domains (i.e., be a minor difference, it could produce inconsisten-
complex attention, executive function, learning cies in the way in which patients are classified
and memory, language, perceptual–motor, or social and lead to confusion among the general public
cognition). This can be based on the subjective regarding the difference among dementia, AD, and
report of the individual (or clinician or a knowl- major NCD.
edgeable informant), objective evidence from stan- A second difference is that the DSM–5 requires
dardized neuropsychological testing or quantified learning and memory to be impaired for a clas-
clinical assessment, or both. Second, cognitive defi- sification of probable AD, whereas the NIA–AA
cits must interfere with independence in everyday criteria allow for probable AD even if a patient
activities to the point that one requires assistance demonstrates a nonamnestic presentation (i.e.,
with complex instrumental activities of daily living deficits primarily in the domain of language,
(IADLs; i.e., paying bills, managing medications). visuospatial abilities, or executive function). Even
Third, cognitive deficits cannot occur exclusively though an amnestic profile is the most common
in the context of a delirium. Finally, cognitive clinical presentation of AD, as discussed later in
deficits cannot be better explained by another this chapter, nonamnestic presentations occur,
mental disorder (e.g., major depressive disorder, particularly in early-onset AD (i.e., onset before
schizophrenia). age 65; Koedam et al., 2010; Licht, McMurtray,
Once it is determined that a patient meets criteria Saul, & Mendez, 2007; Mendez, Lee, Joshi, & Sha-
for major NCD, the diagnosis may be further speci- pira, 2012). Retrospective studies have found that
fied as being “due to AD.” Major NCD due to AD is as many as one third to two thirds of patients with
specified when there is insidious onset of cognitive early-onset AD initially demonstrate nonamnestic
impairment, gradual progression, and at least two profiles of cognitive impairment (Koedam et al.,
cognitive domains affected. A clinician’s confidence 2010; Mendez et al., 2012). In addition, nonam-
in the diagnosis can be specified as “probable” AD nestic profiles are seen in 6%–13% of late-onset
when there is evidence of a causative genetic muta- sporadic AD patients. Thus, recognition of atypical
tion (via family history or genetic testing), and/or presentations is important for accurate AD diagno-
the patient demonstrates impairment in learning sis (Galton, Patterson, Xuereb, & Hodges, 2000)
and memory as one of the two cognitive domains and an advantage of the NIA–AA criteria over those
affected, the course is characterized by gradual of the DSM–5.
decline with no extended plateaus, and there is no A third difference between the two sets of diag-
evidence of mixed etiology for the cognitive decline nostic criteria is the manner in which biomarkers
(i.e., no other neurological, mental, or systemic are used to support the AD diagnosis. Both the
­disease or condition that is likely contributing). DSM–5 and the NIA–AA criteria include causative

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Clinical Assessment of Alzheimer’s Disease

genetic mutations—amyloid precursor protein, pre- limitations to our knowledge about these biomark-
senilin 1, or presenilin 2—as a defining feature of ers, including appropriate cutoffs for labeling a
probable AD. These genes are inherited in an auto- biomarker as normal versus abnormal. Given this
somal dominant fashion and have been linked to lack of standardization and limited access to bio-
the development of early-onset familial AD (Selkoe, marker assessment methods in community settings,
2001). The most notable divergence between the the NIA–AA workgroup does not advocate for the
diagnostic criteria in this regard is that the NIA–AA routine use of biomarkers for diagnostic purposes
guidelines have incorporated additional biomark- (McKhann et al., 2011) but suggests that they can be
ers into the diagnosis of AD (including late-onset used to enhance certainty about an AD pathophysi-
sporadic AD). According to NIA–AA guidelines, if a ological process for clinical trials. At this time, AD
patient meets core criteria for probable AD demen- dementia or major NCD due to AD remains primar-
tia, biomarker evidence may increase the certainty ily a clinical diagnosis based on history taking and
that the basis of the clinical dementia syndrome is objective cognitive assessment.
Copyright American Psychological Association. Not for further distribution.

AD pathophysiology (McKhann et al., 2011). The


two major classes of biomarkers that have been
NEUROPSYCHOLOGICAL PROFILE OF
linked to AD are (a) biomarkers related to amyloid-
ALZHEIMER’S DISEASE
beta protein deposition in the brain and (b) bio-
markers related to neuronal degeneration or injury The pathology of AD is characterized by neuronal
(for a review, see Hampel et al., 2008). The presence atrophy, synapse loss, and the abnormal accumula-
of amyloid-beta in the brain can be measured indi- tion of amyloid plaques and neurofibrillary tangles
rectly via cerebrospinal fluid levels of amyloid-beta in medial temporal lobe limbic structures (e.g.,
(Seppala et al., 2012; Strozyk, Blennow, White, & entorhinal cortex, hippocampus) and the associa-
Launer, 2003) or using positron emission tomog- tion cortices of the frontal, temporal, and parietal
raphy amyloid neuroimaging (C. M. Clark et al., lobes (Braak & Braak, 1991; see Figure 13.1). Con-
2012; Klunk et al., 2004). Neuronal degeneration sistent with these widespread neuropathological
or injury can be detected through biomarkers in changes, the primary clinical manifestation of AD
the cerebrospinal fluid (i.e., levels of tau or hyper- is a progressive global dementia syndrome. How-
phosphorylated tau; Buerger et al., 2006; Seppala ever, particular neuropsychological deficits that
et al., 2012) or via neuroimaging modalities such as occur in the early stages of AD enable one to clini-
18fluorodeoxyglucose–positron emission tomogra-
cally differentiate the disease from normal aging.
phy or structural MRI. On the basis of the NIA–AA Typically, the dementia syndrome is characterized
guidelines (McKhann et al., 2011), if an individual by prominent memory impairment (i.e., amnesia)
meets clinical criteria for AD dementia and is posi- with additional deficits in language and semantic
tive for both biomarkers, there is a high likelihood memory (e.g., aphasia and agnosia), executive
of an AD etiology. If only one biomarker is positive, functioning, visuospatial and visuoconstructional
there is an intermediate likelihood of an AD etiol- abilities (i.e., apraxia), and attention (Salmon &
ogy. When a patient is classified as having possible Bondi, 1999, 2009). Specific patterns of impair-
AD by clinical criteria, two positive biomarkers ment in each of these cognitive domains are dis-
increases confidence that the cause of the dementia cussed below.
is AD, but it does not rule out the possibility of a
second etiology. Finally, if a patient meets criteria Memory
for dementia, but AD biomarkers are negative, it Episodic memory impairment (i.e., amnesia) is
is unlikely that AD is the cause of the cognitive usually the earliest and most salient aspect of the
impairment. AD dementia syndrome (for a review, see Salmon,
The use of biomarkers to guide the diagnosis 2000). This is consistent with the underlying neu-
of AD and other dementias is clearly a direction in ropathology, as medial temporal lobe structures
which the field is heading. However, there are still such as the hippocampus and entorhinal cortex,

251
Edmonds, Salmon, and Bondi

(a) (b) (c)

Figure 13.1.  Braak and Braak’s (1991) neuropathological staging system showing progression of pathology:
(a) Neurofibrillary changes are initially limited to entorhinal and transentorhinal regions; (b) severe involvement
of transentorhinal regions, moderate changes in the hippocampus, and mild changes in some cortical association
areas; (c) cortical association areas severely involved; only primary sensory and motor areas are spared. From
“Neuropathological Stageing of Alzheimer-Related Changes,” by H. Braak and E. Braak, 1991, Acta Neuropathologica,
82, p. 246. Copyright 1991 by Springer. Reprinted with permission.
Copyright American Psychological Association. Not for further distribution.

