Advances in Alzheimer’s Disease, 2014, 3, 168-186

Published Online December 2014 in SciRes. http://www.scirp.org/journal/aad

http://dx.doi.org/10.4236/aad.2014.34016

Cognitive and Functional Profiles in

Mild-to-Moderate Alzheimer’s Disease
and Mild Cognitive Impairment
Compared to Healthy Elderly
Mark Marsico1*, Celeste A. de Jager2,3, April Grant1, Xingshu Zhu4, Arwen Markwick2,
Julie Chandler1
1
Epidemiology Department, Merck Research Laboratories, North Wales, USA
2
OPTIMA, Nuffield Department of Medicine, University of Oxford, Oxford, UK
3
Division of Geriatric Medicine, Department of Medicine, Faculty of Health Sciences, University of Cape Town,
Cape Town, South Africa
4
Statistical Programming, Merck Research Laboratories, North Wales, USA
Email: *[email protected]

Received 24 October 2014; revised 26 November 2014; accepted 9 December 2014

Academic Editor: Lei Xue, School of Life Science, Tongji University, China

Copyright © 2014 by authors and Scientific Research Publishing Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/

Abstract
Background: Amnestic mild cognitive impairment (aMCI) and mild-to-moderate Alzheimer’s dis-
ease (AD) are clinically distinct but impact cognitive and functional ability similarly. Comprehen-
sive assessment of cognitive and functional deficits may prove useful in informing differential di-
agnosis in early stages of dementia and in informing endpoint selection in therapeutic AD trials.
Objective: The objective of this study was to characterize patterns of cognitive and functional im-
pairment in aMCI and mild-to-moderate AD subjects compared to cognitively intact healthy elder-
ly (HE). Methods: Thirty-one healthy elderly, 20 aMCI and 19 AD participants were administered a
cognitive test battery that included the ADAS-Cog and functional assessments. Z-scores were cal-
culated for all endpoints based on the HE reference group. Results: Cognitive deficits were ob-
served in AD and aMCI participants relative to the referent group. On average, aMCI participants
performed 1 - 2 standard deviations below HE on cognitive tests, and AD participants performed 2
- 3 standard deviations below HE. Domain-specific functional deficits among AD participants (z-
score −0.4 to −6.4) were consistently greater than those of aMCI participants (z-score 0 to −1.7).
Conclusion: This study provides further support for comprehensive assessment and monitoring of
*
Corresponding author.

How to cite this paper: Marsico, M., de Jager, C.A., Grant, A., Zhu, X.S., Markwick, A. and Chandler, J. (2014) Cognitive and
Functional Profiles in Mild-to-Moderate Alzheimer’s Disease and Mild Cognitive Impairment Compared to Healthy Elderly.
Advances in Alzheimer’s Disease, 3, 168-186. http://dx.doi.org/10.4236/aad.2014.34016
 M. Marsico et al.

cognitive and functional domain scores in the diagnosis and treatment of aMCI and mild AD. Do-
main-specific cognitive scores may be more useful than composite scores in characterizing im-
pairment and decline. Measuring domains such as attention, processing speed and executive
function may increase the sensitivity of detecting disease progression and therapeutic effects,
particularly in mild-moderate AD where memory decline may be too slow to detect drug effects
during a typical clinical trial.

Keywords
Alzheimer’s Disease, Amnestic Mild Cognitive Impairment, Dementia, Cognition

1. Introduction
Mild Cognitive Impairment (MCI) is characterized by changes in cognition which are less severe and wide-
spread than those of Alzheimer’s disease (AD), but represent a decline from cognitive functioning of normal
aging and predisposes one to the risk of developing AD [1]. Initially, recognition of MCI was identified by de-
tection of memory performance below age-associated norms [2]. However, recent revisions of this syndrome
acknowledge that deficits may also occur in other cognitive domains [3].
Cognitive decline is known to be preceded by neuropathology including beta-amyloid plaque deposition,
neurofibrillary tangle formation and atrophy in the brain. Novel research with neuroimaging and CSF markers of
pathology has led to revised research criteria for AD diagnosis [4]. The criteria include memory impairment as
assessed with sensitive episodic memory tests. This new diagnostic framework has stimulated debate about the
definition of AD and related conditions. The Mini-Mental State Examination (MMSE) and Alzheimer’s Disease
Assessment Scale-Cognitive subscale (ADAS-Cog) have typically been used as outcome measures in AD drug
intervention trials [5]; however, these measures may be insensitive for detecting early and subclinical changes [6].
It is widely accepted that the typical cognitive profile in early AD is marked by episodic memory impairment
with semantic memory, working memory, executive functioning, and visuospatial and attentional dysfunction
emerging as the disease progresses [7]-[9]. The heterogeneity of cognitive decline suggests endpoints that com-
prehensively assess cognition may be best suited for detecting cognitive change [10]-[12].
AD is also marked by deficits in functional ability, characterized by progressive deterioration of activities of
daily living (ADL), including early decline in instrumental activities, and later activities relating to basic self-
care [13]. Once loss of ADL occurs and independent living is problematic, diagnosis will include dementia.
ADL impairments associated with MCI may occur for instrumental activities that require high-level cognitive
skills [14] [15] such as use of technology, understanding cultural expectations [16], managing money [17], me-
dication use [18] and executive functioning [13]. As with cognitive measures, indications of differential profiles
of functional impairment have also been found for AD as compared to other dementia groups [19].
Countless cognitive tests have been used worldwide [20] to assess cognitive change in observational studies
and clinical trials. In many instances, cognitive tests are included alongside the MMSE and ADAS-Cog in order
to evaluate the potential utility of the measures as compared to these “gold standard” trial endpoints. An objec-
tive of the Oxford Project to Investigate Memory and Aging (OPTIMA) study was to identify cognitive tests
capable of discriminating between cognitively healthy and cognitively impaired groups [21]-[23] as a first step
in identifying the tests most likely to identify preclinical AD and to aid in diagnosis of dementia types. For this
study, an adjunct to the original OPTIMA cohort, a selection of cognitive measures was added to the OPTIMA
battery with the objective of identifying psychometrically sound cognitive measures for use as cognition end-
points in future AD clinical trials.
The purpose of this analysis was to determine, in a single cohort of participants, the pattern of cognitive and
functional impairment of amnestic MCI-subtype (aMCI) and AD participants, using scores from HE as a refer-
ence. Clarification of cognitive and functional profiles is important for accurate differential diagnosis and moni-
toring decline across dementia syndromes [8] [24]-[27]. Furthermore, comprehensive understanding of domain-
specific cognitive and functional profiles in aMCI and AD is the first step in identifying particular measures that
are sensitive to impairment and the domains that can be utilized as endpoints to better characterize disease and
assess impact on the early treatment to mild AD in clinical trials.

169
M. Marsico et al.

2. Materials and Methods

2.1. Participants
Participants were recruited from a larger cohort of living subjects enrolled in the Oxford Project to Investigate
Memory and Aging (OPTIMA) study within the United Kingdom [28], a longitudinal study of memory and ag-
ing established at the University of Oxford. All enrolled subjects undergo a clinical and informant-based inter-
view, a comprehensive cognitive assessment including the Cambridge Cognitive Examination (CAMCOG) [29]
[30] and ADAS-Cog, physical examination, MRI brain scan and blood-screening tests as part of the scheduled
protocol for diagnostic purposes. Potential participants for the current prospective study were identified from the
OPTIMA participant database according to clinical diagnosis at last visit. Those with Mini-Mental State Ex-
amination (MMSE) [31] score of ≥16 (N = 224) had their medical records screened for inclusion/exclusion cri-
teria and rescreened to assess suitability for inclusion in the study. Sixty one subjects were excluded (27%)
based on a review of their medical record. A further 73 (33%) were excluded after not responding to study invi-
tation letters and telephone calls. The most common reasons for exclusion based on the chart review and tele-
phone screen were: acute illnesses, recent stroke, advanced cancer, other dementia diagnosis than AD, advanced
dementia or unwillingness to participate. The remaining 90 subjects (40%) were screened by telephone. Current
dementia medication and administration of the Telephone Interview for Cognitive Status-Modified (TICS-M)
[32] were used to establish a preliminary diagnostic classification.
General inclusion criteria applicable to all subjects for this sub-study, except where noted, were 60 years of
age or older, no medical condition affecting cognition (excluding AD), a reliable informant willing to act as a
study partner (not required for HE), adequate sensory and motor capabilities to perform cognitive testing, fluen-
cy in English as determined by the investigator; and the ability to understand study procedures and give verbal
consent to participate. Exclusions included: a history of disease that might confound study results, a significant
psychiatric history, recent (within 2 years) or current evidence of major untreated depressive or psychiatric dis-
order, uncontrolled or untreated endocrine disease or other medical condition causing transient or continuous al-
teration of consciousness or attention, recent (within 2 years) or current evidence of major stroke, multiple lacu-
nar infarcts, transient ischemic events (within 3 months), epilepsy, Parkinson’s disease, progressive supranuclear
palsy, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis or other central neurological dis-
order or a history of significant head trauma with loss of consciousness.
Final diagnostic classification was made at a consensus meeting of at least two research staff consisting of
neuropsychologists and nurses. Cognitive and functional cohort specific diagnostic classification criteria are
provided in Table 1.

