Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer’s disease: a selective review
Alzheimer's Research & Therapy
Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer's disease: a selective review
Dorene M Rentz 0 3
Mario A Parra Rodriguez 2
Rebecca Amariglio 0 3
Yaakov Stern 1
Reisa Sperling 0 3
Steven Ferris 4
0 Center for Alzheimer Research and Treatment, Departments of Neurology, Brigham and Women's Hospital and Massachusetts General Hospital, Harvard Medical School , 221 Longwood Avenue, Boston, MA 02115 , USA
1 Cognitive Neuroscience Division, Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons , 630 West 168th Street, New York, NY 10032 , USA
2 Department of Psychology, University of Edinburgh, Centre for Cognitive Aging and Cognitive Epidemiology, Alzheimer Scotland Dementia Research Centre and Scottish Dementia Clinical Research Network , 7 George Square, Edinburgh EH8 9JZ , UK
3 Center for Alzheimer Research and Treatment, Departments of Neurology, Brigham and Women's Hospital and Massachusetts General Hospital, Harvard Medical School , 221 Longwood Avenue, Boston, MA 02115 , USA
4 Alzheimer's Disease Center, Comprehensive Center for Brain Aging, Department of Psychiatry, NYU Langone Medical Center , 145 East 32nd Street, New York, NY 10016 , USA
Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer's disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer's disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer's disease in presymptomatic individuals.
Over the next 30 years, more than 20 million Americans
are at risk for developing Alzheimer’s disease (AD)
dementia and there is no effective disease-modifying
treatment. Recently published guidelines suggest that the
best time to intervene in AD might be during a
preclinical phase [
], when the underlying pathophysiological
changes are occurring up to 15 years in advance of
clinical symptoms [
]. With the advent of in vivo amyloid
imaging, approximately 20 to 30% of all cognitively
normal older individuals harbor a significant burden of
amyloid pathology, a hallmark of AD [
], and these
individuals are now the target population for planned
secondary prevention trials in the treatment of AD .
As these treatment trials are being contemplated, they
will focus on recruiting individuals who have no
detectable cognitive impairment on our standardized
instruments but instead display biomarker evidence as being
at risk for progressing to AD dementia. AD treatment
trials in the past have used cognitive tests and
questionnaires that may not be optimal for these
currently planned studies, which are aimed at detecting
subtle cognitive changes in clinically normal individuals
and reliably tracking treatment change over time. The
field has therefore been challenged to modify and
improve the sensitivity of our current standardized tests
through the use of sophisticated psychometric
techniques or to develop a new generation of cognitive
instruments and questionnaires that can be used in these
Cognitive and behavioral assessments have long been
considered the gold standard for the diagnosis and
prediction of AD progression. However, numerous studies
have failed to find a relationship between cognitive
performance and biomarker evidence of AD in clinically
asymptomatic at-risk individuals [
]. In part, the
relationship between early amyloid-beta (Aβ) deposition and
performance on traditional standardized cognitive tests
was found to be influenced by cognitive reserve (CR)
]. The concept of CR was initially introduced as a
possible explanation for the delayed onset of dementia
among individuals who had high occupational or
educational attainment. One theory is that those with
high CR may tolerate AD pathology for longer before
demonstrating declines on cognitive testing , and
thus may interfere with our ability to detect subtle
cognitive changes thought to be associated with
preclinical AD [
]. Therefore, as we develop tests sensitive to
the early cognitive changes associated with biomarker
evidence of preclinical AD, we will need to use better
approaches for measuring CR or our new tests will need
to take into account age, education, sex and race/
ethnicity effects on performance, all of which will
provide some relative anchoring of an individual’s
performance vis-à-vis CR.
