Clinical trial NCT01951118
Conditions: Alzheimer Disease Mild Cognitive Impairment Delirium, Dementia, Amnestic, Cognitive Disorders
Keywords: Smell Olfaction Disorders Atropine Donepezil Cholinesterase Inhibitors Cognition Disorders
Sponsor: New York State Psychiatric Institute
Start date: 2013-10-01; Completion date: 2019-05-01
Enrollment: 121 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Olfactory identification deficits occur in patients with Alzheimer's disease (AD), are associated with disease severity, predict conversion from mild cognitive impairment (MCI) to AD and are associated with healthy elderly subjects developing MCI. Odor (olfactory) identification deficits may reflect degeneration of cholinergic inputs to the olfactory bulb and other olfactory brain regions. Acetylcholinesterase inhibitors (ACheI) like donepezil show modest effects in improving cognition but can be associated with adverse effects and increased burden and costs because of the need for prolonged, often lifelong, treatment. Converging findings on odor identification test performance (UPSIT, scratch and sniff 40-item test) from four pilot studies, including two of our own, suggest that acute change in the UPSIT in response to an anticholinergic challenge (atropine nasal spray), incremental change over 8 weeks, and even the baseline UPSIT score by itself, may predict cognitive improvement with ACheI treatment in MCI and AD. If change in odor identification deficits can help to identify which patients should receive ACheI treatment, this simple inexpensive approach will advance the goal of improving personalized treatment, improve selection and monitoring of patients for ACheI treatment, reduce needless ACheI exposure with risk of side effects, and decrease health care costs.

Detailed description:
In this clinical trial, the investigators will evaluate, treat and follow two broad samples of adult patients at New York State Psychiatric Institute/Columbia University Medical Center. Study 1 will include 70 patients with amnestic Mild Cognitive Impairment (MCI). Study 2 will include 100 patients with probable Alzheimer's Disease (AD). Recruitment will be from clinics and/or advertisements. In the protocol, all 170 patients will receive baseline memory and olfactory assessments and are treated with donepezil. Patients will be followed for a total of 1 year. During this time, patients will be monitored closely by the study physician and will receive memory and olfactory assessments at weeks 0, 8, 26, and 52. In addition, an olfactory challenge test will be done at baseline.

This project will be of value in the selection of patients with MCI and AD for treatment based on the evaluation of olfaction tests to predict response to donepezil. Since mild cognitive impairment is widespread and Alzheimer's disease represents a major public health problem, this study has considerable public purpose and significance.

Arms: arm 1: Atropine nasal spray is administered at baseline for the atropine challenge which involves administration of the 40-item UPSIT immediately before and 45 minutes after atropine administration. Immediately after the atropine challenge, donepezil treatment is started and continues for 52 weeks.
Interventions: intervention 1: Donepezil
Intervention descriptions: intervention 1: Donepezil 5mg will be given for 4 weeks and if tolerated, the dose will be increased to 10 mg per day. The dose range of 5 to 10 mg of donepezil per day will be continued for the study duration, and this is the recommended dose for donepezil in the treatment of mild to moderate Alzheimer's disease. For patients who do not tolerate donepezil or have a history of intolerance to donepezil or cannot take donepezil for other reasons, treatment with other cholinesterase inhibitors (galantamine or rivastigmine) is permitted at any stage of the protocol. Data will be analyzed in two ways: for donepezil alone, and for any cholinesterase inhibitor (donepezil or rivastigmine or galantamine) as the intervention.

Protocol documents:
Prot_000.pdf: 
 
 
Olfactory Deficits and Donepezil Treatment in Cognitively Impaired 
Elderly 
NCT01951118 
Document Date: 08/05/2019 


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Protocol Title:
Olfactory Deficits and Donepezil Treatment 
in Cognitively Impaired Elderly
Protocol Number:
6655
First Approval:
09/28/2012
Expiration Date:
09/01/2020
Version Date:
08/05/2019
Contact Principal Investigator:
Davangere Devanand, MD
Email: dpd3@columbia.edu
Telephone: 646-774-8658
Co-Investigator(s):
Yaakov Stern, PHD
Gregory Pelton, MD
Howard Andrews, PHD
Edward Huey, MD
Research Chief:
Davangere Devanand, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation without modifications 
Division & Personnel
Division
What Division/Department does the PI belong to?
Geriatric Psychiatry
Within the division/department, what Center or group are you affiliated with, if any? 
N/A
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 


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State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.
Bruce Levin, PhD -- Co-investigator
Application for Continuation of Research
Status
Current Status of Study: 
All research interventions were completed. Only data analysis is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
Subject recruitment has ended. The last subject completed the protocol on March 25, 2019. No other 
research interventions have been completed since that date, nor will they be completed in the future. Data 
analysis is ongoing. Project goals are to evaluate odor identification deficits as predictors of improvement in 
100 patients with amnestic mild cognitive impairment (MCI, Study 1) and in 70 patients with mild to 
moderate Alzheimer’s disease (AD, Study 2) who are treated openly with the ACheI Donepezil.
 
Research participants were very amenable to continue the study until completion. The infrequent side 
effects of the medication, availability of the research team, and comprehensive testing have all contributed 
to a high pre-screening to enrollment ratio and participant retention rate. When the study was completed, an 
appropriate referral was always provided to the participant.
 
As stated in the protocol, if donepezil was not tolerated, galantamine or rivastigmine was used. These 
alternatives were used for 12 participants. There were no SAEs or other safety concerns among the 12 who 
received the alternative medications, galantamine or rivastigmine.
 
As described below, we enrolled 131 participants to date. The distribution of participants is as anticipated. 
We have consented 108 participants to sample #1: Mild Cognitive Impairment and 23 participants to sample 
#2: Alzheimer's disease.
 
Lastly, there are no new developments in the field that impact on the science of the risk/benefit balance of 
this protocol.
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 


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the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
No
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality? 
Yes
Certificate expiration date (mm/dd/yyyy) 
12/02/2018
Overall Progress
Approved sample size
170
Total number of participants enrolled to date
131
Number of participants who have completed the study to date 
94
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 
Sample Demographics
Specify population
Adults with Mild Cognitive Impairment
Total number of participants enrolled from this population to date 
108
Specify population #2
Adults with Mild to Moderate AD
Total number of participants enrolled from this population to date 
23
Gender, Racial and Ethnic Breakdown 


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Of the 108 adults with Mild Cognitive Impairment (MCI) recruited for this protocol, 56 have been female 
and 52 have been male. 59 subjects identify as Caucasian, 3 identify as Asian, 26 identify as African 
American, 18 identify as Hispanic, and 2 identify as a Mix of two or more races.
 
Of the 23 adults with Mild to Moderate Alzheimer's Disease (AD) recruited for this protocol, 11 have been 
female and 12 have been male. 12 subjects identify as Caucasian, 2 identify as Asian, 3 identify as African 
American, 5 identify as Hispanic, and 1 identifies as a Mix of two or more races.
 
Of the 131 total subjects recruited for this protocol, 67 have been female and 64 have been male. 71 subjects 
identify as Caucasian, 29 identify as African American, 23 identify as Hispanic, 5 identify as Asian, and 3 
identify as a Mix of two or more races.
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year
0
Did the investigator withdraw participants from the study? 
No
Did participants decide to discontinue study involvement? 
No
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Neuropsychological Evaluation
   Collection of Biological Specimens
   Medication Trial
   Biological Challenge Procedure
   Medication-Free Period or Treatment Washout
   Off-label Use of Drug or Device
Population
Indicate which of the following populations will be included in this research
   Adults who may have impaired decision-making ability
   Adults who lack capacity to consent
   Adults over 50
   Non-English Speaking Participants


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Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
Yes
Select one of the following
The grant/contract is currently funded
Source of Funding
Federal
Institute/Agency
National Institutes of Health
Grant Name
Olfactory deficits and donepezil treatment in cognitively impaired elderly
Grant Number
1 R01 AG041795
Select one of the following
Single Site
Business Office
CU
Does the grant/contract involve a subcontract? 
No
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
   Other Columbia University Medical Center Facilities
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
Olfactory identification deficits occur in patients with Alzheimer’s disease (AD), are associated with disease 
severity, predict conversion from mild cognitive impairment (MCI) to AD and are associated with healthy 


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elderly subjects developing MCI. Odor (olfactory) identification deficits may reflect degeneration of 
cholinergic inputs to the olfactory bulb and other olfactory brain regions. Acetylcholinesterase inhibitors 
(ACheI) like donepezil show modest effects in improving cognition but can be associated with adverse 
effects and increased burden and costs because of the need for prolonged, often lifelong, treatment. 
Converging findings on odor identification test performance (UPSIT, scratch and sniff 40-item test) from 
four pilot studies, including two of our own, suggest that acute change in the UPSIT in response to an 
anticholinergic challenge (atropine nasal spray), incremental change over 8 weeks, and even the baseline 
UPSIT score by itself, may predict cognitive improvement with ACheI treatment in MCI and AD. If change 
in odor identification deficits can help to identify which patients should receive ACheI treatment, this 
simple inexpensive approach will advance the goal of improving personalized treatment, improve selection 
and monitoring of patients for ACheI treatment, reduce needless ACheI exposure with risk of side effects, 
and decrease health care costs.
Project goals are to evaluate change in odor identification deficits as predictors of improvement in 
100 patients with MCI (Study 1) and in 70 patients with mild to moderate AD (Study 2) during open 
treatment with the ACheI, donepezil. In both studies, we hypothesize that the decrease in UPSIT scores 
from pre- to post-atropine nasal spray challenge conducted at baseline will be associated with cognitive and 
global improvement from baseline to both 26 weeks and 52 weeks of donepezil treatment. The rationale is 
that those MCI patients who have AD brain pathology will have a cholinergic deficit and worsening of odor 
identification with the acute atropine challenge, and these patients will be more likely to improve with 
ACheI treatment. In both studies, we hypothesize that the increase in UPSIT scores from baseline (pre-
atropine) to 8 weeks of donepezil treatment will be associated with cognitive and global improvement from 
0 weeks to both 26 weeks and 52 weeks of donepezil treatment. This is the first systematic effort to evaluate 
the clinical utility of short-term changes in odor identification deficits to predict long-term cognitive and 
global improvement on ACheI treatment, and includes the first use of an anticholinergic challenge that has a 
sound neurobiological basis.
Background, Significance and Rationale
Background, Significance and Rationale
Background 
In autopsies of patients at the earliest pathological stages of AD, neurofibrillary tangles, and to a lesser 
extent amyloid plaques, are seen in olfactory sensory neurons and the olfactory bulb. The piriform cortex, 
entorhinal cortex, and periamygdaloid nucleus are olfactory projection areas that show the greatest density 
of neurofibrillary tangles. Olfactory deficits in early AD likely reflect pathology in the olfactory bulb and 
higher order projection areas for olfactory processing, including the anterior olfactory nucleus, orbitofrontal 
cortex, piriform cortex, amygdala, entorhinal cortex and hippocampus. 
Olfactory perception, including detection, identification and memory, are impaired in AD. These deficits 
cannot be explained by naming deficits or lexical difficulty with written words in the test format. All 
published studies show odor identification deficits in AD and MCI compared to healthy control subjects. 
The sensory dysfunction is fairly specific to olfaction, as taste and vision remain intact in mild AD. In AD, 
these deficits may precede or coincide with the onset of memory loss. Patients with MCI show some 
impairment in olfactory sensitivity (detection threshold) and considerable identification deficits, while 