2.2. Procedures
In addition to screening and diagnostic assessments (i.e. Clinical Dementia Rating (CDR) [33], MMSE, Subjec-
tive Memory Complaint (SMC) [30] and Geriatric Depression Scale (GDS) [34]), eligible subjects underwent
cognitive testing and completed functional and self- and informant-reported assessments at the screening visit.
Cognitive and functional data collected at this visit were considered “baseline” data. At subsequent study visits,
administrations of cognitive and functional measures were repeated. Information about changes in subject health

Table 1. Cognitive and functional diagnostic classification criteria.

HE aMCI AD
• CDR ≤ 0.5
• CDR = 0 • CDR > 0.5
• MMSE ≥ 23
• MMSE ≥ 28 • MMSE ≥ 16
• GDS < 20
• GDS < 20 • GDS < 20
• TICS-M total score < 29 and > 14
• TICS-M total score ≥ 29 • TICS-M total score < 29 and > 14
• TICS-m WLR < 10
• TICS-m WLR ≥ 11 • TICS-m WLR < 10
• Without dementia and with minimal or
• No significant SMC • Possible or probable AD according to
no ADL impairment
• Without evidence of depression previous or new clinical diagnosis using the
• Met Petersen criteria including the
• Without dementia of ADL impairment NINCDS-ADRDA criteria
presence of SMC
Abbreviations: CDR: Clinical Dementia Rating; MMSE: Mini-Mental State Examination; GDS: Geriatric Depression Scale; TICS-M: Telephone In-
terview for Cognitive Status-Modified; WLR: Word List Recall; SMC: Subjective Memory Complaint; ADL: Activities of Daily Living; NINCDS-
ADRDA: National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association.

170
 M. Marsico et al.

or medical conditions, including changes in medication use and medical events occurring between visits, was
collected. The structure of study visits and sequence of study assessments were consistent for all subjects. All
study procedures and assessments were administered by either trained research nurses or research neuropsy-
chologists. Only the study’s baseline, cross-sectional data are presented in this paper. Longitudinal data col-
lected across subsequent visits (6 and 12 months after baseline) are not presented.
Subjects were not administered any marketed or investigational compound in this study. Subjects were how-
ever, undergoing usual care by their healthcare providers for their disease which may have included medication
indicated for the treatment of AD. Because most subjects began their AD treatment prior to their inclusion in the
study, responsiveness (i.e. the ability of a measure to detect pharmacological change) could not be assessed. All
study procedures were in accord with the ethical standards of the Committee on Human Experimentation of the
institution in which the experiments were done or in accord with the Helsinki Declaration of 1975. Informed
consent was taken on recruitment into the OPTIMA cohort. Ethical approval for this study was granted by the
Frenchay Regional Ethics Committee, reference 09/H0107/09.

2.3. Measures
Cognitive tests were chosen for this study based on published evidence of the tests’ psychometric properties and
their usefulness in assessing cognition in AD and aMCI [35]. Tests sensitive to mild impairment were chosen for
comparison with the broadly used ADAS-Cog. The overarching aim in selecting cognitive measures was to
achieve broad domain coverage with at least two measures assessing each cognitive domain known to be im-
pacted in AD.
The cognitive test battery included the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-
Cog) [36]; the Cambridge Automated Neuropsychological Test Battery (CANTAB) [37] Paired Associate
Learning (PAL), Reaction Time Index (RTI) and Spatial Working Memory tests; the CAMCOG; and domain-
specific tests in verbal and visuospatial episodic memory, semantic memory, attention, executive function and
information processing speed (see Table 2). Functional measures included the Alzheimer’s Disease Cooperative
Study-Activities of Daily Living (ADCS-ADL) [38], scored on basic and instrumental ADL, and the Everyday
Memory Questionnaire (EMQ) [39]. Detailed description of all study measures can be found in the online sup-
plement.

2.4. Statistical Methods

Standardized z-scores were calculated for all cognitive and functional baseline data based on the mean and
standard deviation scores in the HE group. Standardizing the aMCI and mild-to-moderate AD performance to a
z-score based on a HE sample allows all test and domain scores to be reported based on the same scale with
mean of 0 and a standard deviation of 1. Domain composite scores were calculated by summing the individual
tests’ z-score means and dividing by the number of tests comprising that domain. Individual cognitive tests were
grouped according to domain as indicated in Table 2. The effects of age and education were assessed using
one-way analysis of variance (ANOVA); independent t-tests were conducted to investigate the potential influ-
ence of gender. A p-value of <0.05 was considered significant for all comparisons. Because cognitive perfor-
mance was not impacted by any of these covariates (data not shown), unadjusted, raw data were used in all
z-score calculations. Because the ADAS-Cog was not administered to HE in this study, standard scores were
created using previously published normative data [40] [41].
This study was designed to descriptively assess cognitive performance and functional status in non-demented,
aMCI and mild-to-moderate AD. The study was not powered to support formal statistical testing comparing the
cognitive and functional outcomes across the three groups. However, statistical tests (ANOVA) were performed
and p-values presented to facilitate interpretation of the differences between groups with regard to their cogni-
tive and functional scores. Imputation was not performed for missing data so the number of subjects contributing
to group means may vary by endpoint. All statistical analyses were performed using SAS version 9.3.

3. Results
3.1. Demographic Characteristics
Seventy five OPTIMA subjects prescreened with the TICS-M were invited to come into the study clinic for a

171
M. Marsico et al.

Table 2. Cognitive and functional test characteristics.

Cognitive/
Functional Test Name Abbreviation Cognitive Domain Outcome Variables Range
Battery
CANTAB Reaction Time 5-Choice Movement
5cRT Movement Attention & Processing Milliseconds 0-∞
Time*
*
CANTAB Reaction Time 5-Choice Reaction Time 5cRT Reaction Attention & Processing Milliseconds 0-∞

CANTAB CANTAB Reaction Time Simple Movement Time* sRT Movement Attention & Processing Milliseconds 0-∞
Computerized
Battery† CANTAB Reaction Time Simple Reaction Time* sRT Reaction Attention & Processing Milliseconds 0-∞
*
CANTAB Paired Associates Learning Total Errors PALTOTEA Visuospatial Memory Total Errors Adjusted 0 - 158
CANTAB Spatial Working Memory Between
SWMBE Working Memory Errors 0 - 326
Errors*
*
ADAS-Cog Total Score ADAS-Cog Total General Cognition Total Errors 0 - 70
*
ADAS-Cog Naming Objects and Fingers ADAS-cog Objects Semantic Memory Total Incorrect 0 - 17
ADAS-Cog Verbal Episodic Mean Words per Trial Not
and ADAS-Cog Word Recall* ADAS-cog Recall 0 - 10
Memory Recalled
Subtests‡,§ ADAS-Cog Verbal Episodic
*
ADAS-Cog Word Recognition Words Not Recognized 0 - 24
Recognition Memory
Mazes Seconds* Mazes Executive Function Seconds 0 - 240
Verbal Episodic
Hopkins Verbal Learning Test (Total Recall) HVLT TR Words Recalled 0 - 36
Memory
Verbal Episodic
Hopkins Verbal Learning Test (Delayed Recall) HVLT DR Words Recalled 0 - 12
Memory
The Placing Test TPT Objects Visuospatial Memory Number Correct 0 - 10

CAMCOG Learning Learn Episodic Memory Number Correct 0 - 17

CAMCOG Recent Memory Recent Episodic Memory Number Correct 0-4

CAMCOG Remote Memory Remote Episodic Memory Number Correct 0-6

CAMCOG Comprehension Comprehension Semantic Memory Summed Ordinal Scale 0-9

CAMCOG Expression Expression Semantic Memory Summed Ordinal Scale 0 - 21

Graded Naming Test GNT Semantic Memory Number Correct 0 - 30

CAMCOG Calculation Calculation Working Memory Number Correct 0-2

‡
OPTIMA Symbol Digit Modalities Test SDMT Executive Function Completed Minus Errors 0 - 110

Clock Drawing Task 1 CLOX 1 Executive Function Number Correct 0 - 15

CAMCOG Abstract Thinking Thinking Executive Function Summed Ordinal Scale 0-8

CAMCOG Orientation Orientation Orientation Number Correct 0 - 10

CAMCOG Perception Perception Perception Number Correct 0 - 11

CAMCOG Praxis Praxis Praxis Number Correct 0 - 12

Accuracy & Summed
CAMCOG Attention Attention Attention & Processing 0-7
Scale
Map Search from the Tests for Everyday Attention MAP Search Attention & Processing Items Circled 0 - 80

Letter Comparison Speed LCS Processing Speed Accuracy Score 0 - 20

Pattern Comparison Speed PCS Processing Speed Accuracy Score 0 - 30

Cambridge Cognitive Examination
CAMCOG Total General Cognition Subscales Total Score 0 - 107
(CAMCOG total score)
ADCS-ADL Basic Activities of Daily Living Basic ADL Functioning Summed Item Score 0 - 18
ADCS-ADL¶
ADCS-ADL Instrumental Activities of Daily Living Instrumental ADL Functioning Summed Item Score 0 - 60

172
 M. Marsico et al.

Continued
ADCS-ADL Total Score ADCS-ADL Total Functioning Summed Item Score 0 - 78

EMQ Speech* EMQ Speech Functioning Summed Item Score 0 - 52

EMQ Reading and Writing* EMQ Read Write Functioning Summed Item Score 0 - 16
Everyday *
Memory EMQ Actions EMQ Actions Functioning Summed Item Score 0 - 24
Question- EMQ Learning New Things *
EMQ Learn New Functioning Summed Item Score 0 - 24
naire¶
EMQ Faces and Places* EMQ Faces Places Functioning Summed Item Score 0 - 24

EMQ Total Score* EMQ Total Functioning Summed Item Score 0 - 140

Abbreviations: CANTAB: Cambridge Neuropsychological Test Automated Battery [37]; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subs-
cale; OPTIMA: Oxford Project to Investigate Memory and Aging; CAMCOG: Cambridge Cognitive Examination; ADCS-ADL: Alzheimer’s Disease Coopera-
tive Study-Activities of Daily Living; EMQ: Everyday Memory Questionnaire. *Higher score equals greater impairment. †Mode of administration is via a Cen-
tral Processing Unit (CPU). ‡Mode of administration is paper and pencil. §ADAS-Cog normative data was obtained from previous literature. ¶Mode of adminis-
tration is interview-based.