which are critical for episodic memory, are affected California Verbal Learning Test (CVLT), with the
in the earliest stages of AD (Braak & Braak, 1991; performance of MCI patients falling in between the
see ­Figures 13.1a and 13.1b). Mildly demented AD normally aging and AD groups in terms of overall
patients produce characteristic patterns of responses learning (see Figure 13.2a). Similarly, Gifford et al.
on measures of learning and memory for new infor- (2015) found a progressive deterioration of learn-
mation, which are quite effective in differentiating ing across the spectrum from normal aging to MCI
individuals with AD from normal older adults to mild to moderate AD. Within the MCI group, a
(Bayles, Boone, Tomoeda, Slauson, & Kaszniak, 1989; steeper learning slope corresponded to larger vol-
Delis et al., 1991; Eslinger, Damasio, Benton, & Van umes within regions of the medial temporal lobe
Allen, 1985; Huff et al., 1987; Kaszniak, Wilson, and prefrontal cortex on MRI. These findings sug-
Fox, & Stebbins, 1986; Storandt, Botwinick, gest that compromised learning slope performance
Danziger, Berg, & Hughes, 1984). The most notable in MCI may reflect underlying neurodegeneration
aspect of patients’ performance is impaired consoli- before the onset of dementia (Gifford et al., 2015).
dation, which is a deficit in the process of stabilizing An abnormal serial position curve may also be
a memory trace and transferring the newly learned observed during the encoding phase on episodic
information into long-term storage. On neuro- memory tests (Bayley et al., 2000; Capitani, Della
psychological measures of episodic memory, this Sala, Logie, & Spinnler, 1992; Carlesimo, Sab-
consolidation deficit manifests itself in several ways badini, Fadda, & Caltagirone, 1995; Greene, Bad-
and is apparent during all phases of a test, including deley, & Hodges, 1996; Massman, Delis, & Butters,
encoding, recall, and recognition. 1993). Specifically, patients with early AD may
During the encoding phase of an episodic show an attenuated primacy effect (i.e., recalling
memory task (e.g., a list-learning test), patients may fewer items from the beginning of a word list than
show a flattened learning slope in which there is normal older adults) and a heightened recency
little or no improvement in the amount of informa- effect (i.e., recalling more items from the end of a
tion encoded with repeated learning trials. This word list). Items at the end of a word list are likely
reduced ability to benefit from repetition reflects still in short-term or working memory, whereas
patients’ difficulty with transferring information items at the beginning of a word list require transfer
from short-term or working memory into long-term to long-term storage. This pattern of performance
memory. Alterations in learning slope have also during the learning trials illustrates the dissociation
been observed in individuals with MCI, a transi- between memory consolidation, which is impaired
tional state between normal aging and AD (Petersen, early in the course of AD, and short-term or work-
2004). Greenaway et al. (2006) showed a flattened ing memory, which remains relatively intact early
learning slope in both MCI and AD groups on the in the disease.

252
Clinical Assessment of Alzheimer’s Disease

(a) 14 (b) 12

12 10

10 8

Words Recalled
Words Learned

8 6

6 4

4 2
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2 0
1 2 3 4 5 SD Free SD Cued LD Free LD Cued
Trials Recall

AD MCI Normal Aging AD MCI Normal Aging

Figure 13.2.  (a) Learning curves for Alzheimer’s disease (AD; n = 65), mild cognitive impairment (MCI; n = 65),
and normal aging (n = 65) groups on the California Verbal Learning Test. Mean performance for each trial was sig-
nificantly different across all three groups (p < .001). (b) Short delay (SD) and long delay (LD) free and cued recall
was significantly reduced in MCI compared with normal aging (p < .001) and further reduced in AD (p < .001). From
“Patterns of Verbal Memory Performance in Mild Cognitive Impairment, Alzheimer Disease, and Normal Aging,”
by M. C. Greenaway, L. H. Lacritz, D. Binegar, M. F. Weiner, A. Lipton, and C. Munro Cullum, 2006, Cognitive and
Behavioral Neurology, 19, pp. 81–82. Copyright 2006 by Wolters Kluwer. Reprinted with permission.

Individuals with MCI may also show changes Another aspect of learning that may differentiate
in their serial position curve relative to normally patients with AD from normal older individuals is
aging individuals (Howieson et al., 2011; Moser that patients are less likely to use semantic encod-
et al., 2014), and this may be particularly useful in ing strategies such as grouping semantically related
predicting who is at risk of progressing from MCI items together (Bäckman & Small, 1998; Buschke,
to AD. A study by Cunha, Guerreiro, de Mendonça, Sliwinski, Kuslansky, & Lipton, 1997; Goldblum
Oliveira, and Santana (2012) found a diminished et al., 1998; Knopman & Ryberg, 1989). Failure to
primacy effect on a delayed word recall test (Word use such strategies may be secondary to a broader
Recall Task of the Alzheimer’s Disease Assessment difficulty with semantic knowledge (discussed in
Scale–Cognitive) in participants with MCI who later the Language and Semantic Memory section below).
progressed to AD compared with those who did not Individuals with amnestic MCI show similar diffi-
progress over a 4-year period. Egli et al. (2014) also culty using semantic encoding strategies and do not
found that poor primacy recall on the CVLT was benefit from deep encoding cues to the same extent
more sensitive than other memory measures at pre- as healthy older adults (Hudon, Villeneuve, &
dicting progression to AD. Another study showed Belleville, 2011).
that cognitively intact individuals with a parental In addition to impaired encoding, patients
family history of AD showed an exaggerated recency with early AD demonstrate deficits on measures of
effect on the Rey Auditory Verbal Learning Test rel- delayed recall. This feature of their performance was
ative to control participants with no family history originally recognized by Alzheimer (1907) and is
of AD, despite equivalence between groups in the particularly valuable clinically for detection and dif-
total number of words recalled (La Rue et al., 2008). ferential diagnosis of the disease (Butters et al., 1988;