Ultimately, these newly developed measures will need
to be simple, cost-effective, and capable of capturing the
subtle changes that can differentiate healthy aging from
preclinical AD. These tests also need to be useful across
all ethnicities and educational strata as well as proving
sensitive to change over the short timeframe of a clinical
trial. Given the significant advances made toward the
in vivo detection of biomarkers in preclinical AD (that
is, amyloid imaging, cerebral spinal fluid (CSF) amyloid/
tau, magnetic resonance imaging (MRI) volume loss)
], a recent meta-analysis indicated that early
amyloid pathology, a biomarker of preclinical AD,
appears to have a greater influence on memory-related
] in clinically normal older adults than other
cognitive domains. The authors therefore selected the
Memory Capacity Test [
Face Name Associative
Memory Exam (FNAME) [
Verbal associative binding
Binding test [
Visual recognition, change
detection, feature binding
Separation-Object test [
Spatial Pattern Separation
Transfer task [
Visual recognition, pattern
separation, spatial discrimination
Dual tasking task [
instruments presented here because they were essentially
tests of memory that were derived from knowledge
gained through these translational efforts in
neuroimaging, neuroscience, and clinical and experimental
neuropsychology. The instruments were also designed to
target the neural pathways involved in the basic
components of memory including encoding (that is, learning of
new information), retrieval (that is, accessing information)
and storage (that is, recognition of information), as
well as additional features including associative binding,
semantic encoding, pattern separation and spatial
discrimination that may be vulnerable in preclinical AD
cohorts. We included tests of executive function because the
meta-analysis suggested that these tests [
] also had a
significant although weaker association with amyloid
deposition than episodic memory. No other cognitive
domains were related to biomarker evidence of preclinical
AD. Finally, we have included a section on
patientoriented outcome measures related to subjective cognitive
concerns because there is recent interest in and support
for these very early complaints in clinically normal
individuals perhaps also heralding evidence of preclinical AD
and risk of subsequent cognitive decline.
Hence, the overall goal of this article is to present
a selective summary of just some of the newer,
potentially promising approaches for detecting cognitive
34 HC, decrements in second-list learning associated with amyloid burden
45 HC, decrements in face name versus face occupation associated with amyloid
210 HC, good test–retest and discriminate validity for name, occupation and
summary scores, useful across all educational strata
129 HC, FNAME performance summary scores were associated with reduced
hippocampal volume and APOE4 carrier status
30 asymptomatic carriers with E280A mutation showed impairment in visual
short-term memory binding, suggesting short-term memory binding may be a
preclinical marker for familial AD
31 HC, impairments in pattern separation were noted in those with
weaker RAVLT Delayed Recall Scores. Recognition Memory was normal.
In 23 aMCI individuals, pattern separation deficits improved in those
exposed to drug treatment during a clinical trial
37 HC, Spatial Pattern Separation performance was associated with reduced
bilateral hippocampal volume and with the CSF Aβ42/pTau181 ratio. Paragraph
recall was not sensitive to these biomarker correlates
37 HC, reduced transfer performance was associated with mild-to-moderate
hippocampal atrophy in CN and associated with clinical impairment 2 years later.
Performance also correlated with CSF Aβ42 and the Aβ42/pTau181 ratio
39 E280A mutation carriers showed dual tasking impairments despite normal
performances on other standard neuropsychological tests of cognition and
memory. Dual tasking performance discriminates asymptomatic carriers with
familial AD from healthy controls
Aβ, amyloid beta; AD, Alzheimer’s disease; aMCI, amnestic mild cognitive impairment; APOE4, apolipoprotein E4; CN, cognitively normal; CSF, cerebrospinal fluid;
HC, healthy older controls; RAVLT, Rey auditory verbal learning test.
evidence of preclinical AD in presymptomatic individuals
(see Table 1). Presenting an exhaustive list of all tests and
measures that have demonstrated the ability to detect
cognitive decline at the stage of mild cognitive impairment
(MCI) is beyond the scope of this review, but rather we
select a few tests/questionnaires that have shown promise
for having an association with biomarker evidence of
preclinical AD. Some of these tests were developed recently,
and therefore are not fully validated, and some are
unpublished. However, these tests are included here because they
show promise in targeting neural pathways that might be
useful in early detection studies.
Tests of memory associated with evidence of
preclinical Alzheimer’s disease
Memory Capacity Test
The Memory Capacity Test from Herman Buschke was
recently published as showing sensitivity to Aβ
deposition on amyloid imaging in normal older adults [
Similar to the Free and Cued Selective Reminding Test,
the Memory Capacity Test improves encoding specificity
by means of pairing the word to be remembered with a
category/semantic cue [
], inducing deep semantic
encoding to maximize learning and retrieval.