Table 3. Baseline demographic characteristics and cognitive function scores.

Amnestic Mild Cognitive
Healthy Elderly Alzheimer’s Disease
Baseline Characteristics Impairment p Value*
(n = 31) (n = 19)
(n = 20)
Age, mean years (SD) 80.94 (5.47) 80.85 (5.38) 77.79 (6.90) .15

Gender, males (%) 13 (41.94) 16 (80.00) 11 (57.89) .03

Education, mean years (SD) 14 (2.92) 13 (2.84) 13 (3.00) .63

MMSE, mean score (SD)† 29.52 (0.68) 27.80 (1.20) 22.89 (2.87 ) <.001
‡
GDS, mean score (SD) 4.10 (3.92) 6.40 (3.98) 7.50 (4.20) .01
§
Baseline ADCS-ADL Instrumental, mean score (SD) 53.52 (1.82) 52.82 (1.91) 42.00 (6.42) <.001
¶
Baseline EMQ, mean score (SD) 27.10 (13.27) 47.10 (22.30) 75.95 (18.26) <.001

Abbreviations: MMSE: Mini-Mental State Examination; GDS: Geriatric Depression Scale; ADCS-ADL: Alzheimer’s Disease Cooperative Study-Activities of
Daily Living; EMQ: Everyday Memory Questionnaire. *ANOVA was used to calculate p values for continuous variables and chi-square test for categorical
variables. †MMSE scores range from 0 to 30, with higher scores indicating less impairment. ‡GDS scores range from 0 to 30, with higher scores indicating more
depressive symptoms. §ADCS-ADL Instrumental scores range from 0 to 60, with higher scores indicating less impairment. ¶EMQ scores range from 0 to 140,
with higher scores indicating greater dysfunction.

baseline visit. Only 5 (7%) participants (all MCI or AD) failed to meet inclusion criteria. The final sample con-
sisted of 31 HE, 20 aMCI and 19 AD.
Results comparing demographic factors by group are presented in Table 3. On average, AD subjects had less
education than the HE and were approximately 3 years younger than the HE and aMCI, but the differences were
not statistically significant. There were significantly more males recruited into the aMCI and AD groups com-
pared to HE. MMSE scores were statistically different across the groups with highest scores among the HE (29.5
± 0.7) and aMCI (27.8 ± 1.2) compared to AD (22.9 ± 2.9). A gradient of increasing functional impairment and
depressive symptoms with increasing cognitive impairment was observed between the groups. At baseline, 8
(42%) mild-to-moderate AD subjects had received cognitive-enhancing treatment as part of their usual medical
care for an average of 3.9 ± 3.2 years.

3.2. Cognitive Performance

All means and standard deviations for cognitive test performance in the mild-to-moderate AD, aMCI, and HE
groups can be found in Table 4. Figure 1 presents the cross-sectional baseline z-scores for AD and aMCI,
grouped by cognitive domain, for each of the cognitive endpoints evaluated. Cut-off lines of 1.5 and 2 standard
deviations below the mean are indicated as the usual thresholds of significant deficit from normal control per-
formance for MCI and AD, respectively [2]. All references made to the deficits observed in AD and aMCI
groups are always relative to the HE referent group. Minimum and maximum z-scores within a cognitive do-

173
M. Marsico et al.

Table 4. Means and standard deviations for cognitive and functional tests.

Test Abbreviation N HE Mean ± SD N aMCI Mean ± SD N AD Mean ± SD

*
5cRT Movement 31 311.32 ± 100.74 20 335.75 ± 117.27 17 425.76 ± 171.22

5cRT Reaction* 31 383.94 ± 51.94 20 466.10 ± 73.63‡ 17 491.71 ± 112.49

sRT Movement* 31 312.26 ± 158.18 20 311.75 ± 131.15 17 444.00 ± 213.33

*
sRT Reaction 31 342.65 ± 65.17 20 431.70 ± 114.87 17 466.12 ± 254.93
* ‡
PALTOTEA 30 37.80 ± 23.93 19 74.53 ± 33.27 18 117.94 ± 18.53

SWMBE* 31 62.84 ± 15.76 20 25.60 ± 13.00‡ 17 30.35 ± 5.59

* †
ADAS-Cog Total 107 5.6 ± 3.3 20 11.38 ± 4.78 19 24.74 ± 10.40§

ADAS-Cog Objects* 124 0.05 ± 0.22† 20 1.10 ± 0.97 19 2.26 ± 2.21§

ADAS-Cog Recall* 107 2.7 ± 1.2† 20 4.53 ± 1.30 19 6.63 ± 1.60§

ADAS-Cog Recognition* 107 2.0 ± 2.2† 20 4.35 ± 3.15 19 8.16 ± 3.85§

Mazes* 107 30.0 ± 27.9† 20 33.00 ± 15.50 19 40.21 ± 16.51

HVLT TR 31 24.35 ± 4.32 19 19.05 ± 4.56‡ 19 11.32 ± 5.20§

HVLT DR 30 8.13 ± 2.29 19 5.79 ± 2.42‡ 19 0.05 ± 0.23§

TPT Objects 31 9.29 ± 0.90 19 8.58 ± 1.98 19 3.58 ± 1.87§

Learn 31 13.74 ± 1.79 19 11.26 ± 2.51‡ 13 4.38 ± 1.45§

Recent 31 3.97 ± 0.18 19 3.79 ± 0.54 13 1.92 ± 1.04§

Remote 31 5.45 ± 0.62 19 5.11 ± 0.88 13 3.38 ± 0.96§

Comprehension 31 8.94 ± 0.25 19 8.74 ± 0.56 13 8.31 ± 0.63§

Expression 31 19.52 ± 1.31 19 17.82 ± 1.07‡ 13 16.38 ± 2.87

GNT 31 26.35 ± 3.22 19 23.26 ± 4.17 19 14.05 ± 8.39§

Calculation 31 1.97 ± 0.18 19 1.79 ± 0.54 13 1.54 ± 0.66

SDMT 12 40.33 ± 9.59 11 30.91 ± 10.63 18 24.06 ± 11.83

CLOX 1 5 14.20 ± 0.45 9 12.22 ± 1.72 12 9.67 ± 3.87

Thinking 31 7.68 ± 0.60 19 7.16 ± 1.01 13 5.85 ± 2.12§

Orientation 31 9.97 ± 0.18 19 9.53 ± 0.70 13 6.46 ± 1.85§

Perception 31 10.42 ± 0.85 19 10.32 ± 1.16 13 8.54 ± 2.03§

Praxis 31 11.68 ± 0.48 19 10.89 ± 1.15‡ 13 10.62 ± 1.12

Attention 31 6.68 ± 0.79 19 6.89 ± 0.32 13 6.15 ± 1.07§

MAP Search 31 52.29 ± 13.86 18 43.72 ± 14.93 19 30.05 ± 16.02§

LCS 10 7.70 ± 2.50 10 7.30 ± 2.06 15 5.60 ± 2.13

PCS 10 11.60 ± 1.51 9 11.78 ± 2.59 15 8.93 ± 2.31§

CAMCOG Total 31 100.00 ± 3.49 19 93.32 ± 5.10‡ 13 73.54 ± 10.13

Basic ADL 29 22.00 ±1.20 17 22.00 ± 1.20 18 21.50 ± 1.20

Instrumental ADL 29 53.62 ± 1.82 17 52.82 ± 1.91 18 42.00 ± 6.42§

ADCS-ADL Total 29 75.52 ± 1.82 17 74.82 ± 1.91 18 63.50 ± 7.11§

174
 M. Marsico et al.

Continued
EMQ Speech* 31 11.35 ± 6.19 20 19.30 ± 9.50‡ 19 36.26 ± 7.03§

EMQ Read Write* 31 3.10 ± 2.02 20 4.95 ± 3.50 19 7.05 ± 3.76

EMQ Actions* 31 3.48 ± 3.08 20 7.20 ± 4.41‡ 19 12.47 ± 3.96§

EMQ Learn New* 31 5.94 ± 2.66 20 9.05 ± 2.50‡ 19 10.68 ± 5.98

* ‡
EMP Faces Places 31 3.23 ± 2.04 20 6.60 ± 4.43 19 9.47 ± 4.01§

EMQ Total* 31 27.10 ± 13.27 20 47.10 ± 22.30‡ 19 75.95 ± 18.26§

Abbreviations: HE: Healthy Elderly; aMCI: Amnestic Mild Cognitive Impairment; AD: Alzheimer’s Disease; 5cRT: Five-Choice Reaction Time;
sRT: Simple Reaction Time; PALTOTEA: Paired Associates Learning Total Errors Adjusted; SWMBE: Spatial Working Memory Between Errors;
ADAS- Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; HVLT TR: Hopkins Verbal Learning Test Total Recall; HVLT DR:
Hopkins Verbal Learning Test Delayed Recall; TPT: The Placing Test; GNT: Graded Naming Test; SDMT: Symbol Digit Modalities Test; CLOX1:
Clock Drawing Task 1; LCS: Letter Comparison Speed; PCS: Pattern Comparison Speed; CAMCOG: Cambridge Examination for Mental Disorders
of the Elderly-Cognitive Examination; ADL: Activities of Daily Living; ADCS-ADL: Alzheimer’s Disease Cooperative Study-Activities of Daily
Living; EMQ: Everyday Memory Questionnaire. *Higher score equals greater impairment. †ADAS-Cog normative data was obtained from previous
literature. ‡p < 0.05 aMCI compared to HE; significance not assessed for ADAS-Cog. §p< 0.05 AD compared to aMCI.