253
Edmonds, Salmon, and Bondi

Locascio, Growdon, & Corkin, 1995; Welsh, Butters, multiple memory processes in at-risk individuals as
Hughes, Mohs, & Heyman, 1991). Specifically, these processes do not necessarily decline at similar
rapid forgetting is a hallmark characteristic of rates across time (Cloutier et al., 2015).
AD and reflects patients’ difficulty with memory One qualitative aspect of the memory perfor-
consolidation. Evidence that the deficit in delayed mance of patients with AD is a tendency to pro-
recall is related to poor consolidation, as opposed to duce intrusion errors (Butters, Granholm, Salmon,
another cognitive process (such as difficulty retriev- Grant, & Wolfe, 1987; Davis, Price, Kaplan, &
ing information from memory), comes from the Libon, 2002; Delis et al., 1991; Fuld, Katzman,
finding that patients’ performance generally does Davies, & Terry, 1982; Jacobs, Salmon, Tröster, &
not improve when retrieval demands are reduced Butters, 1990). These are errors in which a patient
through the use of a recognition memory test format incorrectly “recalls” items that were never presented
(Delis et al., 1991). A measure of rapid forgetting during learning or recall trials. Intrusions may be
can be ascertained by calculating a “savings” score particularly prominent in response to memory
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on an episodic memory task. This is calculated as cuing. For example, when cued that a word list
the number of items recalled after a delay divided contained different types of animals, a patient may
by the number of items recalled on an immediate produce the names of several animals but not nec-
learning trial. Research has shown that savings scores essarily the specific animals that were provided on
can differentiate mildly demented AD patients from the word list. Intrusion errors also occur during free
normal older adults with 85%–90% accuracy recall on learning trials, and patients may repeat
(Butters et al., 1988; Flicker, Ferris, & Reisberg, these same intrusions throughout the learning phase
1991; Knopman & Ryberg, 1989; Morris et al., 1991; (Davis et al., 2002). Intrusions are typically exem-
Salmon, 2000; Welsh et al., 1991). Reduced delayed plars from the same semantic categories as the to-be-
recall is also characteristic of amnestic MCI. Delayed remembered words. On measures such as the CVLT,
recall performance on measures such as the CVLT intrusion errors may make up as much as 35% of
can discriminate MCI from normal aging, as well as patients’ responses across learning and recall trials,
MCI from AD. This finding was demonstrated in a compared with minimal intrusions (5%) for nor-
study by Greenaway et al. (2006), which showed mal controls (Greenaway et al., 2006). An elevated
that short- and long-delay recall on the CVLT was number of intrusion errors (during both free and
significantly reduced in MCI compared with cued recall) has also been demonstrated in individu-
normal aging (p < .001) and further reduced in AD als with amnestic MCI. Similar to AD patients, the
(p < .001; see Figure 13.2b). intrusions made by MCI patients tend to be highly
The time course of decline in immediate and prototypic exemplars from the same semantic cat-
delayed memory abilities was examined in a study egories included in the to-be-remembered list (e.g.,
that analyzed patterns of memory performance hammer if the category is tools; Libon et al., 2011).
on a word-list test in individuals with amnestic This latter tendency led Delis, Kramer, Kaplan, and
MCI (Cloutier, Chertkow, Kergoat, Gauthier, & Ober (1987, 2000) to refrain from choosing the
Belleville, 2015). In this study, 47 of the MCI most highly prototypical exemplars of the categories
participants later progressed to a diagnosis of AD when they constructed the original and revised ver-
dementia and 74 did not. In those who progressed, sions of the CVLT.
delayed recall abilities were observed to be relatively Another feature of memory impairment in AD
stable for many years, followed by a period of rapid is retrograde amnesia, which is the inability to
decline in the 1–2 years just before diagnosis. This remember events from one’s past that occurred
contrasted with a more gradual and linear rate of before the onset of the disease. Events that occurred
decline for learning trials/immediate memory (as more recently (i.e., closer in time to disease onset)
well as for executive function and visuospatial abili- are typically affected to a greater extent than memories
ties) in the years before dementia onset. This study from the distant past (Beatty, Salmon, Butters, Heindel, &
highlights the utility of assessing and monitoring Granholm, 1988; Hodges, Salmon, & Butters, 1993;

254
Clinical Assessment of Alzheimer’s Disease

Kopelman, 1989; Sagar, Cohen, Sullivan, Corkin, & memory deficit manifests itself in a number of ways,
Growdon, 1988; Wilson, Kaszniak, & Fox, 1981), including poor confrontation naming (Bayles &
a phenomenon known as Ribot’s law (Ribot, 1881). Tomoeda, 1983; Bowles, Obler, & Albert, 1987;
Retrograde amnesia and the observed temporal Hodges, Salmon, & Butters, 1991; Huff, Corkin, &
gradient of memory impairment are thought to Growdon, 1986; Martin & Fedio, 1983), decreased
be a consequence of disruption of the long-term verbal fluency (Butters et al., 1987; Martin & Fedio,
memory consolidation process. The purported 1983; Monsch et al., 1994), deficits in semantic cat-
mechanism behind this observation is that recent egorization (Aronoff et al., 2006; Chan, Salmon, &
memories are thought to be in a more fragile state Butters, 1998), and difficulty recalling overlearned
and vulnerable to forgetting since they are depen- facts (e.g., the number of days in a year; Chan et al.,
dent on the medial temporal lobe structures (e.g., 1998, Hodges & Patterson, 1995; Nebes, 1989;
hippocampal–diencephalic memory system) dam- Norton, Bondi, Salmon, & Goodglass, 1997).
aged in AD. More remote memories, however, may Decline in language abilities (i.e., aphasia) may
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be less vulnerable to disruption since they are more also manifest as spontaneous speech that is vague,
fully consolidated and no longer dependent on these lacking in content words, and containing indefi-
medial temporal lobe structures (Cermak, 1984; nite phrases and circumlocutions (Nicholas, Obler,
Squire, 1987; Squire & Zola, 1997; Zola-Morgan & Albert, & Helm-Estabrooks, 1985).
Squire, 1990). An alternative possibility is that On a test of confrontation naming, such as the
memories remain dependent on the hippocampus Boston Naming Test, patients with AD may demon-
throughout life, with new memory traces formed strate agnosia, in which they are unable to recognize
each time a memory is retrieved (Moscovitch et al., familiar objects. They also tend to make semantically
2005; Nadel & Moscovitch, 1997). Older, frequently based errors, such as superordinate naming errors
recalled memories thus become stronger and less (e.g., responding with “bird” or “animal” when
susceptible to disruption by brain damage than more attempting to name a pelican) as opposed to more
recent, less frequently recalled memories. perceptually based errors that are seen in other types
Taken together, these various quantitative and of dementia (e.g., Huntington’s disease; Salmon &
qualitative aspects of episodic memory performance Filoteo, 2007). On verbal fluency tests, patients gen-
are effective for the early detection and characteriza- erally demonstrate a more pronounced impairment
tion of AD and for differentiating the disease from in category fluency relative to letter fluency (Henry,
both normal aging and other types of dementia Crawford, & Phillips, 2004; Monsch et al., 1994).
(Buschke, 1973; Buschke et al., 1997; Delis et al., This discrepancy is secondary to category fluency
1991; Knopman & Ryberg, 1989). being more dependent on semantic organization, as
words generated during category fluency must be
Language and Semantic Memory from the same semantic category, whereas words
As the disease progresses, the neuropathology of generated during letter fluency do not need to be
AD spreads beyond medial temporal lobe structures semantically or conceptually related. These char-
and begins to affect association cortices of the tem- acteristic patterns of performance on confrontation
poral, frontal, and parietal lobes (Braak & Braak, naming and verbal fluency measures in AD patients
1991; see Figure 13.1c). This results in impairments are indicative of a loss of semantic knowledge for
in cognitive domains other than episodic memory. particular items or concepts.
One result of this spread of cortical pathology is There is additional evidence to suggest that AD
a decline in language abilities and a degradation results in a true loss of semantic knowledge rather
of semantic memory. Semantic memory refers to than an impaired ability to retrieve semantic infor-
general knowledge about the world that encom- mation (Salmon et al., 1999). A longitudinal study
passes facts and concepts and their relationships by Norton et al. (1997) found that mildly demented
(Hodges & Patterson, 1995; Nebes, 1989; Salmon, AD patients were consistent in the items that they
Butters, & Chan, 1999). Clinically, this semantic missed on a test of general knowledge from year to