The Memory Capacity Test uses two 16-item word lists
(32 pairs) to be remembered from the same category cues
as the first list. The test measures associative binding with
the objective that decrements in the second-list recall
would be more sensitive to the early pathological changes
associated with preclinical AD. In fact, individuals with
greater Aβ burden on amyloid imaging showed normal
recall on the first list but lower than normal binding scores
on the second list despite performing normally on other
standardized tests of memory [
Tests that challenge the associative binding system, such
as the Memory Capacity Test, show promise for being able
to distinguish older adults in the preclinical phase of AD.
Face Name Associative Memory Exam
The Face Name Associative Memory Exam (FNAME)
] is a cross-modal associative memory test based on a
functional magnetic resonance imaging (fMRI) task that
pairs pictures of unfamiliar faces with common first
names. Previous fMRI work from multiple groups has
suggested that the successful formation and retrieval of
face–name pairs requires the coordinated activity of a
distributed memory network [
]. This network
includes not only the hippocampus and related structures
in the medial temporal lobe, but a distributed set of
cortical regions, collectively known as the default mode
]. The face–name fMRI task has shown
sensitivity to longitudinal clinical decline in MCI [
well as in those at genetic risk for AD [
], and is
associated with Aβ burden in clinically normal older
The FNAME is a short behavioral version of the fMRI
task that requires the individual to remember 16
unfamiliar face–name pairs and 16 face–occupation pairs,
for a total of 32 cross-modal paired associates to be
remembered (see Figure 1).
The distribution of scores on the FNAME in clinically
normal adults did not exhibit the same ceiling effects, in
contrast to other standardized tests of memory in this
asymptomatic cohort [
], and is useful over a range of
education and CR. Performance for face–names as well as
a summary score of names and occupations showed good
test–retest reliability [
] and was correlated with Aβ
burden on amyloid imaging [
], reduced hippocampal
volume on MRI, as well as APOE4 carrier status in
cognitively normal older adults [
]. A simpler 12-item
version of the FNAME was developed for face–name pairs
only, similar to the original fMRI task. A computerized
version of the FNAME is being developed on the iPad
(Apple, Cupertino, CA, USA) in conjunction with
CogStateW (Cogstate Ltd, Melbourne, Australia) and will
be used as a secondary outcome measure in the
Dominantly Inherited Alzheimer Network and the Anti-Amyloid
Treatment in Asymptomatic AD secondary prevention
trials, purposely designed to treat presymptomatic
individuals at risk for AD. Further validation work is being done
to determine whether this alternate version of the
FNAME will be useful for measuring clinical change over
the course of a clinical trial in asymptomatic individuals at
risk for AD.
this novel methodology can predict who among those
with MCI will go on to develop AD.
The Short-Term Memory Binding test
The Short-Term Memory Binding (STMB) test is a
recognition task that relies on a change detection paradigm.
The individual is presented with two consecutive visual
arrays of stimuli, which appear simultaneously on the
screen and are composed of polygons, colors or
combinations of polygon–color targets. The two visual arrays,
which are separated by a short delay, are either identical
or different, as the stimuli in the second array may
change. The individual is asked to decide whether or not
there have been changes in the second array. Memory
performance of only the polygons and colors are
contrasted with performance of the polygon–color
combinations. The STMB test assesses feature binding in
short-term memory, and recent evidence suggests that
this engages the subhippocampal stages of AD [
rather than the hippocampus [
] (see Figure 2).
Contrary to other standard neuropsychological
functions, binding deficits on the STMB test do not appear
to be a general characteristic of age-related memory
changes in healthy aging [
] but the test is impaired
in sporadic and familial AD as well as asymptomatic
carriers of the Presenilin-1 mutation E280A more than
10 years prior to the onset of AD [
]. The STMB
test is also able to discriminate subjects with preclinical
AD from other cohorts [
], between healthy aged
individuals and those with chronic depression [
], as well
as between patients with AD and non-AD dementias
]. In addition, the STMB test is impervious to
differences in age and factors of CR, such as education and
cultural background [
]. The STMB task is also not
affected by practice or learning effects because the
repeated presentation of meaningless stimuli such as
polygon–color combinations is quickly overwritten,
leaving no memory trace from previous exposures [
The STMB binding task is being currently used in a
multicenter international trial that investigates whether
Behavioral Pattern Separation-Object task
The Behavioral Pattern Separation-Object (BPS-O) is a
visual recognition memory test designed to tax pattern
]. The individual is presented with pictures
of common everyday objects interspersed with highly
similar lures that vary in levels of mnemonic similarity
and the amount of interference with target items. When
stimuli were made very different from each other, there
was no difference in performance between young and
older adults. However, as the stimuli became more
similar, performance in older adults was more impaired. This
object discrimination task in older adults has shown
evidence of robust hippocampal/dentate gyrus/CA3
activation in fMRI studies and sensitivity to early dysfunction
in the perforant pathway in aging and amnestic MCI
Given the task’s sensitivity to early dysfunction in the
perforant pathway, a behavioral version was recently
]. The BPS-O consists of two phases. In the
first phase, individuals engage in an indoor/outdoor
judgment of common everyday objects. Immediately following
this encoding task, individuals are presented with a
recognition memory task, in which they must identify each item
as old, similar or new. One-third of the items are exact
repetitions of items previously presented, one-third of
items are new objects never seen before and one-third are
perceptually similar but not identical to the target items
(that is, lures). The inability to discriminate the lures from
the actual target objects indicates a failure in pattern
separation (that is, the inability to encode all the details of the
object that make it unique; see Figure 3).