Figure 1. Cognitive and functional z-scores for subjects with mild-to-moderate AD and aMCI normalized to HE. *Actual z-
score is greater than −8. †See Table 2 for information on cognitive and functional assessments, including abbreviations.

main refer to the minimum and maximum scores for the subset of measures classified within each domain. Clas-
sifications can be found in Table 2; z-scores are presented in Figure 1.
Deficits were observed among AD subjects relative to aMCI subjects on each cognitive endpoint assessed,
with the exception of CANTAB Spatial Working Memory. The greatest cognitive deficits observed in the AD
group were within the domains of episodic memory (z-score −3.3 to −11.4), executive function (z-score -0.4 to
−10.1), orientation (z-score −19.5), and semantic memory (z-score −2.4 to −10.1). Smaller deficits were ob-
served within the domains of processing speed (z-score −0.8 to −1.8) and attention and processing (z-score −0.7
to −2.1). Measureable cognitive deficits were also observed for most endpoints among aMCI with a pattern
similar to that seen in the AD group, with the largest deficits in executive function (z-score −0.1 to −4.4) and
semantic memory (z-score −0.8 to −4.8) domains, and the smallest deficits in the processing speed domain (z-
scores > −0.2). Endpoints such as the CAMCOG and ADAS-Cog, which utilize a single score to summarize
cognitive performance across a variety of domains (categorized in the tables as “general cognition”), detected
large differences from HE in both AD and aMCI and were able to clearly differentiate between aMCI (CAMCOG:
z-score −1.9; ADAS-Cog: z-score −1.8) and AD (CAMCOG: z-score −7.6; ADAS-Cog: z-score −5.8). Both AD
and aMCI had marked deficits in executive function (Clock Drawing Task 1 (CLOX1) [42]; z-scores −10.1 and

175
M. Marsico et al.

−4.4) and semantic memory (ADAS-Cog Object naming; z-scores −10.1 and −4.8). Deficits in verbal episodic
memory (ADAS-Cog Recall and ADAS-Cog Recognition) were approximately twice as large in AD (z-scores
−3.3 and −2.8) as compared with aMCI (z-scores −1.5 and −1.1), as were those for visuospatial memory
(CANTAB PAL; AD z-score −3.4; aMCI z-score −1.5), working memory (CAMCOG Calculation; AD z-score
−2.4; aMCI z-score −1.0), semantic memory (CAMCOG Comprehension; AD z-score −2.5; aMCI z- score −0.8
and CAMCOG Expression; AD z-score −2.4; aMCI z-score −1.3), and executive function (Symbol Digit Mo-
dalities Test (SDMT) [43]; AD z-score −1.7; aMCI z-score −1.0). Both AD and aMCI had deficits compared to
HE in CANTAB Reaction Time tasks (AD z-score −1.9 to −2.1; aMCI z-score −1.4 to −1.6), MAP Search (AD
z-score −1.6; aMCI z-score −0.6) [44], CANTAB Spatial Working Memory (AD z-score −2.1; aMCI z-score
−2.4) and CAMCOG Praxis (AD z-score −2.2; aMCI z-score −1.6).
Figure 2 displays mean composite z-scores by cognitive domain for domains that were assessed by at least 2
tests.

3.3. Functional Status

All means and standard deviations for functional measures in the AD, aMCI, and HE groups can be found in
Table 4. Figure 1 also presents the cross-sectional baseline group z-scores for the AD and aMCI groups for
each of the composite and individual functional endpoints evaluated.
The ADCS-ADL and EMQ total scores summarize functional status across several domains using a compos-
ite score. Measurable deficits relative to HE were observed in both AD (ADCS-ADL: z-score −6.6; EMQ:
z-score −3.7) and aMCI (ADCS-ADL: z-score −0.4; EMQ: z-score −1.5). Domain-specific functional deficits
were also detected; the deficits were greater among AD (z-score −0.4 to −6.4) compared to aMCI (z-score 0.0 to
−1.7). There were no deficits observed in ADCS-ADL Basic ADLs for aMCI compared to HE, but impairment
was seen in the ADCS-ADL’s instrumental items. The mean instrumental ADL deficit in AD (z-score −6.4) was
16-fold greater than in aMCI (z-score −0.4). Both AD and aMCI had large deficits compared to HE in EMQ
sub-domains (AD z-score −1.8 to −4.0; aMCI z-score −0.9 to −1.7). Functional deficits on the EMQ Total Score
were more than twice as large in AD (mean z-score −3.7) compared to aMCI (mean z-score −1.5).

4. Discussion
Although both the cognitive and functional deficits in mild-to-moderate AD have been well-documented in the
literature, the deficits have rarely been so well characterized and in a single cohort of participants that spans the
spectrum of cognitively intact HE, aMCI and mild AD. The cognitive and functional profiles presented in this
study provide insight into the comprehensive impairment among aMCI and mild AD.
Detailed characterization of domain-specific cognitive and functional profiles in aMCI and mild-to-moderate
AD populations plays an important role in identifying domains whose exploration may improve the sensitivity
of detecting therapeutic effects in clinical trials; albeit, identification of domain-specific measures for use in

Figure 2. Mean composite z-scores by domain, aMCI and mild-to-moderate

AD subjects. *z-scores represent a composite of all the study’s tests that as-
sessed the domain listed.

176
 M. Marsico et al.

clinical trials requires further evaluation of the psychometric properties of the tests (i.e. reliability, construct and
known-groups’ validity, sensitivity to detect longitudinal change). A better understanding of expected cognitive
and functional deficits across the spectrum of AD can also aid in improving the accuracy of diagnosing early
and late stages of disease and differentiating between dementia subtypes [8] [21] [24]-[27].
Measurable cognitive and functional deficits were observed in aMCI compared to HE. Despite some overlap
in the distribution of individual subject scores, on average, aMCI subjects performed 1 - 2 standard deviations
below HE on cognitive tests and within 1 standard deviation on functional tests. The aMCI deficits were mark-
edly less than those observed in AD. Although only a proportion of the aMCI subjects are expected to progress
to AD, the consistency of their deficits suggests widespread impairment in cognition and function is present
years before a clinical diagnosis of AD. Our data corroborates previous research suggesting that the most pre-
cipitous domain-specific decline on the continuum from MCI to AD conversion usually takes place in episodic
memory [7]-[9].
The cognitive deficits observed in the mild-to-moderate AD group are consistent with previous research
demonstrating the greatest differences from HE present in the domains of visuospatial memory (z-score −3.4 to
−6.3), episodic memory (z-score −3.3 to −11.4), semantic memory (z-score −2.4 to −10.0) and executive func-
tion (z-score −0.4 to −10.1) [7]-[9] [21] [41]. The consistency of the deficits in attention and information proc-
essing in aMCI and AD suggest that deficits in higher-level cognitive processes (e.g. memory, executive func-
tion) may be associated with a fundamental attention deficit that manifests very early in the disease. The data
presented here support prior experience indicating that domains other than episodic memory are compromised in
aMCI or preclinical AD [45]-[47].
Based on the data presented, ADAS-Cog Immediate Recall and Recognition items, the Hopkins Verbal Learning
Test revised (HVLT) Immediate and Delayed Recall [48], CAMCOG Calculation, Comprehension and Expres-
sion sub-scores, CANTAB PAL Total Adjusted Errors and the SDMT show the most promise as trial endpoints
as they exhibit the ability to differentiate between HE, aMCI and AD and are appropriately scaled for these
populations. General cognition scores such as the CAMCOG and ADAS-Cog total scores would appear to be
less useful clinical trial endpoints since changes in total scores are more difficult to map to the underlying do-
main-specific impairment. Furthermore, most of the ADAS-Cog items are inappropriately scaled for use in mild
AD and therefore lack the sensitivity to measure widespread domain specific impairment. As a result, in mild
AD, the ADAS-Cog total score is an endpoint primarily impacted by only a couple of verbal episodic memory
items (namely Word Recall and Recognition). Consequences of excluding impacted domains in a global cogni-
tion endpoint include underestimating overall impairment and the difference between mild and moderate AD
and missing clinical change in mild patients when it occurs [49].
Functional decline was previously thought to be a feature that distinguished those with AD from those with
more mild impairment, such that early criteria for MCI indicated that one should demonstrate “normal activities
of daily living” [50]. However, as with cognitive criteria, recent revisions have noted that there may be subtle
but detectable changes in functional ability in MCI as well [51].
Our data indicate a subtle but consistent impairment of functional activities in aMCI, particularly in the EMQ
functional activities that correlate highly with memory performance. Activities that require use of high-level
cognitive skill, including reasoning, planning, organization, and initiation abilities are more likely to be im-
pacted in aMCI [13], perhaps because these kinds of activity are less routine and well-learned [16]. In the AD
group, the instrumental ADCS-ADL and EMQ Speech domain impairment indicated is consistent with cognitive
dysfunction in executive, orientation and episodic memory domains. Executive dysfunction has previously been
associated with Instrumental ADL impairments [52].
A number of limitations should be considered when interpreting these results. Impairment observed in this
study may not be representative of a larger and more culturally diverse sample of subjects with aMCI and mild-
to-moderate AD. Recruitment of a convenient community sample of well-educated Caucasians and the study’s
small sample size may limit the generalizability of our findings to demographically and clinically similar popu-
lations. A major strength of the study is that it was conducted at a single study site with highly experienced neu-
ropsychologists and nurses trained in cognitive assessments. It should however be acknowledged that the use of
a single site with very qualified test administrators, which ensures high data quality and minimal loss to follow
up, likely resulted in less performance-related variability than what might be observed in a multi-site, multi-
country clinical trial setting.
Standard scores normalized to a healthy elderly population were used to allow for simple comparison of cog-