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Edmonds, Salmon, and Bondi

year. Others have shown that patients consistently Executive Functioning


miss the same individual items across different Patients with early AD exhibit impairments in
semantic memory tasks that involve varying meth- executive functioning. This includes deficits in abili-
ods of accessing semantic information (Chertkow & ties such as problem solving, planning, set shifting,
Bub, 1990; Hodges, Salmon, & Butters, 1992). working memory, concept formation, inhibition,
Such consistency would be unlikely if information judgment, reasoning, and self-monitoring (Duke &
remained intact from year to year but could not be Kaszniak, 2000; Lefleche & Albert, 1995; Perry &
retrieved at one particular point in time. Hodges, 1999). Neuropsychological measures sen-
Semantic memory decline may occur early in the sitive to these impairments in patients with AD
course of AD (Dudas, Clague, Thompson, include the Wisconsin Card Sorting Task, Trail
Graham, & Hodges, 2005; Joubert et al., 2010). Jou- Making Test Part B, Stroop Color–Word Test,
bert et al. (2010) showed that individuals with amnes- Tower of London, Porteus Maze Task, and Raven
tic MCI and early AD performed similarly at naming Progressive Matrices Task (Bondi, Monsch, Butters,
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objects and famous faces, and both were significantly Salmon, & Paulsen, 1993; Bondi et al., 2002;
more impaired than control participants. The same Duke & Kaszniak, 2000; Grady et al., 1988; Lange,
pattern also emerged when participants were asked Sahakian, Quinn, Marsden, & Robbins, 1995).
questions assessing semantic knowledge about each Research has shown that there is considerable
object or face. On tests of verbal fluency, individuals heterogeneity among AD patients in the pattern
with MCI demonstrate the same discrepancy seen in of executive function deficits they exhibit and the
AD patients, with more impaired category fluency specific neuropsychological test performances that
relative to letter/phonemic fluency (Adlam, Bozeat, are affected (Stokholm, Vogel, Gade, & Waldemar,
Arnold, Watson, & Hodges, 2006; Cottingham & 2006). To identify which aspects of executive func-
Hawkins, 2010; Lonie et al., 2009; Teng et al., 2013). tioning are usually impaired earliest in the course of
Deficiencies in semantic memory can contribute AD, Brandt et al. (2009) conducted an exploratory
to some of the characteristic findings in the episodic principal-components analysis with MCI patients
memory domain. For example, loss of semantic using 18 different tests that measure six conceptu-
knowledge can account for patients’ reduced ability ally distinct domains of executive ability: (a) spon-
to use semantic encoding strategies when attempt- taneous flexibility and generativity, (b) inhibition of
ing to learn new information (Bäckman & Small, prepotent responses, (c) planning and sequencing,
1998; Buschke et al., 1997; Goldblum et al., 1998; (d) concept/rule learning and set shifting, (e) deci-
Knopman & Ryberg, 1989). In addition, semantic sion making and judgment, and (f) working mem-
memory impairment may underlie retrograde amne- ory. Results revealed three primary components:
sia in AD. When memories are consolidated into planning and problem solving, working memory,
long-term storage, the process is thought to involve and judgment. The first two components were
a shifting of memories from an episodic form to a found to be selectively impaired in persons with
more semantic form (Cermak, 1984; Squire, 1987; MCI, even in those individuals classified as having
Squire & Zola, 1997; Zola-Morgan & Squire, 1990). primarily memory impairment (i.e., amnestic MCI).
The semantic nature of these remote events may In contrast, judgment remained relatively intact
explain the difficulty that patients exhibit in remem- (Brandt et al., 2009). These findings suggest that
bering past events that were successfully remem- planning, problem solving, and working memory
bered before the onset of the disease (Salmon, may be the executive function abilities that are first
2000). In individuals with MCI, retrograde memory affected in the early stages of AD and that measures
impairment has been observed for public events and tapping these abilities may be particularly useful for
news stories (Bizzozero, Lucchelli, Saetti, & Spinn- predicting risk of progression to dementia (see also
ler, 2009; Leyhe, Müller, Eschweiler, & Saur, 2010; Aretouli, Tsilidis, & Brandt, 2013).
C. N. Smith, 2014), consistent with a loss of seman- Executive dysfunction may also underlie some of
tic knowledge early in the disease process. the difficulty that AD patients have in the domain of

256
Clinical Assessment of Alzheimer’s Disease

social cognition. An ability that is adversely affected informant report. A review by Henry et al. (2016)
in AD is theory of mind (ToM), which refers to described various other social cognitive assessment
one’s ability to attribute mental states to others and measures (e.g., false-belief tasks; tests of emotion
understand their beliefs and intentions. ToM places labeling) that clinicians could consider implement-
a high demand on many executive functioning skills, ing in their clinical practice.
including inhibition, cognitive flexibility, updating,
working memory, verbal abilities, and reasoning Visuospatial/Visuoconstructional Ability
skills (for a review, see Sandoz, Démonet, & Fossard, Patients with early AD may exhibit deficits on visuo-
2014). Impairment in these abilities is thought to at constructional tasks such as the Block Design Test
least partially account for observed deficits on ToM (Mohr, Litvan, Williams, Fedio, & Chase, 1990; Pado-
tasks in patients with AD (Castelli et al., 2011; Greg- vani et al., 1995; Villardita, 1993), Clock Drawing Test
ory et al., 2002; Koff, Brownell, Winner, Albert, & (for a review, see Freedman et al., 1994), or copying
Zaitchik, 2004; Laisney et al., 2013; Verdon et al., a complex figure (Locascio et al., 1995; Mohr et al.,
Copyright American Psychological Association. Not for further distribution.

2007; Zaitchik, Koff, Brownell, Winner, & Albert, 1990; Padovani et al., 1995; Villardita, 1993). Impair-
2006). Deficits in social functions that are dependent ment in visuoperception and visual orientation may be
on ToM may be manifested as loss of empathy, social apparent on tasks such as the Judgment of Line Ori-
withdrawal, or inappropriate social behavior. entation test (Ska, Poissant, & Joanette, 1990) and the
It is unclear whether ToM is affected early in Hooper Visual Orientation Test (Paxton et al., 2007).
the course of AD because studies examining ToM Deficits in visuospatial abilities often occur later in the
in individuals with MCI have shown conflicting course of AD than deficits in other higher order cogni-
results; some have provided evidence of a ToM defi- tive processes. There are, however, relatively rare cases
cit in amnestic MCI (Baglio et al., 2012; Poletti & in which primary visual and visuospatial deficits are
Bonuccelli, 2013), but others have found no differ- the earliest manifestation of AD pathology (i.e., poste-
ence between amnestic MCI and healthy controls rior cortical atrophy; Caine, 2004).
(Dodich et al., 2016). Differences in the way in
which ToM was assessed could account for these Attention
mixed findings, or they could be due to heterogene- Basic attention is generally intact in early AD. Mildly
ity within and across MCI samples. This heteroge- demented AD patients typically show essentially
neity was highlighted in a study by Moreau et al. normal performance on measures such as the Atten-
(2015), which showed that MCI participants with tion/Concentration Index of the Wechsler Memory
isolated episodic memory dysfunction were only Scale–Revised, a composite measure derived from
impaired in some aspects of their ToM assessment, performance on tests of digit span (forward and back-
whereas MCI participants with more widespread ward), visual memory span (forward and backward),
cognitive dysfunction had more extensive ToM and mental control (Butters et al., 1988). However,
impairment. Unlike many other executive function tasks requiring dual processing, shifting of attention,
abilities, standard neuropsychological tests may or working memory are often impaired early in the
lack the precision and sensitivity to detect impair- course of AD (Duke & Kaszniak, 2000; Parasura-
ments in ToM or other aspects of social functioning man & Haxby, 1993; Perry & Hodges, 1999) and
(Henry, von Hippel, Molenberghs, Lee, & Sachdev, may be related to deficits in executive functioning.
2016). Therefore, clinicians should inquire about
any changes in behavior or personality as part of
DISTINGUISHING ALZHEIMER’S DISEASE
the clinical interview with the patient and a knowl-
FROM OTHER DEMENTIAS
edgeable informant. In addition, instruments such
as the Frontal Systems Behavior Scale (Grace & As mentioned above, AD is the most common cause
Malloy, 2001) are useful to assess behavior changes of dementia, accounting for 60%–80% of dementia
related to frontal lobe dysfunction (i.e., apathy, dis- cases. The other most common forms of dementia
inhibition, and executive dysfunction) via self- and are vascular dementia (VaD), dementia with Lewy