In cognitively normal older adults, pattern separation
linearly declined with increasing age [
recognition memory did not (that is, subjects correctly
recognized whether they saw the object or not). Interestingly,
individuals with amnestic MCI had both impaired
pattern separation and recognition memory.
In contrast to other traditional tests of memory, the
BPS-O allows for the assessment of both recognition
memory and pattern separation, making it somewhat
unique as a memory measure. The BPS-O also predicts
underlying neural function, suggesting that pattern
separation performance may serve as a proxy for the
integrity of the perforant pathway to the dentate gyrus.
Whether the BPS-O may help distinguish normal
agerelated changes from those in preclinical stages of AD is
yet to be determined, but the test does provide an early
signal of memory impairments. The BPS-O has been
successfully used in a recent MCI intervention trial as
an outcome measure [
]. In that trial, pattern
separation deficits improved in those MCI subjects exposed
to the drug. The BPS-O therefore shows promise for
being able to assess change over the brief timeframe of a
clinical trial. A computerized version of the BPS-O is
also being developed on the iPad with CogStateW
measures to be used as a secondary outcome measure in the
Dominantly Inherited Alzheimer Network and the
AntiAmyloid Treatment in Asymptomatic Alzheimer’s
Disease prevention trials.
Spatial Pattern Separation task
The process of separating similar and overlapping
representations into discrete, nonoverlapping representations
is a key component of memory formation that is affected
in normal aging [
]. A pattern separation task with a
spatial component has shown potential sensitivity to
preclinical AD [
]. This task requires subjects to
discriminate the novel locations of target stimuli. The
Spatial Pattern Separation task was adapted from rodent
work showing that selective lesions of the dentate gyrus
interfere with the ability to discriminate nearby spatial
]. The spatial discrimination element of the
pattern separation task may make it more sensitive to
early AD pathology because AD-vulnerable regions such
as the hippocampus and entorhinal cortex are critically
important for spatial memory [
In each trial of the Spatial Pattern Separation task,
subjects view a dot on a computer screen for 3 seconds,
followed by a delay of 5 to 30 seconds (during which
they read numbers displayed on the screen). Two
identical dots then appear, one in the prior location and one
in a new location (one of three distances). Individuals
must identify the dot at the prior location (see Figure 4).
A recent study examined task performance on the
Spatial Pattern Separation task in relation to MRI
hippocampal volume and CSF measures of amyloid and tau in
37 cognitively normal older individuals [
regression analyses (controlling for age and years of education)
demonstrated significant relationships between task
performance and both bilateral hippocampal volume
and CSF Aβ42/pTau181 ratio, a composite measure
of amyloid and tau pathology. In contrast to the Spatial
Pattern Separation task, a standard paragraph recall test
that is sensitive to the MCI stage of AD [
] was not
sensitive to these biomarker correlates of preclinical AD.
Similar to the BPS-O task, these findings suggest that
spatial discrimination in a pattern separation task may
also be a sensitive probe for detecting preclinical AD.
Discrimination and Transfer task
The hippocampus and entorhinal cortex are especially
important for generalizing familiar associations in
]. Dysfunction in these areas leads to deficits
in generalization when familiar information is presented
in new ways [
]. In this Discrimination and
Transfer task [
], subjects learn to discriminate pairs
of stimuli determined by shape or color in the
discrimination phase and then have to transfer this learned
information (the preferred shapes/colors) to novel stimuli in
the transfer phase (see Figure 5).