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patients with AD are impaired in both these domains and odor discrimination (choice between two 
contrasting odors). Odor identification deficits remain the most consistently identified olfactory impairment 
in AD. We showed that odor identification deficits (UPSIT) increased the risk of conversion from MCI to a 
clinical diagnosis of AD. The effect size may be comparable to that of tests of verbal memory. Odor 
discrimination also predicts conversion to AD, but to a lesser degree. Overall, the literature strongly 
supports the use of an odor identification test as the primary measure of olfaction in the proposed project.
Subjective reports of olfactory function may relate more to cognition than objective olfactory impairment. 
We will obtain self-reports of olfactory functioning with a Likert-type scale (range 1-7, ancillary measure) 
with one question each about the ability to detect and identify odors; we use this in another MCI study.
Odor identification deficits as a biomarker of response to cholinergic therapy in AD
Olfactory epithelium and bulb cells regenerate throughout life. AD affects neurons and synapses that use 
acetylcholine, including soluble amyloid oligomers. Neurons with choline acetyltransferase are detected in 
all olfactory bulb layers, cholinergic synapses are concentrated on dendrites of periglomerular or granule 
cells, and olfactory bulb function is enhanced by acetylcholine and impaired by anticholinergic agents. In 
mice, donepezil treatment rescues the cholinergic neurons in the medial septum from the neurodegeneration 
induced by olfactory bulbectomy. Olfactory bulb cholinergic receptors are mainly muscarinic. Atropine and 
donepezil act almost entirely on muscarinic, and not nicotinic, cholinergic transmission.
In a British study, twenty-five of 28 patients with mild to moderate AD (Mini Mental State Exam/MMSE 
score 15-25 out of 30) completed a 3-month open trial with donepezil (5 mg/day for 4 weeks followed by 5 
mg/day or 10 mg/day). Eighteen of 25 patients remained on donepezil by end-trial. The 40-item UPSIT was 
given at baseline and at 8 weeks. Using the criterion of a 4-point improvement on the 40-item UPSIT, there 
were 5 improvers and 13 non-improvers. Patients who received donepezil had improvement in UPSIT and 
CIBIC-plus (1-7 scale: global assessment of dementia) scores. Increase in UPSIT scores correlated with 
improvement in the CIBIC-plus (r=0.7, p < 0.01) and the Bristol Activities of Daily Living Scale (r=0.7, p < 
0.01). In regression analyses that included the MMSE and neuropsychiatric inventory (NPI) scores, only 
change in UPSIT scores over 8 weeks was associated with improved CIBIC-plus scores at end-point (12 
weeks). Short study duration and MMSE as the only cognitive assessment were limitations. We will follow 
patients for 52 weeks with systematic cognitive assessment, and evaluate change in UPSIT over the first 8 
weeks to predict improvement on donepezil at 26 and 52 weeks.
Pilot studies at NYSPI. In a pilot study of patients with comorbid depression and cognitive impairment, we 
found that, worse performance on the UPSIT predicted cognitive improvement after donepezil treatment. 
Similar findings may be obtained in amnestic MCI patients without depression as proposed in Study 1. Pilot 
study 2. In our naturalistic follow-up study of 148 MCI patients (R01AG17761) with baseline UPSIT, we 
examined change in SRT total recall for the first 12 months after an ACheI (most patients were on 
donepezil) was started (variable time-point, doctor’s choice). Low baseline UPSIT was associated with 
increase in SRT total recall over 12 months in those MCI patients who received ACheI (n=24, r=0.52, 
p=0.009) and in the subset that converted to AD and received ACheI (n=16, r=0.51, p=0.04). These results 
were obtained in both the MCI sample treated with ACheI and in the subset that converted from MCI to AD 
and received ACheI. In regression analyses on the increase in SRT total recall over 12 months, low baseline 
UPSIT but not baseline SRT total recall predicted improvement in SRT total recall over 12 months of 


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ACheI treatment; baseline age, sex and education were not significant. To date, no clinical predictor or 
biomarker has been shown consistently to predict response to ACheI, e.g., MRI hippocampal volume. This 
may be related to donepezil’s small effect size, which makes our olfaction findings quite striking.
Atropine challenge. In the olfactory bulb, increase in cholinergic input enhances odor discrimination, and 
cholinergic receptor blockade lowers discrimination. The thin cribriform plate separates the olfactory bulb 
from the nasal cavity. Intranasally-administered drugs can cross the ‘nose-brain barrier’. Animal studies 
using radio-labelled drugs applied intranasally show peak levels in the olfactory bulb, and concentrations in 
other brain regions decline with distance from the olfactory bulb. The atropine nasal spray challenge 
strategy was presented by Schofield et al. In patients with mild AD (n=13), MCI (n=14) and healthy control 
subjects (n=29), change in UPSIT scores from pre- to post-atropine sulfate (1 mg) nasal spray challenge was 
evaluated. In hierarchical regression analyses on episodic memory domain score, the change in UPSIT 
scores from pre- to post-atropine explained more variance in episodic memory than left hippocampal 
volume. We will evaluate the change in UPSIT scores from pre- to post-atropine sulfate nasal spray 
challenge as a predictor of improvement on donepezil.
Significance and Innovation 
1. This is the first systematic effort to evaluate odor identification deficits to predict the likelihood of 
improvement on ACheI treatment. One small-scale short-term study examined concurrent changes in UPSIT 
scores and donepezil effects over 8 weeks. We will study the more clinically relevant question of whether 
short-term change in odor identification deficits predicts long-term response in much larger samples.
2. A simple, inexpensive odor identification test to predict clinical improvement with ACheI has not been 
tested systematically, in contrast to the extensive efforts with expensive imaging procedures that require 
complex analytic techniques but have shown inconsistent results in predicting improvement with ACheI in 
AD.
3. A challenge procedure to predict cognitive improvement has never been conducted for ACheI or other 
treatments in MCI or AD. This will be the first project to use the atropine nasal spray challenge for this 
purpose. The first published challenge procedure to examine the pathophysiology of the cholinergic system 
in AD was conducted with intravenous scopolamine in a small sample, and there has been limited work in 
MC. The use of an intravenous agent as a predictor is impractical, and scopolamine at higher doses is toxic.
4. We will evaluate an anticholinergic challenge and change in the UPSIT, and baseline UPSIT in 
exploratory analyses, in order to predict cognitive change with ACheI treatment. Directly testing changes in 
a specific neurotransmitter system to evaluate changes in response to treatment that works by affecting the 
same system is unique and innovative in MCI and AD in addition to having a sound neurophysiological 
basis.
Rationale
Implications of the project. Accurate prediction using short-term change in odor identification deficits (0-8 
weeks, pre-post atropine nasal spray in this project) to identify who should receive ACheI improves 
potential benefit while avoiding the risk of side effects with needless exposure in patients without AD brain 


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pathology. Treatment for many years increases costs even if costs are low per generic pill. Our MCI study 
provides a cost-effective, simple approach to personalize selection for treatment that may delay clinical 
conversion to AD and to select/stratify patients in treatment trials. The olfactory bulb has regenerative 
capacity throughout the life span. Change in olfactory identification performance may be an early indicator 
of disease and could prove useful in predicting response to future disease-modifying treatments for MCI and 
AD. An odor identification test is inexpensive and easy to administer compared to MRI/PET imaging and 
lumbar puncture for cerebrospinal fluid (CSF). If the hypotheses are supported by the results in one study 
but not both studies, the results will still provide important information about how change in odor 
identification deficits should be used as a predictor of improvement for treatment selection or for monitoring 
treatment in MCI and AD.
Specific Aims and Hypotheses
Specific Aims and Hypotheses
Study 1 Aim. To evaluate short-term changes in odor identification deficits as predictors of long-term 
cognitive and global improvement in patients with MCI who receive donepezil or other cholinesterase 
inhibitor treatment.
Hypotheses. 1. Among MCI patients, the acute decrease in UPSIT scores from pre- to post-atropine nasal 
spray challenge conducted at baseline (0 weeks) will predict cognitive (SRT total recall and modified 
Alzheimer’s Disease Assessment Scale-cog, ADAS-cog) and global improvement (Clinician’s Interview 
Based Impression, CIBIC-plus)93 from 0 weeks to both 26 weeks and 52 weeks of donepezil or other 
cholinesterase inhibitor treatment. The rationale is that MCI patients who have AD brain pathology will 
have a cholinergic deficit and worsening of odor identification with the acute atropine challenge, and these 
patients will be more likely to improve with ACheI.
2. Increase in UPSIT scores from baseline (0 weeks, pre-atropine) to 8 weeks of donepezil or other 
cholinesterase inhibitor treatment will predict cognitive and global improvement from 0 weeks to both 26 
and 52 weeks of donepezil or other cholinesterase inhibitor treatment.
Exploratory hypotheses. 1. Lower baseline UPSIT score will predict cognitive improvement (change in SRT 
total recall and ADAS-cog) on donepezil or other cholinesterase inhibitor over 12 months (based on our new 
pilot data). 2. The acute atropine nasal spray-induced decrease in UPSIT scores at baseline, and the increase 
in UPSIT scores from 0 to 8 weeks, will be associated with a decreased likelihood of conversion to 
dementia at 52 weeks. This hypothesis is exploratory because the small number of converters to dementia in 
one year will limit statistical power.
Study 2 Aim. To evaluate short-term changes in odor identification deficits as predictors of long-term 
cognitive and global improvement in patients with mild to moderate AD who receive donepezil or other 
cholinesterase inhibitor treatment. The hypotheses are similar to those for the MCI sample.
Hypotheses. 1. Among mild to moderate AD patients, the acute decrease in UPSIT scores from pre- to post-
atropine challenge at baseline (0 weeks) will predict cognitive (SRT total recall and modified ADAS-cog) 
and global (CIBIC-plus) improvement from 0 weeks to both 26 weeks and 52 weeks of donepezil or other 