177
M. Marsico et al.

nitive and functional performance across domains. It should, however, be noted that some z-scores were gener-
ated using non-normally distributed normative data. On a number of the tests the confluence of a compressed
range of performance and ceiling effects (i.e. a meaningful number of subjects scoring at the upper limit of a
scale’s range) among healthy elderly resulted in z-scores among mild-to-moderate AD that may not accurately
reflect the true percentage of scores that fall below a given z-score value.
A cross-sectional analysis limits the ability to assess key psychometric properties of the tests, such as test-re-
test reliability, the presence and persistence of learning effects and the sensitivity to change due to cognitive
worsening. Data on these properties is necessary to determine the appropriateness of the endpoints for clinical
trials. Future analyses of these data will include comprehensive psychometric analysis of each of the study’s
tests including their longitudinal performance in each of the study’s cohorts.

5. Conclusion
The results of this study provide further support for comprehensive assessment and monitoring of cognitive and
functional domain scores in the diagnosis and treatment of aMCI and mild-to-moderate AD. Establishing cogni-
tive and functional profiles and assessing their change over time may inform differential diagnosis, particularly
as cognitive decline is expected to be reflected in, or correlated with functional decline [53]. Domain-specific
cognitive scores may be more useful than composite total scores in identifying impairment and decline in cogni-
tive function related to regional brain function. Measuring domains such as attention, processing speed and ex-
ecutive function may increase the sensitivity of detecting disease progression and therapeutic effects, particu-
larly in mild-to-moderate AD patients whose memory decline may be too slow to detect drug effects during a
typical clinical trial. Further exploration of patterns of impairment may also have potential to be predictive of
those at greatest risk of disease progression or who may benefit most from treatment.

References
[1] Levey, A., Lah, J., Goldstein, F., Steenland, K. and Bliwise, D. (2006) Mild Cognitive Impairment: An Opportunity to
Identify Patients at High Risk for Progression to Alzheimer’s Disease. Clinical Therapeutics, 28, 991-1001.
http://dx.doi.org/10.1016/j.clinthera.2006.07.006
[2] Petersen, R.C., Doody, R., Kurz, A., Mohs, R.C., Morris, J.C., Rabins, P.V., et al. (2001) Current Concepts in Mild
Cognitive Impairment. JAMA Neurology, 58, 1985-1992. http://dx.doi.org/10.1001/archneur.58.12.1985
[3] Artero, S., Petersen, R., Touchon, J. and Ritchie, K. (2006) Revised Criteria for Mild Cognitive Impairment: Validation
within a Longitudinal Population Study. Dementia and Geriatric Cognitive Disorders, 22, 465-470.
http://dx.doi.org/10.1159/000096287
[4] Dubois, B., Feldman, H.H., Jacova, C., Dekosky, S.T., Barberger-Gateau, P., Cummings, J., et al. (2007) Research Cri-
teria for the Diagnosis of Alzheimer’s Disease: Revising the NINCDS-ADRDA Criteria. Lancet Neurology, 6, 734-
746.
[5] Birks, J. (2006) Cholinesterase Inhibitors for Alzheimer’s Disease. The Cochrane Database of Systematic Reviews, Ar-
ticle ID: CD005593.
[6] Markwick, A., Zamboni, G. and de Jager, C.A. (2012) Profiles of Cognitive Subtest Impairment in the Montreal Cogni-
tive Assessment (MoCA) in a Research Cohort with Normal Mini-Mental State Examination (MMSE) Scores. Journal
of Clinical and Experimental Neuropsychology, 34, 750-757. http://dx.doi.org/10.1080/13803395.2012.672966
[7] Bondi, M.W., Jak, A.J., Delano-Wood, L., Jacobson, M.W., Delis, D.C. and Salmon, D.P. (2008) Neuropsychological
Contributions to the Early Identification of Alzheimer’s Disease. Neuropsychology Review, 18, 73-90.
http://dx.doi.org/10.1007/s11065-008-9054-1
[8] Karantzoulis, S. and Galvin, J.E. (2011) Distinguishing Alzheimer’s Disease from Other Major Forms of Dementia.
Expert Review of Neurotherapeutics, 11, 1579-1591. http://dx.doi.org/10.1586/ern.11.155
[9] Nordlund, A., Rolstad, S., Hellstrom, P., Sjogren, M., Hansen, S. and Wallin, A. (2005) The Goteborg MCI Study:
Mild Cognitive Impairment Is a Heterogeneous Condition. Journal of Neurology, Neurosurgery and Psychiatry, 76,
1485-1490. http://dx.doi.org/10.1136/jnnp.2004.050385
[10] Caine, D. and Hodges, J.R. (2001) Heterogeneity of Semantic and Visuospatial Deficits in Early Alzheimer’s Disease.
Neuropsychology, 15, 155-164. http://dx.doi.org/10.1037/0894-4105.15.2.155
[11] Carter, S.F., Caine, D., Burns, A., Herholz, K. and Ralph, M.A.L. (2012) Staging of the Cognitive Decline in Alz-
heimer’s Disease: Insights from a Detailed Neuropsychological Investigation of Mild Cognitive Impairment and Mild
Alzheimer’s Disease. International Journal of Geriatric Psychiatry, 27, 423-432.