257
Edmonds, Salmon, and Bondi

bodies (DLB), and frontotemporal lobar degenera- VaD is characterized as a subcortical dementia,
tion (FTLD). (There are also many other causes as opposed to AD, which is a cortical dementia.
of dementia that are not discussed here, including A number of contrasting features are associated
Parkinson’s disease, Huntington’s disease, progres- with cortical versus subcortical dementias that
sive supranuclear palsy, normal pressure hydro- can assist a clinician in determining whether the
cephalus, and Creutzfeldt-Jakob disease, to name a cause of a dementia syndrome is AD, VaD, or
few.) Although each of these are considered distinct both (for reviews, see Duke & Kaszniak, 2000;
etiologies, the neuropathology of these disorders Salmon & Bondi, 2009; Salmon & Filoteo, 2007;
has substantial overlap. Neuropathological studies G. E. Smith & Bondi, 2013). In a cortical demen-
have shown that AD and MCI are heterogeneous tia such as AD, episodic memory and semantic
disorders and that the presence of “pure” AD pathol- memory/language deficits are typically apparent
ogy is rarer than the presence of AD plus other first, with other domains affected later as the dis-
pathologies that could also contribute to cognitive ease progresses. In contrast, subcortical dementias
Copyright American Psychological Association. Not for further distribution.

decline (e.g., cerebrovascular disease, Lewy body such as VaD are associated with early prominent
disease, hippocampal sclerosis, transactive response deficits in executive functioning, attention, and
DNA-binding protein 43) in late-onset AD cases visuospatial/visuoconstructional skills. Consis-
(Schneider, Arvanitakis, Leurgans, & Bennett, 2009; tent with this distinction, studies have shown that
Toledo et al., 2013; Wilson et al., 2013). It is now patients with subcortical VaD are more impaired
recognized that mixed dementia is quite common; on tests of executive functions than those with AD,
around half of older adults with dementia have evi- whereas patients with AD are more impaired on
dence of more than one etiology, most commonly tests of episodic memory than those with subcortical
AD and vascular dementia (Schneider et al., 2009). VaD (Desmond, 2004, Graham, Emery, & Hodges,
In the DSM–5, these cases would be diagnosed as 2004; Kertesz & Clydesdale, 1994; Lafosse et al.,
major NCD due to multiple etiologies (American 1997; Lamar et al., 1997).
Psychiatric Association, 2013). Consistent with this Patients with VaD may also show impair-
mixed pathology, many AD patients also demon- ment on measures of episodic memory; however,
strate a neuropsychological profile with features of these deficits can often be attributed to executive
more than one form of dementia. Even in patients dysfunction rather than a memory deficit per se.
who have one primary etiology for their cognitive Specifically, individuals with VaD demonstrate a
impairment, distinguishing AD from other common memory retrieval deficit that leads to a pattern of
causes of dementia can be challenging since there is performance in which recognition memory is less
overlap in the pattern of cognitive deficits, particu- impaired relative to free recall (Salmon & Filoteo,
larly in the later stages of the disease. Nevertheless, 2007; G. E. Smith & Bondi, 2013). This contrasts
each type of dementia has certain hallmark features with AD, in which a deficit in consolidation leads
that can allow one to deduce the primary cause with to poor performance on both free recall and rec-
some level of confidence. ognition formats. Patients with VaD are also more
VaD refers to a cumulative decline in cognitive likely to have a normal serial position curve, more
functioning secondary to blocked or reduced cere- likely to benefit from semantic encoding strategies,
bral blood flow. Cerebrovascular pathology can be and less likely to make intrusion errors relative to
caused by acute events such as stroke or a series of patients with AD (G. E. Smith & Bondi, 2013). A
strokes or by slower accumulative processes such retrieval deficit may also be apparent on confronta-
as small vessel ischemic disease. As a sole cause of tion naming tasks (e.g., Boston Naming Test) in
dementia, VaD accounts for approximately 10% of those with early VaD, although their overall naming
dementia cases. However, about 50% of older adults performance is typically more preserved than those
with dementia have pathological evidence of vascu- with AD. Individuals with subcortical dementias
lar dementia (e.g., infarcts), often coexisting with also tend to benefit from cuing and are more likely
AD pathology (Alzheimer’s Association, 2016). to make perceptually based errors on naming tasks

258
Clinical Assessment of Alzheimer’s Disease

(e.g., calling a pretzel a snake) than the semantically FTLD refers to a category of disorders associ-
based errors seen in AD (Salmon & Filoteo, 2007; ated with dementia and atrophy in the frontal
G. E. Smith & Bondi, 2013). and temporal lobes of the brain. Types of FTLD
Verbal fluency can be a useful measure to help include behavioral-variant frontotemporal demen-
distinguish AD from a subcortical dementia such as tia (bvFTD), primary progressive aphasia, and
VaD. In AD, the classic pattern is for performance semantic dementia. bvFTD is unique compared
on category fluency to be worse than letter flu- to the other forms of dementia described thus far,
ency since category fluency is more dependent on as it begins insidiously with changes in behavior,
semantic organization. The opposite pattern—worse social comportment, and personality (Boxer &
performance on letter fluency relative to category Miller, 2005; Grossman, 2002; Neary, 2005; G. E.
fluency—is seen in VaD (Carew, Lamar, Cloud, Smith & Bondi, 2013). This may include inappro-
Grossman, & Libon, 1997; Lafosse et al., 1997). priate social conduct, apathy, disinhibition, perse-
This pattern reflects VaD patients’ executive dys- verative behavior, loss of insight, hyperorality, or
Copyright American Psychological Association. Not for further distribution.

function, since letter fluency places greater demand decreased speech output. Early in the disease, it is
on self-initiated search strategies (to generate words not uncommon for symptoms to be mistaken for a
that are not necessarily conceptually related) rela- psychiatric disorder (e.g., depression, bipolar disor-
tive to animal fluency. der, schizophrenia). Cognitive deficits early in the
DLB is a progressive dementia syndrome that course include alterations in executive functions,
occurs in the presence of cell loss and abnor- language impairment (i.e., aphasia; Boxer & Miller,
mal deposition of alpha-synuclein–positive 2005; Grossman, 2002; Neary, 2005; G. E. Smith &
Lewy bodies. Aggregates of alpha-synuclein are Bondi, 2013), or both.
deposited in subcortical regions (in a pattern FTLD is considered a cortical dementia, and epi-
similar to that of Parkinson’s disease) and may sodic memory can be affected early in the course.
also be diffusely distributed throughout the lim- Hornberger, Piguet, Graham, Nestor, and Hodges
bic system and neocortex; in many cases, AD (2010) have shown that the degree of episodic mem-
pathology (i.e., amyloid plaques, neurofibrillary ory impairment in patients with bvFTD was similar
tangles) is also present in patients with DLB in to that observed in patients with AD. Furthermore,
the same distribution throughout the brain as Mansoor et al. (2015) found that both bvFTD and
in AD (for a review, see Ince & Perry, 2005). AD participants demonstrate more rapid forget-
Patients with DLB are frequently clinically diag- ting than control participants, committed a similar
nosed as having AD (Merdes et al., 2003), as number of intrusion errors on memory testing, and
memory impairment is often the earliest feature showed comparably low rates of improvement on
of both disorders. However, the neuropsycho- cued recall and recognition trials. This striking simi-
logical profile of DLB also includes impair- larity in memory performance between bvFTD and
ments associated with a subcortical dementia, AD may lead to underrecognition of bvFTD (Men-
including disproportionally severe deficits in dez, Selwood, Mastri, & Frey, 1993; Varma et al.,
the domains of executive functioning, atten- 1999). Further research on the behavioral and lan-
tion, and visuospatial/visuoconstructional skills guage manifestations of FTLD is needed to increase
(Salmon & Hamilton, 2006). Several clinical fea- awareness and allow for accurate diagnosis of these
tures also occur with a higher prevalence in DLB, disorders (Rascovsky & Grossman, 2013).
which can assist a clinician in differentiating DLB
from AD. These include fluctuating cognition
FUNCTIONAL IMPAIRMENT IN
and attention, recurrent visual hallucinations,
ALZHEIMER’S DISEASE
spontaneous features of parkinsonism, REM sleep
behavior disorder, sensitivity to neuroleptic med- Functional impairment is a critical component of
ications, and autonomic dysfunction (McKeith establishing a diagnosis of dementia or major NCD.
et al., 2005). Functional impairment is evident when a patient