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cholinesterase inhibitor treatment.
2. Increase in UPSIT scores from baseline (0 weeks, pre-atropine) to 8 weeks of donepezil or other 
cholinesterase inhibitor treatment will predict cognitive and global improvement from 0 weeks to both 26 
and 52 weeks of donepezil or other cholinesterase inhibitor treatment.
Exploratory hypothesis. Lower baseline UPSIT score will be associated with cognitive improvement (SRT 
total recall and ADAS-cog) on donepezil over 12 months. This new hypothesis is based on our new pilot 
data.
Description of Subject Population
Sample #1
Specify subject population
Adults with amnestic mild cognitive impairment
Number of completers required to accomplish study aims
80
Projected number of subjects who will be enrolled to obtain required number of completers
100
Age range of subject population
55-95
Sample #2
Specify subject population
Adults with probable Alzheimer’s disease
Number of completers required to accomplish study aims
60
Projected number of subjects who will be enrolled to obtain required number of completers
70
Age range of subject population
55-95
Gender, Racial and Ethnic Breakdown
Based on our previous studies recruiting a similar subject population, we expect a gender distribution of 
approximately 53% female and the ethnic breakdown of approximately 73% non-Hispanic white, 17% 
Hispanic, 7% African American, 2% Asian American and 1% other. This distribution of patients represents 
the gender and ethnic breakdown of the larger group of patients who present to our clinical services, and is 
comparable to census data from the New York metropolitan area (city and suburbs) that form our referral 
base. No patients will be excluded from study participation on the basis of gender or ethnicity.
Description of subject population
Study 1 (MCI) will include 100 patients with amnestic MCI (subjective memory complaints, WMS-R 


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Logical Memory score >1.5 SD below norms, without functional decline consistent with dementia) will be 
recruited. 
Study 2 (AD). In the new NIA diagnostic criteria, probable AD by NINCDS-ADRDA criteria has been 
updated to “probable AD dementia: core clinical diagnosis with amnestic or nonamnestic initial 
presentation”. In Study 2, all 70 patients whom we will include will need to meet probable AD criteria by 
both the original and recent NIA core clinical criteria definitions that are virtually identical.
Recruitment Procedures
Describe settings where recruitment will occur
Patients will be recruited from the Columbia University Medical Center through the ADRC that includes the 
Memory Disorders Clinic at the New York State Psychiatric Institute (NYSPI), and the Behavioral 
Neurology Practice Group at the Neurological Institute. Drs. Devanand, Pelton, Huey, Bell, Kerner, and 
Deliyannides are attending psychiatrists in these settings.
How and by whom will subjects be approached and/or recruited? 
All patients will be directly recruited by Drs. Devanand, Pelton, Huey, Bell, Kerner, and Deliyannides.
How will the study be advertised/publicized? 
The study will be supported by advertising to recruit subjects, primarily through newspapers. Typically, we 
have utilized the Riverdale Press and AM New York for these types of studies.
Do you have ads/recruitment material requiring review at this time? 
Yes
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT01951118
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Some subjects enrolled in this study may also be concurrently participating in the protocol "Alzheimer's 
Disease Research Center (ADRC) at Columbia University" (NYSPI IRB #5467R, Principal Investigator Dr. 
Lawrence Honig), which is a naturalistic follow-up study of all patients with MCI or AD who are seen 
annually at the Memory Disorders Center until death. This evaluation protocol is conducted entirely through 
the Memory Disorders Center and is identical to that conducted in the approximately 25 ADRC centers 
around the U.S., funded by the National Institute of Aging for this purpose. The goal of the ADRC is to 
characterize patients with MCI and AD, and to facilitate additional research projects that can be piggy-
backed on the core annual ADRC assessments (NACC/UDS assessment battery) in these patients. The 
proposed olfaction-donepezil study fits in with these ADRC goals and therefore does not represent a conflict 
with the ADRC protocol. To avoid practice effects with the ADRC neuropsychogical test battery, the 


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NACC/UDS neuropsychological test battery done at 0 and 52 weeks in our proposed study will be 
scheduled to coincide in time with the ADRC annual assessments. This is feasible because when a patient is 
diagnosed with MCI and then recruited for the ADRC protocol in the Memory Disorders Center, we will 
also recruit the patient for our proposed study.
Subjects may also participate in the following protocols outside of the MDC if eligible:
- ANTIDEPRESSANT RESPONSE IN THE TREATMENT OF DEPRESSIVE SYMPTOMS AND 
FRAILTY CHARACTERISTICS IN OLDER ADULTS (PI Patrick Brown) - IRB #7289R 
 
- PHYSICAL AND MENTAL FATIGABILITY IN LATE LIFE CLINICAL POPULATIONS (PI 
Patrick Brown) - IRB #7360 
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Amnestic MCI patients (Study 1)
Create or insert table to describe the inclusion criteria and methods to ascertain them
Inclusion Criteria
Method of Ascertainment
1. Age 55-95 years
Patient Self-report
2. Diagnosis of amnestic mild cognitive 
impairment by Petersen (1999) criteria. All the 
following criteria need to be met: (i) subjective 
memory complaints, (ii) Wechsler Memory 
Scale-III Logical Memory combined Story A + 
B immediate recall score or combined Story A 
+ B delayed recall score OR Free and Cued 
Selective Reminding Test immediate recall or 
delayed recall score greater than 1.5 SD below 
norms OR Selective Reminding Test immediate 
recall or delayed recall score greater than 1.5 
SD below norms, and (iii) no functional 
impairment consistent with dementia. Patients 
who have cognitive deficits in domains other 
than memory without meeting criteria for 
dementia will be included, i.e., both solely 
amnestic and amnestic-plus MCI will be 
included.
Physician and Neuropsychological evaluation 
(DSM-IV criteria)
 
3. Folstein MMSE 23 or higher out of 30.
Neuropsychological evaluation
4. Clinical Dementia Rating (CDR) of 0.5 
(questionable dementia)
Physician evaluation
5. Availability of informant; patients without an 
Patient Self-report


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informant will not be recruited.
6. Retains capacity to consent
Physician evaluation
Create or insert table to describe the exclusion criteria and methods to ascertain them
Exclusion Criteria
Method of Ascertainment
1. Medical contraindication to donepezil or other 
AchEI treatment. Contraindications to donepezil 
include: Current or recent (past 6 months) 
epileptic seizure, atrioventricular heart block, 
sick sinus syndrome, sinus bradycardia, asthma, 
bronchial muscle spasm resulting from COPD, 
stomach or intestinal ulcer, bleeding of the 
stomach or intestines, blockage of urinary 
bladder, feeling faint, stomach ulcer from 
aspirin or ibuprofen-like drugs.
 Physician Evaluation, EKG
 
2. Medications with anticholinergic effects that 
have been shown to adversely impact cognition 
(e.g. diphenhydramine, all tricyclic 
antidepressants, antipsychotics with strong 
anticholinergic effects (thioridazine, 
chlorpromazine, olanzapine, clozapine) will not 
be permitted. Benzodiazepines in lorazepam 
equivalents ≥ 2 mg daily and narcotics will also 
not be permitted.  Medications with less 
prominent anticholinergic effects (e.g. SSRIs 
including paroxetine) will be permitted for as 
long as dose is stable for at least 6 months prior 
to signing consent. If medications with 
anticholinergic effects are used within the above 
permitted parameters, the medication dose will 
be expected to remain stable and will not be 
changed during the course of the study.
Physician Evaluation
3.      Current clinical diagnosis of dementia (includes 
Alzheimer’s disease), schizophrenia, 
schizoaffective disorder, other psychosis, or 
bipolar 1 disorder (DSM-IV TR criteria).
Physician Evaluation
4. Current or recent (past 6 months) alcohol or 
substance dependence (DSM-IV TR criteria).
Physician Evaluation
5. Current untreated major depression or 
suicidality. 
Physician Evaluation
6. Parkinson’s disease, Lewy body disease, 
multiple sclerosis, CNS infection, Huntington’s 
disease, amyotrophic lateral sclerosis, other 
Physician Evaluation