178
 M. Marsico et al.

[12] Perry, R.J. and Hodges, J.R. (1999) Attention and Executive Deficits in Alzheimer’s Disease: A Critical Review. Brain,
122, 383-404. http://dx.doi.org/10.1093/brain/122.3.383
[13] Farias, S.T., Mungas, D., Reed, B.R., Harvey, D., Cahn-Weiner, D. and DeCarli, C. (2006) MCI Is Associated with
Deficits in Everyday Functioning. Alzheimer Disease & Associated Disorders, 20, 217-223.
http://dx.doi.org/10.1097/01.wad.0000213849.51495.d9
[14] Perneczky, R., Pohl, C., Sorg, C., Hartmann, J., Tosic, N., Grimmer, T., Heitele, S. and Kurz, A. (2006) Impairment of
Activities of Daily Living Requiring Memory or Complex Reasoning as Part of the MCI Syndrome. International
Journal of Geriatric Psychiatry, 21, 158-162. http://dx.doi.org/10.1002/gps.1444
[15] Reppermund, S., Brodaty, H., Crawford, J.D., Kochan, N.A., Draper, B., Slavin, M.J., et al. (2013) Impairment in In-
strumental Activities of Daily Living with High Cognitive Demand Is an Early Marker of Mild Cognitive Impairment:
The Sydney Memory and Ageing Study. Psychological Medicine, 43, 2437-2445.
[16] Goldberg, T.E., Koppel, J., Keehlisen, L., Christen, E., Dreses-Werringloer, U., Conejero-Goldberg, C., Gordon, M.L.
and Davies, P. (2010) Performance-Based Measures of Everyday Function in Mild Cognitive Impairment. American
Journal of Psychiatry, 167, 845-853. http://dx.doi.org/10.1176/appi.ajp.2010.09050692
[17] Bangen, K.J., Jak, A.J., Schiehser, D.M., Delano-Wood, L., Tuminello, E., Han, S.D., et al. (2010) Complex Activities
of Daily Living Vary by Mild Cognitive Impairment Subtype. Journal of the International Neuropsychological Society,
16, 630-639. http://dx.doi.org/10.1017/S1355617710000330
[18] Allaire, J.C., Gamaldo, A., Ayotte, B.J., Sims, R. and Whitfield, K. (2009) Mild Cognitive Impairment and Objective
Instrumental Everyday Functioning: The Everyday Cognition Battery Memory Test. Journal of the American Geriat-
rics Society, 57, 120-125. http://dx.doi.org/10.1111/j.1532-5415.2008.02054.x
[19] Mioshi, E., Kipps, C.M., Dawson, K., Mitchell, J., Graham, A. and Hodges, J.R. (2007) Activities of Daily Living in
Frontotemporal Dementia and Alzheimer Disease. Neurology, 68, 2077-2084.
http://dx.doi.org/10.1212/01.wnl.0000264897.13722.53
[20] Dangour, A.D., Allen, E., Richards, M., Whitehouse, P. and Uauy, R. (2010) Design Considerations in Long-Term In-
tervention Studies for the Prevention of Cognitive Decline or Dementia. Nutrition Reviews, 68, S16-S21.
http://dx.doi.org/10.1111/j.1753-4887.2010.00330.x
[21] de Jager, C.A., Hogervorst, E., Combrinck, M. and Budge, M.M. (2003) Sensitivity and Specificity of Neuropsy-
chological Tests for Mild Cognitive Impairment, Vascular Cognitive Impairment and Alzheimer’s Disease. Psycho-
logical Medicine, 33, 1039-1050. http://dx.doi.org/10.1017/S0033291703008031
[22] de Jager, C.A. and Budge, M.M. (2005) Stability and Predictability of the Classification of Mild Cognitive Impairment
as Assessed by Episodic Memory Test Performance over Time. Neurocase, 11, 72-79.
http://dx.doi.org/10.1080/13554790490896820
[23] Hogervorst, E., Combrinck, M., Lapuerta, P., Rue, J., Swales, K. and Budge, M. (2002) The Hopkins Verbal Learning
Test and Screening for Dementia. Dementia and Geriatric Cognitive Disorders, 13, 13-20.
http://dx.doi.org/10.1159/000048628
[24] Kramer, J.H., Jurik, J., Sha, S.J., Rankin, K.P., Rosen, H.J., Johnson, J.K. and Miller, B.L. (2003) Distinctive Neuro-
psychological Patterns in Frontotemporal Dementia, Semantic Dementia, and Alzheimer Disease. Cognitive & Behav-
ioral Neurology, 16, 211-218. http://dx.doi.org/10.1097/00146965-200312000-00002
[25] Libon, D.J., Massimo, L., Moore, P., Coslett, H.B., Chatterjee, A., Aguirre, G.K., et al. (2007) Screening for Fronto-
temporal Dementias and Alzheimer’s Disease with the Philadelphia Brief Assessment of Cognition: A Preliminary
Analysis. Dementia and Geriatric Cognitive Disorders, 24, 441-447. http://dx.doi.org/10.1159/000110577
[26] Pendlebury, S.T., Markwick, A., de Jager, C.A., Zamboni, G., Wilcock, G.K. and Rothwell, P.M. (2012) Differences in
Cognitive Profile between TIA, Stroke and Elderly Memory Research Subjects: A Comparison of the MMSE and
MoCA. Cerebrovascular Diseases, 34, 48-54. http://dx.doi.org/10.1159/000338905
[27] Perry, R.J. and Hodges, J.R. (2000) Differentiating Frontal and Temporal Variant Frontotemporal Dementia from Alz-
heimer’s Disease. Neurology, 54, 2277-2284. http://dx.doi.org/10.1212/WNL.54.12.2277
[28] de Jager, C.A., Honey, T.E., Birks, J. and Wilcock, G.K. (2010) Retrospective Evaluation of Revised Criteria for the
Diagnosis of Alzheimer’s Disease Using a Cohort with Post-Mortem Diagnosis. International Journal of Geriatric
Psychiatry, 25, 988-997. http://dx.doi.org/10.1002/gps.2448
[29] Huppert, F.A., Brayne, C., Gill, C., Paykel, E.S. and Beardsall, L. (1995) CAMCOG—A Concise Neuropsychological
Test to Assist Dementia Diagnosis: Socio-Demographic Determinants in an Elderly Population Sample. British Journal
of Clinical Psychology, 34, 529-541. http://dx.doi.org/10.1111/j.2044-8260.1995.tb01487.x
[30] Roth, M., Tym, E., Mountjoy, C.Q., Huppert, F.A., Hendrie, H., Verma, S. and Goddard, R. (1986) CAMDEX. A
Standardised Instrument for the Diagnosis of Mental Disorder in the Elderly with Special Reference to the Early De-
tection of Dementia. British Journal of Psychiatry, 149, 698-709. http://dx.doi.org/10.1192/bjp.149.6.698

179
M. Marsico et al.

[31] Folstein, M.F., Folstein, S.E. and McHugh, P.R. (1975) “Mini-Mental State”. A Practical Method for Grading the Cog-
nitive State of Patients for the Clinician. Journal of Psychiatric Research, 12, 189-198.
http://dx.doi.org/10.1016/0022-3956(75)90026-6
[32] Brandt, J., Spencer, M. and Folstein, M. (1988) The Telephone Interview for Cognitive Status. Neuropsychiatry, Neu-
ropsychology, & Behavioral Neurology, 1, 111-117.
[33] Morris, J.C. (1997) Clinical Dementia Rating: A Reliable and Valid Diagnostic and Staging Measure for Dementia of
the Alzheimer Type. International Psychogeriatrics, 9, 173-176. http://dx.doi.org/10.1017/S1041610297004870
[34] Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O., Huang, V., Adey, M. and Otto Leirer, V. (1982) Development and
Validation of a Geriatric Depression Screening Scale: A Preliminary Report. Journal of Psychiatric Research, 17,
37-49. http://dx.doi.org/10.1016/0022-3956(82)90033-4
[35] Ferris, S.H., Lucca, U., Mohs, R., Dubois, B., Wesnes, K., Erzigkeit, H., et al. (1997) Objective Psychometric Tests in
Clinical Trials of Dementia Drugs. Position Paper from the International Working Group on Harmonization of Demen-
tia Drug Guidelines. Alzheimer Disease and Associated Disorders, 11, 34-38.
[36] Rosen, W.G., Mohs, R.C. and Davis, K.L. (1984) A New Rating Scale for Alzheimer’s Disease. American Journal of
Psychiatry, 141, 1356-1364.
[37] Cambridge Cognition Ltd. (2013) Cambridge Cognition—The Home of CANTAB. CANTAB.com [Internet]. Cam-
bridge Cognition Ltd., Cambridge, c2013. http://www.cantab.com/
[38] Galasko, D., Bennett, D., Sano, M., Ernesto, C., Thomas, R., Grundman, M. and Ferris, S. (1997) An Inventory to As-
sess Activities of Daily Living for Clinical Trials in Alzheimer’s Disease. Alzheimer Disease & Associated Disorders,
11, S33-S39. http://dx.doi.org/10.1097/00002093-199700112-00005
[39] Sunderland, A., Harris, J. and Baddeley, A. (1983) Do Laboratory Tests Predict Everyday Memory? A Neuropsy-
chological Study. Journal of Verbal Learning and Verbal Behavior, 22, 341-357.
http://dx.doi.org/10.1016/S0022-5371(83)90229-3
[40] Graham, D., Cully, J.A., Snow, A.L., Massman, P. and Doody, R. (2004) The Alzheimer’s Disease Assessment Scale-
Cognitive Subscale: Normative Data for Older Adults Controls. Alzheimer Disease and Associated Disorders, 18, 236-
240.
[41] Grundman, M., Petersen, R.C., Ferris, S.H., Thomas, R.G., Aisen, P.S., Bennett, D.A., et al. (2004) Mild Cognitive
Impairment Can Be Distinguished from Alzheimer Disease and Normal Aging for Clinical Trials. JAMA Neurology, 61,
59-66. http://dx.doi.org/10.1001/archneur.61.1.59
[42] Royall, D.R., Cordes, J.A. and Polk, M. (1998) CLOX: An Executive Clock Drawing Task. Journal of Neurology,
Neurosurgery & Psychiatry, 64, 588-594. http://dx.doi.org/10.1136/jnnp.64.5.588
[43] Smith, A. (1968) The Symbol-Digit Modalities Test: A Neuropsychologic Test of Learning and Other Cerebral Disor-
ders. In: Learning Disorders, Special Child Publications, Seattle, 83-91.
[44] Robertson, I.H., Thames Valley Test Company (1994) The Test of Everyday Attention. Thames Valley Test Company.
[45] Brandt, J., Aretouli, E., Neijstrom, M.S., Samek, J., Manning, K., Albert, M.S., et al. (2009) Selectivity of Executive
Function Deficits in Mild Cognitive Impairment. Neuropsychology, 23, 607-618. http://dx.doi.org/10.1037/a0015851
[46] Papp, K.V., Snyder, P.J., Maruff, P., Bartkowiak, J. and Pietrzak, R.H. (2011) Detecting Subtle Changes in Visuospa-
tial Executive Function and Learning in the Amnestic Variant of Mild Cognitive Impairment. PLoS ONE, 6, e21688.
http://dx.doi.org/10.1371/journal.pone.0021688
[47] Voss, S. and Bullock, R. (2004) Executive Function: The Core Feature of Dementia? Dementia and Geriatric Cognitive
Disorders, 18, 207-216. http://dx.doi.org/10.1159/000079202
[48] Brandt, J. (1991) The Hopkins Verbal Learning Test: Development of a New Memory Test with Six Equivalent Forms.
Clinical Neuropsychologist, 5, 125-142. http://dx.doi.org/10.1080/13854049108403297
[49] Cano, S.J., Posner, H.B., Moline, M.L., Hurt, S.W., Swartz, J., Hsu, T. and Hobart, J.C. (2010) The ADAS-Cog in
Alzheimer’s Disease Clinical Trials: Psychometric Evaluation of the Sum and Its Parts. Journal of Neurology, Neuro-
surgery & Psychiatry, 81, 1363-1368. http://dx.doi.org/10.1136/jnnp.2009.204008
[50] Petersen, R.C., Smith, G.E., Waring, S.C., Ivnik, R.J., Tangalos, E.G. and Kokmen, E. (1999) Mild Cognitive Impair-
ment: Clinical Characterization and Outcome. JAMA Neurology, 56, 303-308.
http://dx.doi.org/10.1001/archneur.56.3.303
[51] Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni, L., Wahlund, L.O., et al. (2004) Mild Cognitive Impair-
ment—Beyond Controversies, towards a Consensus: Report of the International Working Group on Mild Cognitive
Impairment. Journal of Internal Medicine, 256, 240-246. http://dx.doi.org/10.1111/j.1365-2796.2004.01380.x
[52] Marshall, D.A., Rentz, D.M., Frey, M.T., Locascio, J.J., Johnson, K.A. and Sperling, R.A., the Alzheimer’s Disease
Neuroimaging Initiative (2011) Executive Function and Instrumental Activities of Daily Living in Mild Cognitive Im-