Prior work showed that mild–moderate hippocampal
atrophy in nondemented older individuals disrupts
performance on the transfer phase in this task [
longitudinal follow-up, poor transfer was associated with
clinical impairment 2 years after initial testing [
These results suggest that this task is sensitive to mild
hippocampal atrophy and thus might be a sensitive
cognitive marker of pathology associated with preclinical
AD. This task was included in the study described above
in normal older individuals (n = 37) [
]. In similar
linear regression analyses, performance correlated
significantly with CSF Aβ42 and the Aβ42/pTau181 ratio,
suggesting sensitivity to preclinical AD.
As AD clinical trials move toward treating presymptomatic
individuals, cognitive outcome measures will need to be
sensitive for detecting drug effects in cognitively normal
subjects. This is problematic if presymptomatic
individuals, by definition, are scoring within population-based
normative standards. Alternatively, computerized test
assessments that provide frequent serial measurements of
intra-individual performance over brief time intervals may
be uniquely suited for detecting subtle changes in cognitive
functioning over the course of a clinical trial. In other
words, the measurement of individual variations in
performance (that is, either practice effect, the lack of practice
or decline) may be more preferable for measuring drug
efficacy than determining whether a test score has crossed
an arbitrary threshold [
A number of computerized cognitive tests have been
developed for use in aging populations and clinical trials,
which are comprehensively reviewed elsewhere [
These test batteries often include reaction timed tests,
continuous monitoring and working memory tasks, as
well as incidental and associative learning. A common
advantage of computer batteries is that they provide
precision for measuring reaction time and are nonlanguage
based so they can be used worldwide. One such
commercial battery, CogStateW, is being used in the
Australian Imaging and Biomarkers Lifestyle study. Decreased
performance on specific subtests has been reported in
APOE ε4-positive individuals and cognitively normal
adults with extensive amyloid deposition on amyloid
positron emission tomography scans [
]. In addition,
multiple assessment on a single day was able to successfully
differentiate MCI from normal controls by showing a lack
of practice effect [
Four of the CogStateW tests that measure reaction time,
working memory and incidental learning are being
developed for the iPad along with the FNAME and BPS-O
to be used in the Anti-Amyloid Treatment in
Asymptomatic Alzheimer’s Disease and the Dominantly Inherited
Alzheimer Network studies. A composite of these
computerized tests along with the hippocampal-based episodic
memory measures may provide a sensitive metric for
detecting change during the course of these secondary
Other potentially useful measures for the
detection of preclinical Alzheimer’s disease
Executive function tasks
While tests of episodic memory have a stronger
association with biomarker evidence of preclinical AD,
retrospective studies indicate that executive functions may also
be declining. In particular, decline on tests of word fluency
(that is, F-A-S and category generation), Trailmaking
speed and Digit Symbol accelerated 2 to 3 years prior to
AD diagnosis [
], as did abstract reasoning over a
22year surveillance period [
]. However, the association of
decline in executive function tasks with biomarker
evidence of preclinical AD has been unclear. In a
longitudinal analysis, higher Aβ deposition in the frontal and
parietal regions was associated with longitudinal decline
on Trails B but not at baseline [
]. A recent
metaanalysis showed that the association of Aβ deposition with
episodic memory had a significantly larger effect size but
tests of executive function also showed a significant
although weaker association, as measured by a broad range
of cognitive tasks [
]. Some believe that this weaker
association with executive functions in preclinical AD
may suggest that declines in executive functions occur
later, relative to memory decline in preclinical AD [
On the other hand, an association between white matter
hyperintensities and executive function was found,
suggesting that a separate neuropathological cascade may
occur apart from amyloid accumulation in aging that is
associated with cerebrovascular disease [
One challenging executive task that does show
promise for detecting subtle changes related to preclinical AD
is a dual task paradigm. Dual tasking requires an
individual to perform two tasks simultaneously (for example, a
visuospatial task and a verbal task together) on the
premise that cognitive resources are limited and that the
interference between the two tasks will cause dual task
coordination deficits. A recent study demonstrated that
dual tasking impairments occurred in asymptomatic
carriers of the E280A Presenilin-1 mutation of familial AD
], despite normal performances on other
neuropsychological and episodic memory tasks. Dual tasking
deficits do not normally occur in healthy aging, are
impervious to ceiling and practice effects, and show good
specificity relative to chronic depression in older
]. Whether dual task paradigms will be sensitive
to older adults with preclinical AD is unknown, but the
ability of these tasks to discriminate asymptomatic
carriers with familial AD from healthy controls is
promising. These findings suggest that we may require more
challenging tests of executive function to detect subtle
changes at the preclinical AD stage in asymptomatic
individuals, similar to episodic memory tasks. More
research is needed to determine whether tasks such as the
Flanker Inhibitory Control Test and the Dimensional
Change Card Sort Task from the National Institutes of
Health Toolbox [
] would be sensitive to changes in
executive function in the preclinical stages of AD.