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major neurological disorder.
7. Mental Retardation
Physician Evaluation
8. Cystic Fibrosis
Physician Evaluation
9. Clinical stroke with residual neurological 
deficits. MRI findings of cerebrovascular 
disease (small infarcts, lacunes, periventricular 
disease) in the absence of clinical stroke with 
residual neurological deficits will not lead to 
exclusion.
Physician Evaluation
10.  Patients receiving cholinesterase inhibitors     
(donepezil, rivastigmine, galantamine) or      
memantine. Patients already receiving one of   
these medications at screening who undergo a   2-
week washout before starting all study      
procedures will not be excluded.
Physician Evaluation
11. Acute, severe, unstable medical illness. For 
cancer, patients with active illness or metastases 
will be excluded, but past history of 
successfully treated cancer will not lead to 
exclusion.
Physician Evaluation
12. Exclusion criterion for olfaction: history of 
anosmia due to any cause (e.g. traumatic or 
congenital) verified by UPSIT score of <11 out 
of 40; head trauma with loss of consciousness; 
nasal sinus disease; current upper respiratory 
infection; severe allergies to odors; current 
smoker > 1 pack daily. 
Physician Evaluation, Self report
13. Exclusion criterion for atropine nasal spray: 
presence of nasal deformity or disease that makes 
it difficult to administer the atropine nasal spray 
reliably. A patient who cannot complete the 
atropine nasal spray procedure can still participate 
in the rest of the study.
 Self-report, Review of medical records as needed. 
Inclusion/Exclusion Criteria #2
Name the subject group/sub sample
Probable Alzheimer’s disease patients (Study 2)
Create or insert table to describe the inclusion criteria and methods to ascertain them 
Inclusion Criteria
Method of Ascertainment
1. Age 55-95 years
Patient Self-report


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2. Diagnosis of probable AD by the original 
NINCDS-ADRDA criteria (McKahnn et al, 
1984) and the diagnosis of “Probable AD 
dementia:core clinical diagnosis witn amnsetic 
or nonamnestic initial presentation” by the new 
NIA criteria (McKhann et al, 2011). The two 
sets of diagnostic criteria are virtually identical. 
Physician and Neuropsychological evaluation 
(DSM-IV criteria)
 
3. Folstein MMSE 18-27 out of 30.
Neuropsychological evaluation
4. Availability of informant; patients without an 
informant will not be recruited.
Patient Self-report
5. Patient retains capacity to consent for 
him/herself or retains the capacity to identify a 
surrogate who will consent on his/her behalf.  
Physician evaluation
Create or insert table to describe the exclusion criteria and methods to ascertain them 
Exclusion Criteria
Method of Ascertainment
1. Medical contraindication to donepezil or other 
AchEI treatment. Contraindications to 
donepezil include: current or recent (past 6 
months) epileptic seizure, atrioventricular heart 
block, sick sinus syndrome, sinus bradycardia, 
asthma, bronchial muscle spasm resulting from 
COPD, stomach or intestinal ulcer, bleeding of 
the stomach or intestines, blockage of urinary 
bladder, feeling faint, stomach ulcer from 
aspirin or ibuprofen-like drugs.
Physician Evaluation, EKG
 
2. Medications with anticholinergic effects that 
have been shown to adversely impact cognition 
(e.g. diphenhydramine, all tricyclic 
antidepressants, antipsychotics with strong 
anticholinergic effects (thioridazine, 
chlorpromazine, olanzapine, clozapine) will not 
be permitted. Benzodiazepines in lorazepam 
equivalents ≥ 2 mg daily and narcotics will also 
not be permitted.  Medications with less 
prominent anticholinergic effects (e.g. SSRIs 
including paroxetine) will be permitted for as 
long as dose is stable for at least 6 months prior 
to signing consent. If medications with 
anticholinergic effects are used within the above 
permitted parameters, the medication dose will 
be expected to remain stable and will not be 
changed during the course of the study.
Physician Evaluation


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3.      Current clinical diagnosis of schizophrenia, 
schizoaffective disorder, other psychosis, or 
bipolar 1 disorder (DSM-IV TR criteria).
Physician Evaluation
4. Current or recent (past 6 months) alcohol or 
substance dependence (DSM-IV TR criteria).
Physician Evaluation
5. Current untreated major depression or 
suicidality as assessed by the study 
psychiatrists. 
Physician Evaluation
6. Parkinson’s disease, Lewy body disease, 
multiple sclerosis, CNS infection, Huntington’s 
disease, amyotrophic lateral sclerosis, other 
major neurological disorder.
Physician Evaluation
7. Mental Retardation
Physician Evaluation
8. Cystic Fibrosis
Physician Evaluation
9. Clinical stroke with residual neurological 
deficits. MRI findings of cerebrovascular 
disease (small infarcts, lacunes, periventricular 
disease) in the absence of clinical stroke with 
residual neurological deficits will not lead to 
exclusion.
Physician Evaluation
10.  Patients receiving cholinesterase inhibitors 
(donepezil, rivastigmine, galantamine) or 
memantine. Patients already receiving one of these 
medications at screening who undergo a 2-week 
washout before starting all study procedures will 
not be excluded.
Physician Evaluation
11. Acute, severe, unstable medical illness. For 
cancer, patients with active illness or metastases 
will be excluded, but past history of 
successfully treated cancer will not lead to 
exclusion.
Physician Evaluation
12. Exclusion criterion for olfaction: history of 
anosmia due to any cause (e.g. traumatic or 
congenital) verified by UPSIT score of <11 out 
of 40; head trauma with loss of consciousness; 
nasal sinus disease; current upper respiratory 
infection; severe allergies to odors; current 
smoker > 1 pack daily. 
Physician Evaluation, Self report
 
 13. Exclusion criterion for atropine nasal spray: 
presence of nasal deformity or disease that makes 
it difficult to administer the atropine nasal spray 
reliably. A patient who cannot complete the 
atropine nasal spray procedure can still participate 
in the rest of the study.
 Self-report, Review medical records as needed.


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Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
Yes
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
No
Describe procedures used to obtain consent during the screening process 
Subjects referred to the study will first undergo a screening process (MMSE, WMS-III Logical Memory 
Test, FC-SRT and Clinical Dementia Rating (CDR), initial check for inclusion/exclusion criteria). When the 
Selective reminding test (SRT) immediate and delayed has been administered within three months prior 
to the start of the study, and the patient scored greater than 1.5 SD below norms on the test, that score can 
also be used for the patient to meet inclusion criteria in place of the WMS-III Logical
Memory Test or FC-SRT. If the patient appears eligible based on screening, Drs. Devanand, Pelton, Huey, 
Bell, Kerner, or Deliyannides will confirm by patient interview that all inclusion/exclusion criteria are met 
and they will go over the details of the study with the patient and the informant as described in the informed 
consent form. Subjetcs will also be informed that they need to have an informant available to be interviewed 
in order to be in the study. Patients will be given ample time to review the consent form and will be given 
the opportunity to ask questions. Only Drs. Devanand, Pelton, Huey, Bell, Kerner, or Deliyannides will 
obtain consent from the patients. Throughout the study, the study physicians will cross-cover each other for 
patient assessments and management in the study. All study physicians are board certified psychiatrists and 
their clinical role is to serve as the study physicians. 
The week 0 baseline visit will occur approximately 1 week after the screening visit. MMSE, WMS-III 
Logical Memory, and FC-SRT test done at screening will not be repeated at week 0.
Describe Study Consent Procedures
Clinical Settings.
      Memory Disorders Clinic. All patients who come to the clinic first sign a consent form (IRB protocol # 
6562R) that indicates that their data will be used in research as part of the ADRC consortium (national 


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Alzheimer’s consortium; we are a site) and are informed that they may be approached for participation in 
other studies if they are eligible. Memory Disorders Clinic physicians include Drs. Devanand, Pelton, Huey, 
Bell, Kerner, and Deliyannides who work in a supervisory capacity or follow patients whom they have seen 
for a long period of time. New evaluations are conducted by Neurology fellows. If a patient is potentially 
eligible, these fellows will briefly describe the study and if the patient is interested then refer the patient to 
Dr. Devanand or Dr. Pelton or Dr. Huey, Dr. Bell, Dr. Kerner, or Deliyannides (whoever is available at that 
time). Therefore, in this setting patients will first be approached about the study by a non-study physician.
      Behavioral Neurology Practice Group. Dr. Huey and Dr. Bell, but not Dr. Devanand or Dr. Pelton or 
Dr. Kerner or Dr. Deliyannides is a member of this group. If Dr. Huey or Dr. Bell evaluates a patient who 
may be eligible, he/she will explicitly inform them that they have the option of getting a second opinion 
regarding study participation from a physician in the clinical setting who is not an investigator in the study, 
and immediately arrange for that second opinion if requested. 
 
Documenting Consent. 
Voluntary written informed consent will be obtained from all MCI and AD subjects by Drs. Devanand, 
Pelton, Huey, Bell, Kerner, or Deliyannides. All patients at enrollment will be assessed for capacity to 
consent and this will be documented in the chart.
 
The consent form describes the nature of the procedures and time requirements, potential risks, the 
confidentiality of information, and the rights of research subjects, including their right to withdraw from the 
research at any time without loss of benefits to which they are otherwise entitled. It is made explicit that this 
protocol involves open treatment with donepezil or other Acetylcholinesterase Inhibitors with return visits at 
specified time points, and a description of the research assessments. The consent process also includes 
documentation of permission to obtain previous medical records.
 
The informant must give verbal consent indicating his or her willingness to provide information about the 
patient and complete questionnaires and interviews with the research staff. The waiver of 
consent/authorization only applies to informants only is allowed according to the Federal Regulation 45 
CFR 46.117(c)(2) which states, "the research presents no more than minimal risk of harm to subjects and 
involves no procedures for which written consent is normally required outside of the research context."
 
The IRB-approved forms for informed consent and for assessment of capacity are made part of the patient’s 
permanent medical record, with a copy being filed in the research chart. Specific consent issues and risks 
pertaining to apolipoprotein E genotyping are described below.
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
Waiver of Documentation of Consent
Would the consent form signature be the only link between the subject’s identity and the research data?
Yes


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Is breach of confidentiality the main study risk?
No
Describe the study component(s) for which waiver of documentation is requested.
The informant must give verbal consent indicating his or her willingness to provide information about the 
patient and complete questionnaires and interviews with the research staff. The waiver of 
consent/authorization only applies to informants and is allowed according to the Federal Regulation 45 CFR 
46.117(c)(2) which states, "the research presents no more than minimal risk of harm to subjects and 
involves no procedures for which written consent is normally required outside of the research context."
Assent Procedures
Describe procedures by which subject assent will be assessed and/or recorded
The IRB-approved forms for informed consent and for assessment of capacity are made part of the patient’s 
permanent medical record, with a copy being filed in the research chart.
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Deliyannides, Deborah, MD
Devanand, Davangere, MD
Huey, Edward, MD
Pelton, Gregory, MD
Type in the name(s) not found in the above list
Dr. Karen Bell
Independent Assessment of Capacity
You have indicated that your study involves subjects who MAY LACK capacity to consent.
Does this study require an independent assessment of capacity?
Yes
Methods/procedures for capacity assessment
For NYSPI/Columbia, New York State regulations regarding capacity to consent, as used by the New York 
State Psychiatric Institute IRB, will be followed as we do in all IRB protocols for the following two groups 
within the study. Under no circumstance will a patient objecting to participation be included in the study.
 