180
 M. Marsico et al.

pairment and Alzheimer’s Disease. Alzheimer’s & Dementia, 7, 300-308.

http://dx.doi.org/10.1016/j.jalz.2010.04.005
[53] Perry, R.J. and Hodges, J.R. (2000) Relationship between Functional and Neuropsychological Performance in Early
Alzheimer Disease. Alzheimer Disease & Associated Disorders, 14, 1-10.
http://dx.doi.org/10.1097/00002093-200001000-00001
[54] Cornish, I.M. (2000) Factor Structure of the Everyday Memory Questionnaire. British Journal of Psychology, 91, 427-
438. http://dx.doi.org/10.1348/000712600161916
[55] Salthouse, T.A. and Babcock, R.L. (1991) Decomposing Adult Age Differences in Working Memory. Developmental
Psychology, 27, 763-776. http://dx.doi.org/10.1037/0012-1649.27.5.763
[56] Anderson, E., De Jager, C. and Iversen, S. (2006) The Placing Test: Preliminary Investigations of a Quick and Simple
Memory Test Designed to Be Sensitive to Pre-Dementia Alzheimer’s Disease but Not to Normal Ageing. Journal of
Clinical and Experimental Neuropsychology, 28, 843-858. http://dx.doi.org/10.1080/13803390591001016
[57] McKenna, P. and Warrington, E.K. (1980) Testing for Nominal Dysphasia. Journal of Neurology, Neurosurgery &
Psychiatry, 43, 781-788. http://dx.doi.org/10.1136/jnnp.43.9.781

181
M. Marsico et al.

Online Supplement
1. Measures
1.1. Screening and Diagnostic Assessments
1.1.1. Telephone Interview for Cognitive Status-Modified (TICS-M) [32]
The TICS-M is a cognitive function test, developed as a dementia screen, and is suitable for administration by
telephone. The 13-item version of the test was used, sensitive to early cognitive impairment, in which a higher
proportion of the total score (maximum score 39 points) is contributed to by tasks of immediate and delayed re-
call, than in other screening tools, such as the MMSE or CAMCOG. It also includes tasks of orientation, atten-
tion, semantic memory, and comprehension and language ability. The total score and the Word List Recall score
(WLR; total words recalled on immediate and delayed memory tasks) were used as indicators of cognitive status
for screening and diagnostic purposes. Higher Total and WLR scores indicate better performance.

1.1.2. Mini Mental State Examination (MMSE) [31]

The MMSE is a cognitive screening instrument which assesses cognitive functioning in five areas: Orientation,
Registration, Recall, Attention/Concentration/Calculation, and Language, with each subtest area contributing
approximately equal weight to the total score. The maximum total score is 30 points, where higher scores indi-
cate less impairment.

1.1.3. Subjective Memory Complaint (SMC) Questions (Selected Questions from the Cambridge
Examination for Mental Disorders of the Elderly (CAMDEX)) [30]
A measure of participants’ subjective accounts of memory impairment was assessed with questions assessing
memory complaints from the CAMDEX. Four questions were administered, including those assessing partici-
pants’ subjective ability to remember names of people they know well and whether they had been lost in famil-
iar places. The SMC was scored dichotomously, that is, SMC present or absent, where present indicated en-
dorsement of 2 or more items as SMC items. Note that this measure was not used in the diagnostic classification
of AD participants, as reduced insight may mask subjective reporting of memory difficulties.

1.1.4. Geriatric Depression Scale (GDS) [34]

The GDS is a 30-item depression screen for older adults, covering symptoms such as interest and enjoyment in
activities, energy levels and hopefulness regarding the future, where scores of 0 - 9 indicate normal mood, 10 -
19 mild depression, and 20 - 30 severe depression.

1.1.5. Clinical Dementia Rating (CDR) [33]

The CDR provides a measure of clinical severity of dementia, covering six areas of cognitive and functional
ability: Memory, Orientation, Judgment and Problem-solving, Community Affairs, Home and Hobbies, and
Personal Care. Performance in these areas is rated on a 5-point scale (Personal care, on a 4-point scale) on the
basis of information gathered by means of clinical interview with the participant and a reliable informant. These
scores then contribute, using a mathematical algorithm, to the calculation of an overall CDR score, which pro-
vides a measure of dementia severity on a 5-point scale: 0 indicates no impairment, 0.5, 1, 2, and 3 indicate de-
mentia of increasing severity, that is, very mild, mild, moderate, and severe, respectively. A CDR-SoB score is
also calculated from the sum of all the individual scores for each domain. CDR ratings were made by consensus
decision of at least two research neuropsychologists or nurses.

1.2. Functional Assessments

1.2.1. Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) [38]
This measure assesses elderly participants’ ability to carry out routine activities in everyday life pertaining to
personal care, household maintenance, communicating and interaction, hobbies and interests, and decision-
making and judgement ability. Administered to an informant or caregiver, functioning in the above areas is rated
on 23 items as performed in the previous 4-week period, with each item rated according to the level of inde-
pendence with which the task can be performed (from “can perform task independently” to “needs physical
help”). Total scores range from 0 to 78, with higher scores indicating less impairment. The items are grouped

182
 M. Marsico et al.

into basic ADL (personal care) and instrumental ADL (household maintenance, communicating and interaction,
hobbies and interests, and decision-making and judgement ability). Used with permission from the NIA Alz-
heimer’s Disease Cooperative Study (NIA Grant AG10483).

1.2.2. Everyday Memory Questionnaire (EMQ) [39]

The EMQ is a 35-item questionnaire which assesses memory impairment in 5 domains: speech, reading and
writing, faces and places, actions, and learning new things. The items have been shown to load onto 5 factors,
namely retrieval, task monitoring, conversational monitoring, spatial memory and memory for activities [54].
Each item is ranked on a 5-point scale (0 - 4 points) which indicates the frequency with which a particular
memory difficulty occurs, ranging from “Never” to “Several times in a day”. EMQ score ranges from 0 to 140,
where a higher score indicates greater impairment. A self-report version of the questionnaire was completed by
HE participants, and an informant version was completed when participants were in the aMCI or AD groups to
avoid issues of reduced insight into memory difficulties. If completed by the informant, the EMQ was filled in
following completion of the ADCS-ADL.

1.3. Cognitive Assessment Battery

1.3.1. Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) [36]
The ADAS-Cog is widely used in clinical trials as a measure of cognitive impairment or change. The total score
(maximum of 70) provides an overall measure of cognitive functioning, with higher scores indicating greater
impairment. This score is derived from performance on the subtests which comprise the scale, including tasks of
memory, praxis, orientation, and language. An additional task of executive functioning, the Maze task, derived
from the Alzheimer’s Disease Cooperative Study (ADCS) extended version of the ADAS was included as part
of the ADAS-Cog in this study. The Maze task is scored on the number of seconds it takes the participant to
complete the task; therefore higher scores indicate greater impairment. Three versions of the ADAS-Cog were
administered; one at each of the study visits. Across the three versions, the stimuli for the word recall/recogni-
tion and the Maze task were varied. The more comprehensively assessed CAMCOG Orientation sub-test was
used in this study in place of the ADAS-Cog Orientation sub-test. The ADAS-Cog was administered to aMCI
and AD subjects only. Normative data from the literature.was used for the HE for the purpose of calculating z-
scores [40] [41].

1.3.2. Cambridge Automated Neuropsychological Test Battery (CANTAB) [37]

Three tasks from the computerized CANTAB battery were administered: Paired Associate Learning (PAL), Re-
action Time Index (RTI), and Spatial Working Memory (SWM). Responses on each of these tasks were made by
the participant on a touch-screen computer.
1) PAL
The PAL is a test of episodic memory in the visuospatial modality. In this task, six boxes appear on the screen,
followed by the presentation of a series of visual patterns. Each pattern is shown at a different location (inside
one of the six boxes), and following presentation of the series, participants must respond as to which pattern was
presented in which location. Patterns were included on the basis of being difficult to encode verbally. There are
six levels of difficulty, or stages—constituted by an increased number of patterns that must be encoded and re-
called (2, 3, 4, 5, 6, 8 pattern). The test is discontinued after failure to correctly identify the location of all pat-
terns on up to 6 consecutive trials at each stage. Two main scores were calculated: total number of errors and
number of levels/stages reached. An adjusted total score allowing for predicted errors on levels not completed is
calculated for those who discontinue the task early.
2) RTI
The RTI test provides a measure of attention and processing speed by means of two tasks of a) simple and b)
5-choice reaction time. In this test, participants must hold down a button, and in two separate conditions, re-
spond either to the appearance of a yellow spot stimulus within a single circle or location by touching the screen
at this location (simple reaction time task), or to this same spot when it appears at one of five possible locations
(5-choice reaction time). Several measures are recorded: simple and 5-choice reaction time, and simple and 5-
choice movement time. Simple reaction time is the speed in milliseconds it takes the participant to release the
press pad in response to the stimulus appearing in a single location. Five-choice reaction time is the speed in

183
M. Marsico et al.

milliseconds it takes the subject to release the press pad in response to the stimulus appearing in any one of five
locations. Simple movement time is the time taken to touch the stimulus after the press pad is released and in
trials where stimuli appear in one location only. Five-choice movement time is the time taken to touch the
stimulus after the press pad has been released and in trials where one of five possible different stimuli have been
presented.
3) SWM
SWM measures one’s ability to retain and manipulate spatial information in working memory. In this task, an
array of colored boxes appears on the screen, and the participant must search for a number of blue tokens hidden
inside these boxes. Only one token is hidden at a time, and participants must find enough tokens within a par-
ticular trial, to fill an empty space on the right on the screen. The number of tokens to be found increases with
subsequent trials and importantly, within each trial, once a token has been found at a particular location the par-
ticipants must not search that box for a further token as this constitutes an error. Task instructions are given, but
following this, participants are left to complete the task without guidance, meaning assessment of their strategy
or approach to completing the task can also be assessed. Two main scores are calculated: SWM Errors and
SWM Errors at 6 box stage.