Another area of increasing interest is the endorsement
of subjective cognitive concerns (SCC) that may prove
to be important indicators of an individual’s perception
of change during this preclinical stage [
]. Several large
longitudinal studies have demonstrated that baseline
SCC predict subsequent cognitive decline [
show promise in detecting AD biomarker positivity at
the preclinical stage. For example, cognitively normal
individuals who report SCC have reduced hippocampal,
parahippocampal, and entorhinal cortex volume on
MRI , increased Aβ burden [
] and reduced
glucose metabolism in parietotemporal regions and the
parahippocampal gyrus on positron emission
tomography imaging, as well as altered fMRI activity in the
default mode network [
There are multiple methods for assessing SCC that
range from asking a single question to more formal
]. Efforts are underway to
systematically identify which SCC may be the most sensitive in
the context of preclinical AD. While subjective memory
concerns have been investigated most often, there are a
few studies that suggest other cognitive domains, such
as executive functions, may also be useful [
Additionally, advanced statistical techniques may help
identify specific SCC items that are sensitive at the
preclinical stage [
This selected review has highlighted some of the
promising measures that are being developed to detect the
earliest changes associated with biomarker evidence of
the preclinical stages of AD in clinically normal older
adults. While this is not meant to be an exhaustive
survey of potential measures, the review is meant to
highlight some promising recent efforts and to emphasize
the critical need to develop a new collection of cognitive
tasks that are cost-effective, available within the public
domain, useful across all levels of CR and derived from
translational efforts in cognitive neuroscience. Many of
the tests described here will require additional
validation, but with the start of secondary prevention trials
we now have a unique opportunity to use these trials to
determine whether these measures will be useful for
detecting preclinical AD and tracking cognitive change
In addition, future efforts are exploring whether more
complex activities of daily living (that is, financial
competency, navigating complex telephone trees) and other
subjective and informant questionnaires related to
engagement (that is, physical activities, cognitive stimulation)
or emotional states (that is, social isolation, apathy,
withdrawal) may be associated with biomarker evidence
of preclinical AD. More advanced psychometric
techniques, such as Item Response Theory [
Confirmatory Factor Analysis [
], are now being used to
create more sensitive instruments from our current
standardized tests as well as composite measures that may
capture the individual variance of change in clinically
normal individuals [
]. Home assessments and the use
of iPad and tablet technologies are also being explored
to determine whether more frequent/multiple cognitive
assessments may provide a more reliable estimate of
change and whether they can be performed without the
aid of a technician or extensive travel to a clinic. While
many of these efforts are still in development, clinical
researchers are attempting to meet the challenge of
developing instruments and questionnaires that may be
sensitive to biomarker evidence of early AD. Finally, it
will probably be a combination of these objective and
subjective measures/questionnaires that will be the most
valuable for tracking cognitive change over time.
AD: Alzheimer’s disease; APOE: Apolipoprotein E allele;
APOE4: Apolipoprotein E4 carrier status; Aβ: Amyloid beta; BPS-O: Behavioral
Pattern Separation-Object; CR: Cognitive reserve; CSF: Cerebral spinal fluid;
fMRI: Functional magnetic resonance imaging; FNAME: Face Name
Associative Memory Exam; MCI: Mild cognitive impairment; MRI: Magnetic
resonance imaging; SCC: Subjective cognitive concerns; STMB: Short-Term
Memory Binding; ε4: Carriers of the E4 apolipoprotein E gene.
The authors declare that they have no competing interests.
The authors wish to thank all of the subjects who make research possible.
MAPR is currently a Fellow of Alzheimer’s Society, UK, Project Grant Number
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