Baseline
I. MCI Patients: All MCI patients will have an MMSE score greater than 20 at the beginning of the study 
and therefore are expected to have the capacity to provide informed consent. Before beginning the study, all 
MCI patients will be approached to appoint a surrogate. If the patient does not appoint a surrogate, the 


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patient will still be included in the study. If the patient decides to appoint a surrogate (in case they lose the 
capacity to consent while participating in the study), we will use the following forms to document the choice 
of surrogate: PCS Form III(b) Record of Choice of Surrogate, PCS Form III(c) Statement by Witnesses, and 
PCS Form IV Consent by Surrogate. In order to complete these three forms, the patient, surrogate, study 
physician, and two witnesses must be present and sign in various places on the form. The complete PCS 
Model Consent Form does not need to be completed in these cases since all MCI patients are expected to 
have the capacity to appoint a surrogate and therefore do not need to undergo assessment by an independent 
evaluator.
II. AD Patients: At the beginning of the study, AD patients may have an MMSE score less than or greater 
than 20. 
            (1) All AD patients with an MMSE score equal to or greater than 20 are expected to have the 
capacity to provide informed consent. In order to be included in the study, AD patients with an MMSE score 
greater than 20 will be required to appoint a surrogate. We will use the following forms to document the 
choice of surrogate: PCS Form III(b) Record of Choice of Surrogate, PCS Form III(c) Statement by 
Witnesses, and PCS Form IV Consent by Surrogate. In order to complete these three forms, the patient, 
surrogate, study physician, and two witnesses must be present and sign in various places on the form. The 
complete PCS Model Consent Form does not need to be completed in these cases since AD patients with 
MMSE scores equal to or greater than 20 are expected to have the capacity to appoint a surrogate and 
therefore do not need to undergo assessment by an independent evaluator.
            (2) All AD patients with an MMSE score less than 20 will undergo a formal assessment of capacity 
to consent. The patient will be evaluated by Drs. Devanand, Pelton, Huey, Bell, Kerner, or 
Deliyannides who will document the findings of the assessment in the progress note and on the Assessment 
of Capacity to Consent forms, and based on this assessment the patient will either participate or not 
participate in the study. In order to be included in the study, AD patients with an MMSE score less than 20 
will be required to appoint a surrogate. However, unlike the MCI patients and the AD patients with MMSE 
scores equal to or greater than 20, AD patients with MMSE scores less than 20 are less likely to retain the 
capacity to appoint a surrogate and therefore must first undergo an assessment by an independent evaluator 
before appointing a surrogate. In these cases, the complete PCS Model Consent Form must be completed 
(PCS Form I Capacity to Consent and Capacity to Choose a Surrogate, PCS Form II Consent Form 
Signature Page, PCS Form III(b) Record of Choice of Surrogate, PCS Form III(c) Statement by Witnesses, 
PCS Form IV Consent by Surrogate, and a Consent Procedure Note written by the Independent Evaluator).
 
During the study
Although all MCI patients and some AD patients will have MMSE scores equal to or greater than 20 at 
baseline, it is a possibility that these patients may have cognitive decline during the study, raising the 
question about continued capacity to consent. MCI patients. If the MMSE score drops to <20 or the study 
physician believes that there is a loss of capacity, a formal reassessment of capacity to consent for continued 
participation will be completed. The patient will be evaluated by Drs. Devanand, Pelton, Huey, Bell, Kerner, 
Deliyannides who will document the findings of the assessment in the progress note and on the Assessment 
of Capacity to Consent for Continued Participation form, and based on this assessment the patient will 
continue in the study if capacity is maintained. If capacity is not maintained, the surrogate will be asked to 


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provide informed consent for the patient’s continued participation. If capacity is not maintained and there is 
no surrogate, the patient will be terminated from the study with subsequent clinical follow-up in the 
Memory Disorders Center.
 
AD patients. If during the study the MMSE score is <20 or the study physician believes that there is a loss 
of capacity, a formal reassessment of capacity to consent for continued participation will be completed. The 
patient will be evaluated by Drs. Devanand, Dr. Pelton, Huey, Bell, Kerner, or Deliyannides who will 
document the findings of the assessment in the progress note and on the Assessment of Capacity to Consent 
form, and based on this assessment the patient will continue in the study if capacity is maintained. If 
capacity is not maintained, the surrogate will be required to provide informed consent for the patient’s 
continued participation. If the surrogate does not provide informed consent for the patient’s continued 
participation, the patient will be terminated from the study with subsequent clinical follow-up in the 
Memory Disorders Center.
Choice of Surrogate: Both MCI and AD patients will decide who they want their surrogates to be. The study 
physician will ask the patient whom he or she would like to appoint as the surrogate. If any AD patient does 
not know someone who can act as his or her surrogate, or does not have the capacity to appoint a surrogate, 
then the patient will not be included in the study.
You have indicated that your study involves subjects who DO LACK capacity to consent. Please justify
We expect that all MCI patients and most AD patients will have capacity to consent at baseline. The nature 
of Alzheimer's disease is that some patients may not have the capacity to consent but it is important to 
include these patients if possible in the protocol to ensure representativeness of the sample and to avoid 
inclusion bias. The tests administered, primarily olfaction and neuropsychological tests, are minimal risk 
and the treatment being administered, donepezil, is the standard FDA-approved treatment for Alzheimer's 
disease. Therefore, inclusion of these subjects is justified.
Procedures for surrogate consent
At NYSPI, OMH regulations require that in patients who lack the capacity to consent, surrogate consent is 
acceptable when all the following procedures are conducted:
1. A psychiatrist or licensed clinical psychologist who is independent of the research must confirm that that 
the patient still retains the capacity to designate a surrogate, i.e., identify the surrogate and indicate that the 
surrogate can consent on the patient’s behalf for the research study. Drs. Steven Roose, Bret Rutherford, 
Joel Sneed, Karen Marder, Scott Small, Patrick Brown, and Jamie Noble will be the independent evaluators 
for this study. They will follow the procedures described here using the forms attached as an addendum to 
the Informed Consent Form.
2. The document designating the research surrogate must be witnessed by two persons who are independent 
of the research. The psychiatrist or licensed clinical psychologist who assesses the patient’s capacity to 
choose a surrogate may also witness to the choice of the surrogate.
3. If the patient chooses a surrogate but is unable to sign the document, another person may sign for the 


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patient and the two witnesses shall, in writing, confirm the patient’s choice of a surrogate and witness the 
signature of the person signing for the patient.
4. The surrogate cannot function as a witness to the choice of the surrogate. A family member or friend of 
the patient who is not the surrogate may function as a witness.
5. The surrogate cannot be an administrator or employee of the facility at which the research is conducted or 
the facility conducting the research. This restriction does not apply if the person is related to the patient by 
blood, marriage, or adoption. The selection of a patient’s spouse as a surrogate is revoked upon the legal 
separation or divorce of the patient and spouse unless the patient specifies otherwise.
6. Notice of the appointment of a surrogate must be provided to the Mental Health Legal Service (MHLS).
These procedures for surrogate consent will be followed for patients who lack the capacity to consent to this 
research protocol as specified in the earlier paragraphs in this section. 
 
These procedures for surrogate consent will be followed for patients who lack the capacity to consent to this 
research protocol as specified in the earlier paragraphs in this section. 
Study Procedures
Describe the procedures required for this study
Roles and Responsibilities:
Dr. Devanand will be the Principal Investigator as well as the primary study physician. He will make 
executive decisions including study monitoring, regulatory issues, quality control (QC), and dispute 
resolution. He will have overall responsibility for the clinical care of the patients during the course of the 
study. 
Dr. Pelton will be the Co-Investigator and the second study physician. He will evaluate the patients during 
the visits and be responsible for the clinical care of the patients during the course of the study. 
Dr. Huey will be a Co-Investigator and will play a clinical and research role in the conduct of this study on 
the utility of olfactory identification deficits in predicting cognitive improvement with donepezil treatment 
of patients with mild cognitive impairment and Alzheimer's disease. He will recruit, treat and follow 
patients in this project. He has been involved in the preparation of this grant with Dr. Devanand and will be 
involved in the analysis of data and publications ensuing from this project.t
Dr. Bell will be a Co-Investigator and will play a clinical and research role in the conduct of this study on 
the utility of olfactory identification deficits in predicting cognitive improvement with donepezil treatment 
of patients with mild cognitive impairment and Alzheimer's disease. She will recruit, treat and follow 
patients in this project. She has been involved in the preparation of this grant with Dr. Devanand and will be 
involved in the analysis of data and publications ensuing from this project.


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Dr. Kerner will be the Study Physician. She will evaluate the patients during the visits and be responsible 
for the clinical care of the patients during the course of the study.
 
Dr. Deliyannides will be the Study Physician. She will evaluate the patients during the visits and be 
responsible for the clinical care of the patients during the course of the study.
Study Assistants (2) (To Be Hired) will screen charts and assist in the recruitment of patients through the 
ADRC, including a designated research clinic, the Memory Disorders Center, and a Behavioral Neurology 
private practice group comprising faculty neurologists and psychiatrists (includes Drs. Devanand, Pelton, 
Huey, Bell, Kerner, and Deliyannides). They will be responsible for the conduct of research procedures, 
including administration of the UPSIT at all time-points, the Selective Reminding Test, the ADAS-cog, the 
NACC/UDS battery, and other interviews and procedures in in the project. They will be responsible for data 
checking and integrity for all the data ensuing from this project and will enter the data into the web-based 
data entry system. The research assistants will liaison with the Data Management group (Dr. Howard 
Andrews and Mr. David Merle) that will develop the web-based data entry system and which will be 
responsible for monitoring all data entry. They will also ensure that the blood samples for apolipoprotein E 
genotyping are collected, processed and sent correctly for assay.
 