259
Edmonds, Salmon, and Bondi

requires assistance with IADLs such as paying bills to AD (McKhann et al., 2011), MCI (Albert et al.,
or managing finances, managing medications, food 2011), and preclinical AD (Sperling et al., 2011) all
preparation, housekeeping and laundry, shopping, recognize this fact and the need for better detection
using the telephone or computer, or driving or using and characterization of early phases of AD. In these
public transportation. A clinician may be able to best new criteria, MCI is conceptualized as a symptom-
understand a patient’s everyday functional abilities atic, predementia stage of AD in which objective
by using a combination of (a) informant report, cognitive impairment is present. Preclinical AD is a
(b) performance-based measures, and (c) the largely asymptomatic phase of AD in which a bio-
patient’s performance on cognitive tests. Executive marker of AD is present, but there is no significant
dysfunction, in particular, may be a key contributor cognitive impairment. It is thought that individu-
to decline in everyday functioning (Boyle et al., 2003; als in these prodromal phases of AD have diverged
Marshall et al., 2011; Razani et al., 2007). from a normal aging trajectory of cognitive decline
By definition, individuals with MCI should be and are at risk for the eventual development of AD
Copyright American Psychological Association. Not for further distribution.

independent in their functional abilities (Albert et al., (Sperling et al., 2011; see Figure 13.3).
2011; Petersen, 2004; Petersen et al., 1999). None-
theless, they may have mild problems performing Mild Cognitive Impairment
complex tasks (e.g., paying bills or preparing a meal)
Diagnostic criteria.  MCI is often viewed as a tran-
and may take more time, be less efficient, and make
sitional state between normal aging and AD demen-
more errors than in the past (Albert et al., 2011).
tia. It was initially defined by Petersen et al. (1999)
MCI patients with deficits in IADLs have a higher
using the following diagnostic criteria: (a) memory
risk of progressing to dementia than MCI patients
complaint, (b) objective memory impairment for
without functional changes (Jekel et al., 2015).
age, (c) relatively preserved general cognition,
(d) essentially intact activities of daily living, and
PRODROMAL PHASES OF ALZHEIMER’S
(e) not demented. This classification scheme was
DISEASE
later modified to divide MCI into amnestic MCI
AD is characterized by a gradual worsening of neu- or nonamnestic MCI subtypes. In addition, single-
rodegeneration and pathophysiological changes that domain or multiple-domain classifications were added
precede the clinical diagnosis by a decade or more. to indicate the number of cognitive domains affected
Revisions to the diagnostic criteria for dementia due (Petersen, 2004; Winblad et al., 2004). Updated

The continuum of Alzheimer’s disease

Congnitive Aging
Preclinical
function
MCI

Dementia

Years

Figure 13.3.  Model of the clinical trajectory of Alzheimer’s disease (AD). Note that this diagram represents
a hypothetical model for the pathological–clinical continuum of AD, but does not imply that all individuals with
preclinical AD (i.e., biomarker evidence of AD pathophysiology) will progress to the clinical phases of the ill-
ness. MCI = mild cognitive impairment. From “Toward Defining the Preclinical Stages of Alzheimer’s Disease:
Recommendations From the National Institute on Aging–Alzheimer’s Association Workgroups on Diagnostic
Guidelines for Alzheimer’s Disease,” by R. A. Sperling, P. S. Aisen, L. A. Beckett, D. A. Bennett, S. Craft, A. M. Fagan,
. . . C. H. Phelps, 2011, Alzheimer’s and Dementia, 7, p. 283. Copyright 2011 by Elsevier. Reprinted with permission.

260
Clinical Assessment of Alzheimer’s Disease

diagnostic guidelines for MCI (Albert et al., 2011) and impaired performance on a single memory test.
essentially adopt those previously described by This approach to diagnosing MCI is epitomized in
Petersen et al. (1999) with several minor updates. several clinical trials targeting MCI (e.g., Petersen
The subjective memory complaint criterion was et al., 2005) and in many large-scale studies such
changed to “concern regarding a change in cogni- as the Alzheimer’s Disease Neuroimaging Initiative
tion” (rather than just memory; Albert et al., 2011, (Weiner et al., 2013). Petersen et al. (2014) have
p. 271). This concern can come from the patient, reiterated its merits and concluded that, although
informant, or clinician. In addition, the functional the construct of MCI has evolved, “the core criteria
deficits criterion was modified to allow for mild have remained unchanged” (p. 214).
problems in performing complex IADLs. Clinical cri- Despite the widespread use of this conventional
teria for mild NCD in DSM–5 (American Psychiatric diagnostic criteria, research has shown that this
Association, 2013) are largely consistent with the method of identifying MCI is highly susceptible
NIA–AA criteria (McKhann et al., 2011) for MCI. to false-positive diagnostic errors. For example,
Copyright American Psychological Association. Not for further distribution.

when Edmonds, Delano-Wood, Clark, et al. (2015)


Limitations.  Although there has been considerable applied cluster-analytic statistical techniques to the
progress in identifying sophisticated biomarkers neuropsychological test scores achieved by MCI
indicative of MCI and early AD, methods of charac- patients in the Alzheimer’s Disease Neuroimag-
terizing cognition in prodromal AD have remained ing Initiative cohort, they found that one-third
relatively coarse. The criteria for MCI used by many of conventionally diagnosed participants actu-
large-scale studies of prodromal AD have relied on ally performed within normal limits on this more
subjective complaints, imprecise rating scales such extensive cognitive testing despite their MCI diag-
as the Clinical Dementia Rating (Morris, 1993), nosis (see Figure 13.4). Those Alzheimer’s Disease
Animal Fluency BNT TMT, Part A TMT, Part B AVLT Recall AVLT Recognition
1.5

1
0.5
0
–0.5
–1
Mean z -Score

–1.5
–2
–2.5
–3
–3.5
–4
–4.5
–5
Amnestic MCI Dysnomic MCI Dysexecutive/Mixed MCI “False Positives”
Cluster-Derived Subtypes

Figure 13.4.  Neuropsychological performance for cluster-derived subtypes of mild cognitive impairment
(MCI; amnestic MCI, n = 288; dysnomic MCI, n = 153; dysexecutive/mixed MCI, n = 102) and for false-positive
MCI who had intact performance on the neuropsychological measures (n = 282). Error bars denote standard
error of the mean. The horizontal dashed line indicates the typical cutoff for impairment (−1.5 standard devia-
tions). AVLT = Rey Auditory Verbal Learning Test; BNT = Boston Naming Test; TMT = Trail Making Test. From
“Susceptibility of the Conventional Criteria for Mild Cognitive Impairment to False-Positive Diagnostic Errors,”
by E. C. Edmonds, L. Delano-Wood, L. R. Clark, A. J. Jak, D. A. Nation, C. R. McDonald, . . . M. W. Bondi, 2015,
Alzheimer’s and Dementia, 11, p. 417. Copyright 2015 by Elsevier. Adapted with permission.