1.4. Additional OPTIMA Battery Tasks

1.4.1. Cambridge Examination for Mental Disorders of the Elderly—Cognitive Examination
(CAMCOG) [30]
The CAMCOG is a pencil-and-paper test assessing cognitive function in the domains of orientation, language,
memory and learning, attention and calculation, abstract thinking, praxis, and perception. Some task items in-
cluded in the CAMCOG overlap directly with other cognitive assessments included in the study battery (e.g. the
MMSE), thus, where this occurred, items were not readministered as part of the CAMCOG. Alternate versions
of verbal recall and recognition (e.g. recalling address details), coin recognition and calculation items were ad-
ministered to avoid repetition and learning effects from the previous testing visit. The CAMCOG provides a
measure of overall cognitive functioning by means of a total score, maximum 107 points (where a higher score
indicates better performance), and measures of various cognitive domains by means of subscale scores. Of par-
ticular interest for this study was the CAMCOG Learning score, which provides a measure of learning memory
(maximum score 17 points), where higher scores indicate more intact learning ability.

1.4.2. Hopkins Verbal Learning Test Revised (HVLT) [48]

The HVLT is a test of verbal immediate and delayed recall and recognition memory. Participants are read a list
of 12 words on three occasions (trials 1 - 3) and must recall as many words as possible after each presentation.
The HVLT Total Recall (HVLT TR) score (maximum 36) is the total number of words recalled across the three
trials. The Learning Index score gives an indication of the amount of learning that occurs over subsequent pres-
entations of the word list, and is calculated by subtracting the number of words correctly recalled on trial 1 from
the higher of the total of words correctly recalled on trial 2 or 3. After a delay of approximately 20 minutes, par-
ticipants are again asked to recall as many words as possible from the 12-word list. The HVLT delayed recall
(HVLT DR) score is the number of words (maximum 12) correctly recalled on this trial. A recognition trial is
then administered where 24 words are read, and the participant must identify those which appeared in the origi-
nal 12-word list. The Discrimination Index is the number of true positive words recognised minus false positive
endorsements from the recognition condition. An alternate version of this task was administered on each study
visit.

1.4.3. Pattern and Letter Comparison Test [55]

The Pattern and Letter Comparison task is a test of processing speed. In the Pattern comparison subtest, partici-
pants are shown pairs of line drawings and have to respond as to whether the patterns in each pair are the same
or different, responding correctly to as many pairs as possible within a time limit of 20 seconds. In the Letter
comparison subtest, the premise is the same, but in this case, participants are responding as to whether strings of
letters, arranged in pairs, are the same or different as quickly as possible, also within a time limit of 20 seconds.
The total score for each subtest is the total number of correct responses made within the time limit (maximum of
30 points for Pattern comparison, maximum of 21 points for Letter comparison per page).

184
 M. Marsico et al.

1.4.4. The Placing Test (TPT) [56]

The Placing Test is a test of visuospatial paired associates learning. Participants are shown 12 pictures of objects
(e.g. a vase, a picnic basket). Items are arranged across 6 pages, each divided into a 2 × 2 grid. Two picture
stimuli appear on each page, the locations of which vary randomly, while the remaining grid positions remain
blank. Before starting the task, participants are told that the grid quadrants are numbered 1 - 4 (top left = 1, top
right = 2, bottom left = 3, bottom right = 4). To ensure full attention to the stimulus set, participants are asked to
say whether the objects are “pleasant”, “unpleasant”, or “neutral”, and to respond “blank” to empty quadrants.
The administrator points to each of the quadrants in order, asking the participant to respond as outlined. When
all 6 pages have been administered, participants are shown a further page, also in the above grid formation, with
no picture stimuli, but with the squares numbered as above. Each of the individual picture stimuli is now shown
to the participant, and they must respond as to which square (1 - 4) they previously saw the stimulus appear in.
The total score is the number of object locations correctly identified.

1.4.5. Symbol Digit Modalities Test (SDMT) [43]

The SDMT provides a measure of attention and information processing. Participants are shown a key comprised
of a line of symbols, each of which has a number which corresponds to it. Participants are then presented with a
series of symbols that do not have their corresponding number attached. They must use the key to fill in the
missing numbers for as many symbols as possible within a time limit of 90 seconds. The total score is the num-
ber of digits correctly entered against the series of symbols within the time limit, out of a possible maximum of
110.

1.4.6. Map Search Task (from Test of Everyday Attention) [44]

The Map Search task is a test of visual scanning and selective attention in which participants are required to cir-
cle as many target stimuli as possible (from a total of 80) from amongst an array of different distractors on a
busy road map within a time limit of two minutes. Three alternative versions of this task exist, one of which was
used at each study visit. Target stimuli include petrol stations, garages and restaurants, symbolized by pictures of
a petrol pump, spanner and cutlery, including distractor stimuli such as shopping trolleys. The total score is the
number of target stimuli circled within the time limit (maximum 80).

1.4.7. Graded Naming Test (GNT) [57]

The GNT is a test of semantic memory, where participants are asked to give the name of a series of 30 black and
white line drawings of objects. Test items are of varying familiarity (and thus difficulty), with less familiar ob-
jects presented later in the test. The total score is the number of objects correctly named (maximum 30 points).

1.4.8. CLOX [42]

The CLOX task is a test of both constructional praxis and executive functioning. Participants are instructed to
draw a clock that reads 1.45, and to set the hands and numbers on the face so child could read them. They are
then given a sheet of paper on which to do this, through which the outline of a circle printed on the opposite side
of the page can be seen. Once this part of the test (CLOX 1) is completed, the test administrator then turns the
page over, and in the printed circle, demonstrates drawing a clock, with correct placement, first of the 12, 3, 6,
and 9, and then the remaining numbers and hands (drawn as arrows). The participant is then asked to draw a
clock “just like” the administrators (CLOX 2), eliminating the executive element of the CLOX 1 condition; that
is, the additional requirement of planning an approach to the task. Each part of the CLOX test is scored out of 15
points according to a set of criteria, and a dysexecutive score is calculated by subtracting the CLOX 2 from the
CLOX 1 score.

Acknowledgements Including Sources of Support

The authors thank Audrey Rissmiller, Epidemiology, Merck & Co., Inc., all the OPTIMA participants and study
partners who agreed to take part in the study, and the OPTIMA nurses who helped with medical aspects of the
study. The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Mark Marsico,
Julie Chandler, April Grant and Xingshu Zhu are employees of Merck and own stock/stock options in Merck.
Celeste de Jager and Arwen Markwick were paid for services conducted on behalf of Merck.

185
M. Marsico et al.

List of Abbreviations
AD: Alzheimer’s Disease
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale
ADCS-ADL: Alzheimer’s Disease Cooperative Study-Activities of Daily Living
ADL: Activities of Daily Living
aMCI: Amnestic Mild Cognitive Impairment
ANOVA: Analysis of Variance
CAMCOG: Cambridge Cognitive Examination
CAMDEX: Cambridge Examination for Mental Disorders of the Elderly
CANTAB: Cambridge Automated Neuropsychological Test Battery
CDR: Clinical Dementia Rating
CLOX 1: Clock Drawing Task 1
CPU: Central Processing Unit
EMQ: Everyday Memory Questionnaire
GDS: Geriatric Depression Scale
GNT: Graded Naming Test
HE: Health Elderly
HVLT TR: Hopkins Verbal Learning Test Total Recall
HVLT DR: Hopkins Verbal Learning Test Delayed Recall
LCS: Letter Comparison Speed
MCI: Mild Cognitive Impairment
MMSE: Mini-Mental State Examination
NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s
Disease and Related Disorders Association
OPTIMA: Oxford Project to Investigate Memory and Aging
PAL: Paired Associate Learning
PALTOTEA: Paired Associate Learning Total Errors Adjusted
PCS: Pattern Comparison Speed
RTI: Reaction Time Index
SD: Standard Deviation
SDMT: Symbol Digit Modalities Test
SMC: Subjective Memory Complaint
sRT: Simple Reaction Time
SWM: Spatial Working Memory
SWMBE: Spatial Working Memory between Errors
TICS-M: Telephone Interview for Cognitive Status-Modified
TPT: The Placing Test
5cRT: Five-Choice Reaction Time

186