The flow diagram (attached below) and procedures (main procedures are in the flow diagram; further details 
are in the table attached below) apply to both Study 1(MCI) and Study 2(AD). At the initial screening visit 
(not shown in the flow diagram), the MMSE, WMS-III Logical Memory Test, FC-SRT and Clinical 
Dementia Rating (CDR) are done. If all inclusion/exclusion criteria are met, signed informed consent is 
obtained. The week 0 baseline visit occurs approximately 1 week after the screening visit (MMSE, WMS-III 
Logical Memory, FC-SRT and CDR done at screening will not be repeated at week 0). Clinical Eval refers 
to the physician’s clinical evaluation that covers vital signs monitoring, depression (Geriatric Depression 
Scale), stroke (Hachinski and vascular risk factors), medical illnesses and medications taken.
 SCREENING VISIT
As part of the screening evaluation, a comprehensive history will be taken to include age, age-at-onset of 
memory problems, handedness, education, occupation, medical and psychiatric history.  Concurrent 
medications including putative cognitive enhancers (vitamin E, gingko biloba, estrogen), and over 20 other 
classes of common prescription and over the counter and alternative medications will be documented at all 
visits. Use of medications known to worsen cognition such as, but not limited to, benzodiazepines 
(lorazepam equivalents of equal or greater than 2 mg daily), narcotics, anticholinergics, and current alcohol/ 
substance abuse/dependence will not be allowed. Medications with uncertain adverse impact on cognition, 
e.g, theophylline, nifedipine, beta blockers, will not lead to exclusion and will not be washed out. 
Olfaction history will be obtained to screen out patients who meet any of the specified exclusion criteria for 
olfaction.


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The Folstein Mini Mental State Exam (MMSE), the Wechsler Memory Scale-III (WMS-III) Logical 
Memory Test, and FC-SRT will be administered to determine inclusion. The physician will complete the 
CDR. 
All eligible patients will also be asked to provide an informant who will be available (in-person or by 
phone) and willing to provide information or responses to questionnaires and interviews.
For patients who meet the study entry criteria, informed consent will then be obtained by the study 
physician. 
BASELINE VISIT
Patients who are enrolled will be asked to come for the baseline visit, typically 1 week after the screening 
visit. 
Medical, history, physical examination, UPSIT with atropine challenge, SRT, ADAS-cog, E-cog, extensive 
clinical (NACC) and neuropsychological (UDS) evaluation, and blood draw for apolipoprotein E 
genotyping will be completed. Vital signs (sitting blood pressure and pulse rate, respiratory rate, weight and 
height) will be measured and recorded. 
UPSIT and atropine challenge. 
The full 40-item University of Pennsylvania Smell Identification Test (UPSIT) will be given with birhinal 
administration (odors presented to both nostrils) followed by a 1 mg atropine nasal spray. 
 
The UPSIT is a 40-item scratch-and-sniff multiple choice odor identification test. It comprises 4 booklets 
with 10 odorants apiece, and one odorant per page. Stimuli are embedded in microencapsulated crystals (10-
50 micrometer diameter) located on a brown strip at the bottom of each page (UPSIT odor stimuli were 
originally developed by the 3M company). The subject uses a pencil (provided with the test) to scratch each 
odorant strip left to right several times and then sniff the label before completing the circle against one of 
four multiple choice items, e.g, “this odor smells most like: a) chocolate; b) banana; c) onion; d) fruit 
punch.” The subject is given up to a minute to circle 1 of the 4 alternatives even if no smell is perceived, 
i.e., the test is forced-choice. Patients who score less than 11 will be excluded if there is a history of anosmia 
due to any cause (e.g. traumatic or congenital).  In other words, we will exclude patients with congenital 
anosmia or anosmia after a remote event (e.g. head injury). 
Atropine nasal spray is not commercially available but atropine eye drops are available and our pharmacy 
will provide them for use as a nasal spray. The study physician will administer the spray, consistent with 
Schofield et al.94 The 1 mg dose was used very safely in Schofield’s study in MCI and AD.  Doses of 0.3 to 
0.5 mg are typically used in ENT clinics where nasal anticholinergic effects reach a ceiling at 0.5 mg.38 
 Therefore, the 1 mg dose ensures maximum anticholinergic effects on olfaction and overcomes any loss of 
dose that is intrinsic to a nasal spray. Immediately after the spray, the patient will be in the “Mecca” position 
for 1 minute to ensure that the atropine reaches the cribriform plate at the upper end of the nasal cavity94.  


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This posture involves kneeling on a mat with the body and arms stretched forward with the forehead 
touching the mat.  The half-life of atropine nasal spray is approximately 2 hours, and therefore the 
administration of the repeat UPSIT 45 minutes after the spray as done by Schofield et al takes into account 
the expected peak and duration of atropine effects.
We will also administer the two-item Awareness of Odor Detection and Identification Scale (developed by 
Drs. Tabert and Devanand) that assesses the ability to detect odors, and to identify odors, on a 7-point Likert 
scale for each of the two items (takes 1 to 2 minutes). 
Apolipoprotein E genotype. Apolipoprotein-E genotype will be examined as a potential moderator of 
UPSIT prediction of donepezil response. Blood obtained and the Columbia University Human Genetics 
Resource Core will be used as the laboratory resource that will prepare and process the de-identified blood 
sample for APOE genotyping. De-identified samples are sent to the Columbia University Human Genetics 
Resource Core (HGRC) lab. The HGRC then assigns a new sample number and bar-codes the sample. DNA 
is extracted and stored. The HGRC functions as a sample processing and storage facility in this study. It is 
not a CLIA lab and does not do genetic testing. 
The HGRC then sends an aliquot of DNA to a different laboratory for genotyping. This laboratory belongs 
to the company, Prevention Genetics, which serves as the vendor for APOE genotyping. The alleles are 
"translated" by the HGRC to the APOE 2, 3 and 4 that are familiar to clinical investigators, and the 
modified spreadsheet is then sent by the HGRC to the PI.
Drs. Devanand, Pelton, Huey, Bell, Kerner, or Deliyannides will then give the patient generic donepezil 
(purchased for this project and prepared by the NYSPI pharmacy) in dispensing vials. The patient will be 
instructed to take donepezil 5 mg/day for the first 4 weeks and then increase the dose to 10 mg/day for the 
rest of the trial. Patients who develop side effects, e.g., nausea or diarrhea, on 10 mg/day will remain at 5 
mg/day during the trial.  If side effects persist, donepezil will be stopped and alternative treatment will be 
prescribed (e.g., Exelon patch for gastrointestinal side effects). This is an intent to treat study, therefore, 
patients will be followed for the full 52 weeks. If the patient has taken donepezil in the past and experienced 
side effects that were not serious but caused the patient to be unwilling to try the medication again, the study 
physician can prescribe galantamine or rivastigmine, instead of donepezil, at the start of this study. This has 
been done for 12 participants. There have been no SAEs or other safety concerns among the 12 
participants who have received the alternative medications, galantamine or rivastigmine.
New York State Psychiatric Institute
pasting 
Drs. Devanand and Stern will make a consensus diagnosis based on the NACC/UDS and other available 
information at 0, 26, and 52 weeks. The baseline consensus diagnosis at 0 weeks will be made prior to 
starting donepezil. These two raters will remain blind to UPSIT, CIBIC-plus, SRT and ADAS-cog scores, 
ensuring that the diagnostic process is independent of the predictor and outcome variables. 
FOLLOW-UP VISITS (Weeks 2, 4, 8, 26 and 52)
A telephone contact will be made by the study physician at Week 2 during which an open clinical interview 


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to monitor any side effects and complete the CIBIC-plus will be conducted. If needed the patient will be 
brought in for evaluation at this time.
All patients in Study 1 and 2 will be asked to come to the clinic for follow-up at Weeks 4, 8, 26 and 52. At 
each of these visits, vital signs (sitting blood pressure and pulse rate, respiratory rate, and weight) will be 
measured and recorded.
At Week 26, the Folstein MMSE, which is one of the components of the NACC UDS Neuropsychological 
test battery, will be administered. 
At Weeks 8, 26, and 52, the SRT and ADAS-cog will be administered. 
At Weeks 4, 8, 26, and 52, the study physician will complete the CIBIC-plus for global measurement of 
improvement. Adverse events will be recorded using the TESS. The FAQ as well as the Ecog will also be 
completed with the informant at these time points.
At Weeks 8, 26 and 52, the odor identification test will be administered, using the full 40-item University of 
Pennsylvania Smell Identification Test (UPSIT) birhinally (odors presented to both nostrils). 
At study visits, donepezil will be prescribed by the study physician.
At Week 52, the clinical evaluation by Dr. Devanand, Dr. Pelton, Dr. Huey, Dr. Bell, Dr. Kerner, and 
Deliyannides using the ADRC NACC UDS clinical evaluation will be repeated. In addition, the ADRC 
NACC UDS neuropsychological test battery will also be administered. 
At Weeks 26 and 52, consensus diagnosis will be made by Drs. Devanand and Stern based on the NACC 
UDS and other available information, which will be considered the final diagnosis for study purposes. 
Diagnostic raters will remain blind to the UPSIT, CIBIC-plus, SRT and ADAS-cog scores, thereby ensuring 
independence of the diagnostic process from the predictor and cognitive/global outcomes. 
Cognitive test scores and UPSIT test scores are shared with the patient throughout the protocol. Results of 
apolipoprotein E genotyping are not shared with the patient.
 