261
Edmonds, Salmon, and Bondi

Neuroimaging Initiative MCI participants who fell also problematic due to an inconsistent relationship
into this normal cluster also (a) had normal cerebro- between subjective memory complaints and objec-
spinal fluid AD biomarker levels, (b) overreported tive memory performance in MCI (Buckley et al.,
subjective cognitive complaints, and (c) showed a 2013; Edmonds et al., 2014; Lenehan, Klekociuk, &
low rate of progression to AD. Taken together, this Summers, 2012; Roberts, Clare, & Woods, 2009;
suggests that they represent false-positive errors in Studer, Donati, Popp, & von Gunten, 2014). A study
MCI diagnosis (Edmonds, Delano-Wood, Clark, by Edmonds et al. (2014) found that cognitively
et al., 2015; Edmonds, Delano-Wood, Galasko, intact individuals tended to overestimate their cog-
Salmon, & Bondi, 2014). These results are consis- nitive problems relative to an informant’s report,
tent with previous findings of false-positive errors whereas those with amnestic MCI tended to under-
via conventional MCI diagnostic criteria in a com- estimate their cognitive problems.
munity-based sample of aging (L. R. Clark et al., To address these limitations, an actuarial neu-
2013) and with results showing that conventional ropsychological diagnostic method for MCI was
Copyright American Psychological Association. Not for further distribution.

MCI criteria produce diagnostic instability over time developed by Jak et al. (2009). This method assigns
(e.g., high rates of reversion to cognitively normal; diagnoses of MCI on the basis of scores on multiple
Ganguli et al., 2011; Koepsell & Monsell, 2012; objective neuropsychological tests that assess a
Summers & Saunders, 2012). range of cognitive domains. The approach does not
The current conventional diagnostic criteria for incorporate subjective report or clinical judgment.
MCI can also result in errors in the other direction It has been shown that actuarial methods are supe-
(i.e., false-negative diagnoses) by failing to identify rior to clinical judgment when it comes to diagno-
those who showed neuropsychological impairments sis and clinical decision making (Dawes, Faust, &
on more extensive testing and are truly at risk for Meehl, 1989), and this appears to be true for MCI.
progression to AD, but this was less likely than Jak, Bondi, and their colleagues have shown that
false-positive errors in the Alzheimer’s Disease MCI diagnosed via actuarial methods produces
Neuroimaging Initiative MCI cohort (Edmonds greater diagnostic stability (Jak et al., 2009) and
et al., 2016). stronger relationships between cognition, biomark-
The reliance on cognitive screening measures, ers, and rates of progression to AD (Bondi et al.,
staging-based rating scales, and limited neuropsy- 2014) than MCI diagnosed by conventional criteria.
chological testing in diagnosing MCI across many Thus, diagnostic rigor for MCI can be dramatically
research studies may miss individuals with subtle improved through these methods (Bondi et al.,
cognitive declines or misdiagnose MCI in those 2014; L. R. Clark et al., 2013; Jak et al., 2016). In
who are otherwise cognitively normal on a broader addition, statistical techniques (e.g., cluster analysis,
neuropsychological battery of tests (Bondi & Smith, latent class analysis) can identify various cognitive
2014). The use of a single impaired test score to subtypes within MCI cohorts beyond the standard
determine an MCI diagnosis also likely contributes amnestic/nonamnestic distinction (L. R. Clark et al.,
to a high rate of false-positive errors because this 2013; Delano-Wood et al., 2009; Edmonds, Delano-
methodology ignores base rates of obtaining an Wood, et al., 2015; Libon et al., 2011, 2014).
impaired score in neurologically normal popula- Current diagnostic criteria lack clarity regard-
tions (Brooks, Iverson, Holdnack, & Feldman, 2008; ing how much functional dependence is sufficient
Brooks, Iverson, & White, 2007; Palmer, Boone, for a diagnosis of AD versus MCI. The NIA–AA
Lesser, & Wohl, 1998). For example, a study by criteria (McKhann et al., 2011) for MCI now per-
Brooks et al. (2007) found that 55.5% of healthy mit those with MCI to have mild difficulty with
older adults had at least one memory score that was complex IADLs, including minimal use of aids or
1 standard deviation below the mean across a battery assistance to complete tasks (Albert et al., 2011).
of memory tests, and 30.8% had at least one score Morris (2012) has argued that this updated defini-
that was 1.5 standard deviations below the mean. tion of functional independence has blurred the line
The inclusion of subjective cognitive complaints is between MCI and milder stages of AD dementia.

262
Clinical Assessment of Alzheimer’s Disease

In a large sample of patients with probable AD, Jack, Knopman, et al., 2013; see Figure 13.5). These
he showed that the majority (93%) of individuals criteria are currently intended for research purposes
diagnosed with mild AD dementia could be reclas- only and have no clinical or diagnostic utility at
sified with the new criteria as MCI on the basis of the present time (Sperling et al., 2011), although
their level of functional impairment. The elimina- this could change if a disease-altering medication is
tion of the clear functional boundary between MCI discovered.
and AD dementia means that this distinction will be
Limitations.  A limitation of the criteria for pre-
based solely on the individual judgment of clinicians
clinical AD is the lack of an operational definition
(Morris, 2012).
for subtle cognitive decline. NIA–AA guidelines
(McKhann et al., 2011) simply state that very subtle
Preclinical AD
cognitive impairment may be detected on sensitive
Diagnostic criteria.  Preclinical AD refers to a cognitive measures and that it is unclear whether
Copyright American Psychological Association. Not for further distribution.

condition in which individuals are considered cog- self-complaint of memory decline or other subtle
nitively normal but have biomarkers associated with neurobehavioral changes will be a useful predictor
AD (i.e., evidence of amyloid-beta or tau protein of progression (Sperling et al., 2011). Several stud-
alterations) and possible evidence of subtle cogni- ies have based subtle cognitive decline on a single
tive decline (Sperling et al., 2011). The NIA–AA global cognitive composite score or a memory com-
criteria (McKhann et al., 2011) for preclinical AD posite score when staging preclinical AD (Jack et al.,
propose a staging method based on the notion that 2012; Knopman et al., 2012; Toledo et al., 2014; Vos
the evolution of the pathophysiology of AD follows et al., 2013). By collapsing individual test scores,
an invariable temporal sequence in accordance with most of which would be within normal limits, into
the amyloid cascade hypothesis (Jack et al., 2010; composites, it is likely that their sensitivity to detect

Stage 1
Asymptomatic Amyloidosis
- High PET amyloid tracer retention
- Low CSF Aβ1-42

Stage 2
Amyloidosis + Neurodegeneration
- Neuronal dysfunction on FDG-PET/fMRI
- High CSF tau/p-tau
- Cortical thinning/Hippocampal atrophy on sMRI

Stage 3
Amyloidosis + Neurodegeneration + Subtle Cognitive Decline
- Evidence of subtle change from baseline level of cognition MCI  AD dementia
- Poor performance on more challenging cognitive tests
- Does not yet meet criteria for MCI

Figure 13.5.  Graphic representation of the proposed staging framework for preclinical Alzheimer’s disease (AD).
Aβ = amyloid beta; CSF = cerebrospinal fluid; FDG = fluorodeoxyglucose; fMRI = functional magnetic resonance
imaging; MCI = mild cognitive impairment; PET = position emission tomography; sMRI = structural magnetic
resonance imaging. From “Toward Defining the Preclinical Stages of Alzheimer’s Disease: Recommendations From
the National Institute on Aging–Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s
Disease,” by R. A. Sperling, P. S. Aisen, L. A. Beckett, D. A. Bennett, S. Craft, A. M. Fagan, . . . C. H. Phelps, 2011,
Alzheimer’s and Dementia, 7, p. 288. Copyright 2011 by Elsevier. Reprinted with permission.