 
DROPOUT. Criteria under which loss of capacity to consent leads to study termination have been 
specified. Patients who cannot tolerate donepezil will be offered treatment with alternative cholinesterase 
inhibitors, e.g., galantamine, rivastigmine patch in doses that are FDA-approved to treat patients with AD. If 
they are able to tolerate one of these medications, they will complete the study at 52 weeks as planned. If 
they are unable to tolerate the medication or medication is interrupted for more than 30 days, they will be 
terminated from the protocol but the study visits and evaluations will occur at the scheduled time-points 
using the intent-to-treat principle, i.e., even if the patient is no longer on study medication. For patients who 
do not make an appointment, every effort will be made to maintain the patient in the study including making 
a home visit if feasible. Patients who develop intolerable side effects even at the lowest permitted dose will 
be terminated from the protocol by the study investigator. The study investigator can also terminate the 
protocol if severe medical illness warrants study termination. After an interruption of treatment for any 
reason, e.g., medical illness, the patient can resume the protocol if the interruption is less than 30 days. This 


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is an intent-to treat protocol. Therefore, a patient who is discontinued early in the study due to the above 
reasons will be followed and evaluated (whenever feasible) until the Week 52 visit or until the patient 
withdraws his/her consent to participate. 
 
Safety Monitoring during the course of the entire study will include vital signs assessment, physical exams, 
baseline routine laboratory tests, monitoring of adverse events (TESS plus open-ended interview), and 
monitoring and maintenance of concurrent medication records.
All adverse events occurring after signing the consent forms, regardless to adherence to study treatment, 
will be recorded at all contacts with the patient. At scheduled visits, patients will be interviewed about 
whether he/she experienced any symptoms or side effects since the last visit. Adverse events will be 
recorded and an adverse event form will be completed. If adverse events are noted, they will be rated as 
mild, moderate, or severe based on their clinical severity and frequency. The PI will inform the IRB 
immediately after knowledge of death, or of an event that is life-threatening that results in hospitalization, or 
that involves persistent or significant disability or incapacity. Data collected regarding these serious adverse 
events will include the treatment provided, outcome, and presumed relationship to study drug and will be 
updated as new information becomes available. Dr. Howard Andrews, who leads the data management 
team, will generate a data output that covers AEs, SAEs and study progress which will be reviewed by the 
Independent Safety Monitor. The project comprises of two open-label proof-of-concept trials, and therefore 
blindness to treatment is not an issue.
 Dr. Jose Luchsinger, Associate Professor of Medicine at New York Presbyterian Hospital
(board-certified internist), will serve as the Independent Safety Monitor. The Independent Safety Monitor 
will receive all reports of adverse events and serious adverse events, including deaths, and review all 
unanticipated problems involving risk to subjects or others. He will then provide a written report of the 
event with conclusions and advice for the PI, Dr. Devanand, who will then forward it to the IRB and the 
Program Officer at the National Institute of Aging. 
STATISTICS
General considerations and approach to multiple comparisons. In this proof-of-concept study, we do not 
consider it essential or even important to control for making one or more Type I errors between the two 
different study samples (MCI, AD) or between any of the cognitive or global clinical endpoints (SRT, 
ADAS-cog, CIBIC-plus). Testing this study’s hypothesis (do changes in UPSIT predict outcome?) in these 
different samples with these different measures represents very different research questions, such that a 
positive finding from one sample or with one outcome cannot be claimed to support a positive result in a 
different sample or with a different outcome. However, for a given patient sample and a given outcome, our 
analysis will consider four parameters of interest, any one of which could be used as evidence supporting 
the scientific hypothesis that changes in UPSIT predict the given outcome in the given sample. This creates 
a four-dimensional parameter space and a corresponding family of hypotheses within which we will control 
the probability of making one or more Type I errors at 5%. Therefore, we will repeat the analyses described 
for each study sample and for each endpoint, controlling the family-wise type I error rate in each repetition 
at the 0.05 level. Any positive findings will be viewed as hypothesis-generating for a subsequent, larger 
confirmatory study in the given sample and with the given cognitive or overall clinical endpoint.


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(i)                 All measures other than the hypothesized predictor and outcome variables will be evaluated in 
secondary analyses, e.g., E-cog and FAQ as functional outcomes. Pearson correlation coefficients will be 
used to examine the associations between these measures and UPSIT, other cognitive measures, and 
continuous baseline demographic variables. Student’s t test will compare differences for dichotomous 
variables (e.g., sex). The statistical analytic approach will be similar for testing the primary hypotheses. 
(ii)               In another secondary analysis we will attempt to confirm the findings of the British study108 using 
their choice of dichotomization at 4 or more points change in week eight UPSIT for predicting outcome. We 
will not use that (or any other) dichotomization for our primary analysis in order to retain full power. We 
will, however, be able to evaluate whether the four-point change in 8-week UPSIT cut-point is better or 
worse than other cut-points in predicting outcomes. For this we will use ROC methods for predicting a good 
clinical outcome, such as a 4-point improvement in SRT or ADAS-cog, or a 2-point improvement in CIBIC-
plus. 
(iii)             In other secondary analyses we will determine the robustness of our findings by preparing 
completers-only analyses (see Handling of Missing Data below) and comparing the results to the primary 
analyses. 
Exploratory analyses. We will not assume any time-evolution curve for the responses at 26 and 52 weeks. 
The response-curve is unlikely to be linear over the year of follow-up, as evidence shows a plateau or a 
small decline in cognitive and global measures after an initial positive response to donepezil. In exploratory 
analyses we will check if a simple parametric model in time with subject-specific parameters can 
parsimoniously fit the response data and if the findings relating to UPSIT persist. We will check for 
interactions between the slope parameters β11, β12, β21, β22 and the other covariates of age, sex, education, 
and baseline MMSE, each at the alpha = 0.10 level given reduced power to detect interactions compared 
with main effects. For exploratory hypothesis with baseline UPSIT as a significant predictor in both the 
MCI and AD samples, we will conduct separate simple regression analyses with covariates as appropriate. 
We will also explore the relative utility of the baseline UPSIT compared to the change scores by entering 
them in the same regression model and examining which has a larger standardized coefficient (i.e., the 
regression coefficient times the ratio of standard deviations of the predictor and dependent variables).
 
IMPLICATIONS
The UPSIT (or a comparable test like Sniff’n Sticks) is inexpensive and easy to administer compared to 
conducting MRI/PET imaging and obtaining CSF measures for which the evidence for predicting 
improvement on ACheI remains to be clearly established. If our hypotheses are supported by the results 
obtained, odor identification tests may have clinical utility to predict cognitive improvement and monitor 
treatment with ACheI. If the atropine challenge test is shown to be useful, this research can be expanded to 
the conduct of sequential challenge tests to monitor change with ACheI treatment at more than one time-
point. These approaches to predicting treatment response can be tested in the future for new disease-
modifying drugs for MCI and AD as and when they are developed.


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You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
The reasons for early discontinuation of a patient from the study are as follows:
(1)  intervening severe medical illness that either the PI or the Medical Monitor determines that it requires 
study discontinuation; 
(2) discontinuation of treatment with donepezil for more than 30 days. After an interruption of treatment for 
any reason, e.g., medical illness, the patient can resume the protocol if the interruption is less than 30 days. 
This is an intent-to treat protocol.  Therefore, a patient who is discontinued early in the study due to the 
above reasons will be followed and evaluated (whenever feasible) until the Week 52 visit or until the patient 
withdraws his/her consent to participate.   
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
Routine Laboratory Tests: At baseline, blood will be collected for the following screening laboratory tests 
that will be performed by the OMH Clinical Laboratories-Nathan Kline Institute: CBC, BUN, creatinine, 
electrolytes, liver and thyroid function studies, B-12, lipid panel and folate (total of 20 ml).
Apolipoprotein E genotype testing. At baseline, a blood sample will also be collected for ApoE 
genotyping (total of 8.5 ml).  All procedures related to Apo E genotyping were described earlier.
DNA will not be extracted and stored for any other genetic testing.
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
1.  University of Pennsylvania Smell Identification Test (UPSIT) is a 40-item scratch-and-sniff multiple 
choice odor identification test. It consists of four booklets containing 10 odorants apiece, with one odorant 
per page. The stimuli are embedded in 10-50 micrometer diameter urea-formaldehyde polymer 


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microencapsulated crystals located on a brown strip at the bottom of each page. The subject is asked to use a 
pencil (provided with the test) to scratch each odorant strip left to right several times and then sniff the label 
before completing the circle against one of four multiple choice items, e.g, “this odor smells most like: a) 
chocolate; b) banana; c) onion; or d) fruit punch. The subject is required to answer one of the four 
alternatives, even if no smell is perceived, i.e., the test is forced-choice. It comes in multiple language 
versions including English, French, German, and Spanish. We will use the English and Spanish versions 
that we evaluated in an epidemiological study of 1293 subjects where English and Spanish speakers had 
similar UPSIT scores after controlling for age and education. Test norms have been developed, based on 
UPSIT administration to 1819 men and 2109 women of various ages, with norms categorized within 5-year 
intervals. Rather than obtaining percentile scores, we will evaluate the raw UPSIT scores with relevant 
demographic (age, sex, education) and clinical variables included as covariates in the analyses. In healthy 
subjects, the test-retest reliability coefficients for the UPSIT are uniformly high, ranging from r=0.918 for 
tests administered 6 or more months apart to r=0.949 for tests administered two weeks apart. The UPSIT 
and similar tests show high test-retest reliability with no significant improvement over test sessions 10 
minutes apart, 4 hours apart, and 4 days apart.
The 8-week time-point UPSIT administration is needed to address hypothesis 2 for this protocol. The 26 and 
52 week time-points will be useful to explore the changes in the UPSIT over time relative to changes in 
cognitive, functional, and global measures and to obtain information on its potential in monitoring treatment 
with ACheI.
The research coordinator will administer the UPSIT to patients with MCI.  Subjects will be allowed to sniff 
each item for up to a minute before making a response (each item takes only a few seconds if the subject is 
confident about the odor and selects the multiple choice item). The UPSIT requires rule-based 
administration and scoring and the lack of blindness of the research coordinator or assistant who administers 
the test will not influence the results obtained.
2.  Selective Reminding Test (SRT). Verbal list learning and memory will be assessed by the 12-item, 6-
trial SRT. Total number of words learned over six trials (total immediate recall) will be examined. Delayed 
word recall (15 min delay) will be an ancillary measure. Our use of the total immediate recall measure is 
supported by its wide range in scores with greater sensitivity to small changes (0-72 for total recall versus 0-
12 for delayed recall for the SRT), use in prior clinical trials and our pilot data in DEP-CI.
The choice of the SRT compared to similar tests of episodic verbal memory, e.g., Auditory Verbal Learning 
Test (AVLT) that is used in ADNI, was partly based on our pilot data in the donepezil-placebo add-on trial 
in DEP-CI, our own extensive use for over two decades in our ADRC, and the fact that it is a well-
established neuropsychological test of episodic verbal memory that has been used successfully in clinical 
trials of ACheI. Different equivalent versions will be administered at the specified time-points to reduce 
practice effects. 
3.  Alzheimer’s Disease Assessment Scale-cognition (ADAS-cog, modified version) is used in essentially 
all FDA registration clinical trials in MCI and AD. It covers several areas of neuropsychological functioning 
that include attention, category fluency, episodic verbal memory, non-verbal memory, and naming. There is 
overlap in the cognitive areas assessed between the ADAS-cog and the NACC UDS neuropsychological test 
battery, but we chose to retain the modified ADAS-cog because it is the current standard instrument in the 