263
Edmonds, Salmon, and Bondi

subtle decline is reduced. Instead, basing subtle show limited agreement and ought not be consid-
cognitive decline on individual neuropsychologi- ered interchangeable (Alexopoulos et al., 2014). In
cal test scores (Edmonds, Delano-Wood, Galasko, addition, cognitive symptoms are likely to occur
et al., 2015) might be a more sensitive definitional much earlier than proposed by the amyloid cascade
method for predicting risk of progression to MCI or hypothesis, and studies have shown that episodic
AD dementia. memory measures are as sensitive as other bio-
Another limitation of the criteria for preclinical markers (if not more sensitive) in predicting the
AD is reliance on the proposed temporal sequence development of AD (Gomar, Bobes-Bascaran, Cone-
of the evolution of the pathophysiology of AD. jero-Goldberg, Davies, & Goldberg, 2011; Gomar,
According to the amyloid cascade hypothesis (Jack Conejero-Goldberg, Davies, & Goldberg, 2014;
et al., 2010; Jack, Knopman, et al., 2013), amyloid- Heister, Brewer, Magda, Blennow, & McEvoy, 2011;
beta deposition occurs first and drives downstream Jedynak et al., 2012; Landau et al., 2010; Richard,
effects such as neurodegeneration and cognitive Schmand, Eikelenboom,
Copyright American Psychological Association. Not for further distribution.

symptoms (see Figure 13.6a). Although amyloid is & Van Gool, 2013; Schmand, Eikelenboom, & van
clearly associated with AD, whether it is the cause of Gool, 2011).
AD remains unknown (Drachman, 2014), and there Edmonds, Delano-Wood, Galasko, et al. (2015)
is accumulating evidence contradicting the temporal offered a new approach for staging preclinical AD
sequence proposed by the amyloid cascade hypoth- based simply on the number of abnormal bio-
esis. A number of studies have shown that neuro- markers an individual possesses (i.e., amyloidosis,
degeneration can occur in parallel with, or even neurodegeneration, subtle cognitive decline) with-
before, amyloidosis (Braak, Thal, Ghebremedhin, & out regard for the order of their appearance. This
Del Tredici, 2011; Jack, Wiste, et al., 2013; Ryan method is more parsimonious than the NIA–AA
et al., 2013; Sheline et al., 2010; Wirth et al., 2013), staging system and does not presume that all patients
although various markers of neurodegeneration follow a singular, invariant expression of AD.

(a) (b) Aβ metabolism/deposition

Detection Limit for Biomarker


Aβ metabolism/deposition
Tau metabolism/deposition Tau metabolism/deposition
Neuronal loss/atrophy Neuronal loss/atrophy
Amount of Pathology
Amount of Pathology

Cognitive symptoms Cognitive symptoms

Time/Clinical Stage Time/Clinical Stage

Figure 13.6.  Two hypothetical models of dynamic biomarker changes during the Alzheimer’s disease (AD) patho-
logical cascade. (a) The original amyloid cascade model is based on the hypothesis that AD biomarkers directly
reflect the amount of AD pathology in the brain. In this model, amyloid-beta (Aβ) pathology (as measured by cere-
brospinal fluid Aβ42 or amyloid positron emission tomography) precedes tau pathology (measured by cerebrospinal
fluid tau), neuronal loss (measured by MRI), and clinical symptoms by a relatively extended period of time. (b) An
alternative model is based on the hypothesis that AD pathology (Aβ deposition, tau pathology, neuronal degenera-
tion and loss) affects an increasing number of neurons in a narrow time sequence. According to this model, Aβ
aggregates and plaques, hyperphosphorylated tau with tangles and neuropil threads, and neuronal and synaptic
degeneration and loss all spread simultaneously and extend through the brain. In this scenario, the differences
found between patients at different stages of the disease may be caused or influenced by varying sensitivity of the
biomarkers for a given number of involved neurons. From “Intraneuronal Tau Aggregation Precedes Diffuse Plaque
Deposition, but Amyloid-β Changes Occur Before Increases of Tau in Cerebrospinal Fluid,” by H. Braak,
H. Zetterberg, K. Del Tredici, and K. Blennow, 2013, Acta Neuropathologica, 126, p. 638. Copyright 2013 by
Springer. Reprinted with permission.

264
Clinical Assessment of Alzheimer’s Disease

This staging system is consistent with an alternative intended only for research purposes at the present
model of AD pathogenesis (Braak, Zetterberg, Del time, refers to asymptomatic individuals who test
Tredici, & Blennow, 2013) in which detectable AD positive for AD biomarkers. Clinical assessment
markers (amyloid-beta and tau biomarkers, neuro- of AD during this prodromal period should use
nal loss, and cognitive symptoms) all spread almost multiple sensitive neuropsychological tests and
simultaneously and in a very narrow time sequence move away from the use of brief cognitive screening
(see Figure 13.6b). Any perceived difference in the measures or a single test score to determine impair-
time of occurrence of biomarker abnormalities may ment. Follow-up testing could be recommended for
be due to variability in the sensitivity of various cases in which an individual presents with subjec-
biomarkers and our ability to detect change (Braak tive complaints in the face of normal cognitive test
et al., 2013). scores or for cases in which scores are considered
to be subtly reduced but without clear evidence of
impairment.
Copyright American Psychological Association. Not for further distribution.

CONCLUSION AND FUTURE DIRECTIONS


Future research efforts are needed to further
AD is an age-related degenerative brain disorder develop actuarial methods for assessment and diag-
that is the most common cause of dementia. The nosis that are less dependent on clinical judgment
most updated diagnostic criteria for dementia/major or subjective report. This is particularly important
NCD due to AD were published by the American as the field becomes increasingly focused on early
Psychiatric Association (DSM–5; American Psychi- disease states in which the boundary between nor-
atric Association, 2013) and the NIA–AA (McKhann mal aging and prodromal AD is unclear. Additional
et al., 2011). Although both provide core clinical research is also needed to explore alternate models
criteria, the NIA–AA guidelines have begun to incor- of AD pathogenesis and novel biomarkers rather
porate biomarkers of AD into the diagnosis. The than presuming that all patients follow a common
current suggested use of biomarkers is to enhance disease progression. The field will undoubtedly con-
the diagnostician’s confidence regarding whether tinue to shift toward increased use of biomarkers
a patient’s dementia is due to an underlying AD to identify and diagnose dementia and predementia
pathophysiological process. Thus, the clinical assess- states; however, we must not lose sight of the value
ment and diagnosis of AD remain critical core fea- of neuropsychology and comprehensive clinical
tures of the diagnostic process. assessment to identify cognitive decline, character-
Neuropsychological assessment of AD enables ize unique cognitive profiles, and monitor disease
the clinical differentiation of individuals with the progression.
disease from those who are aging normally or those
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