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field for clinical trials in MCI and AD, thereby allowing for direct comparison of our results with the extant 
literature in ACheI trials.
4.  National Alzheimer’s Coordinating Centers (NACC) Uniform Data Set (UDS) Clinical Evaluation. 
All patients will receive the full NACC physician evaluation at 0 and 52 weeks. The evaluation takes 30-40 
minutes to complete and includes history with in-depth evaluation of family history, neurological 
examination including the Unified Parkinson’s Disease Rating Scale for extrapyramidal signs, psychiatric 
assessment that includes the Neuropsychiatric Inventory and the short version of the Geriatric Depression 
Scale, assessment of all major vascular risk factors in addition to the Hachinski scale, and a Clinical 
Dementia Rating (CDR). 
5.  National Alzheimer’s Coordinating Centers (NACC) Uniform Data Set (UDS) Neuropsychological 
Test Battery.  Tests in the UDS battery: Folstein MMSE, WMS-R digit span forward and backward, 
WAIS-R digit symbol, Trail Making Test Part A and Part B, WMS-R Logical Memory Story A immediate 
and delayed recall, Verbal Fluency animal and vegetable list generation, Boston Naming Test (30 odd 
items). Validated English and Spanish versions exist for these tests. This test battery will be employed to 
assist in diagnosis and is separate from the cognitive outcome measures.
The SRT and ADAS-cog are the main cognitive outcome measures and have validated English and Spanish 
versions. 
6.  Clinician's Interview Based Impression of Change plus Caregiver Input (CIBIC-plus).  The CIBIC-
plus is a well-validated, reliable and widely used measure (range 1-7) of global improvement used in AD 
trials. It also has a version specific for MCI that has been used successfully in ACheI treatment studies in 
MCI. The CIBIC-plus versions specific for MCI will be administered at all study time-points and will be the 
global measure of improvement. 
7.  Pfeffer Functional Activities Questionnaire (FAQ).  FAQ is a widely used 10-item instrument that 
takes 3 minutes to administer and focuses on instrumental, social and cognitive functioning. We published 
the first report showing that informant-reported, but not self-reported, FAQ deficits strongly predicted 
conversion from MCI to AD. We recently showed that specific FAQ items, particularly the financial items 
and the item on remembering appointments/remembering to take medications, strongly distinguished 
patients with AD, MCI and healthy controls in baseline ADNI data. The FAQ is also part of the NACC 
assessment and will be the secondary function measure.
8.  Measurement of Everyday Cognition (Ecog). We will administer the ECog as the primary function 
measure. This instrument has 40 items, takes 20 minutes to administer, and focuses on functional correlates 
of cognitive deficits. It is used in the Alzheimer’s Disease Neuroimaging Initiative-GO (ADNI-GO) and 
ADNI-II studies.
9.  Treatment Emergent Symptom Scale (TESS).  TESS is widely used to evaluate somatic side effects. 
For each item, a rating is made on a 3-point scale, with an additional rating on the likelihood tht the 
medication caused the side effect. The total score of this safety assessment of possible ACheI side effects 
will be an ancillary measure.
 


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Other Scales/Assessments
Demographic and Family History Form
5 min
Pfeiffer Functional Activities Questionnaire (FAQ)
3 min
Everyday Cognition (Ecog)
20 min
University of Pennsylvania Smell Identification Test 
(UPSIT)
20 min
 
Neuropsychological Testing
Folstein Mini Mental State Exam (MMSE)
5 min
Wechsler Memory Scale-R (WMS-R) Logical Memory 
Story A immediate and delayed recall
15 min
WMS-R digit span forward and backward
5 min
WAIS-R digit symbol
5 min
Trail Making Test – Part A and Part B
5 min
Verbal Fluency – Animal and Vegetable List 
Generation
5 min
Boston Naming Test – 30 odd items
10 min
Selective Reminding Test
20 min
Alzheimer’s Disease Assessment Scale – cognition 
(ADAS-cog)
20 min
Please attach copies, unless standard instruments are used
Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study 
   Drug
Select the number of drugs used in this study
2
Drug #1
Name of the drug 
Donepezil
Manufacturer and other information
Donepezil, which became generic in 2011, is also marketed under the trade name Aricept. It is 
manufactured by its developer Eisai and marketed by Pfizer. We will use the generic version supplied to the 
NYSPI pharmacy.
Approval Status
No IND is required
Choose one of the following options


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FDA has determined that IND is not required
Drug #2
Name of the drug
Atropine Nasal Spray
Manufacturer and other information
Atropine sulfate ophthalmic solution 1%, which is also generic, will be constituted by the NYSPI Pharmacy 
as a nasal spray for use as the acute atropine challenge at baseline. A single acute dose of 1 mg of atropine 
nasal spray will be administered to one nostril. The dose chosen reflects clinical doses typically used by 
ENT physicians and this dose was used very safely in the pilot report presented by Schofield et al at ICAD 
2010. It exceeds the threshold required for cholinergic blockade and therefore any loss of dose because of 
the use of a nasal spray will not pose a problem in this study.
Approval Status
No IND is required
Choose one of the following options
FDA has determined that IND is not required
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
Yes
Maximum duration of delay to any treatment 
Donepezil treatment will begin immediately, as long as there is no wash-out period for a cholinesterase 
inhibitor or memantine. If a wash-out period is required, the patient will need to stop taking the 
cholinesterase inhibitor or memantine for two weeks. Afterwards, donepezil treatment can be started 
immediately. Maximum duration of delay to standard care or treatment of known efficacy. 
 
 
Maximum duration of delay to standard care or treatment of known efficacy
During the two-week wash-out period, the patient will be monitored closely by the study physician.
Treatment to be provided at the end of the study
Patients will be on open label treatment with donepezil (range 5 to 10 mg per day) or other 
acetylcholinesterase inhibitor during the entire course of the study. After the study ends, the patient will 
continue to be followed in our ADRC by the physician who was following the patient prior to the start of the 
study.
Clinical Treatment Alternatives


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Clinical treatment alternatives
Donepezil has been approved for the treatment of Alzheimer's disease, however it is not approved for the 
treatment of mild cognitive impairment. The efficacy of donepezil to slow or halt cognitive decline or 
conversion to AD in patients with mild cognitive impairment is not established. There is no FDA-approved 
treatment for mild cognitive impairment.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
Donepezil. Nausea, diarrhea, insomnia (sleep disturbance), vomiting, dizziness, drowsiness, weakness, 
shakiness (tremor), muscle cramp, fatigue and anorexia (loss of appetite with weight loss) are possible side 
effects of donepezil. These side effects are often of mild intensity and transient, resolving during continued 
donepezil treatment without the need for dose modification. The patient may also experience an increase in 
anxiety or nervousness, restlessness, or allergic reactions with donepezil.  The patient is instructed to inform 
the study physician about medical history, especially of: breathing problems (such as asthma, chronic 
obstructive pulmonary disease), fainting, heart disease (such as sick sinus syndrome, other heart conduction 
disorder), seizures, stomach/intestinal disease (such as ulcers, bleeding), trouble urinating (such as enlarged 
prostate). Patients will come for detailed evaluation at baseline and will be monitored during open treatment 
with donepezil. Donepezil is sometimes used off-label to treat patients with mild cognitive impairment but it 
is not approved by the FDA for the use indicated in this study.  However, the dose of donepezil treatment 
will not differ from what would be administered clinically in regular practice, and hence the treatment does 
not entail any research risks beyond the risks of lack of efficacy or the advent of side effects that may occur 
clinically with donepezil treatment.
 
Galantamine. Nausea, vomiting, diarrhea, and anorexia (loss of appetite with weight loss) are possible side 
effects of galantamine. These side effects are often of mild intensity and transient, resolving during 
continued galantamine treatment without the need for dose modification. The patient may also experience 
headache, abdominal pain, fatigue, slow heart rate, depression, sleepiness and fainting. The patient is 
instructed to inform the study physician about medical history. Patients will come for detailed evaluation at 
baseline and will be monitored during open treatment with galantamine.
 
Rivastigmine. Nausea, vomiting, anorexia (loss of appetite with weight loss), diarrhea, weakness, dizziness, 
drowsiness, and shakiness (tremor). These side effects are often of mild intensity and short-lived, resolving 
during continued rivastigmine research treatment without the need for dose modification. The patient is 
instructed to inform the study physician about medical history. Patients will come for detailed evaluation at 
baseline and will be monitored during open treatment with galantamine.
In this elderly patient group, it is not uncommon for inter-current medical illness to lead to interruption of 
treatment, usually for short intervals (e.g., surgery). During the study, interruption of treatment for up to 30 
days will be permitted. Treatment and data collection will resume after the interruption and the patient will 
continue in the protocol.


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Medication Washout: Patients who are already on cholinesterase inhibitors or memantine at screening will 
undergo a two-week wash-out period. No withdrawal syndrome has been reported for any of these 
medications. Since donepezil or other cholinesterase inhibitors or memantine have a marginal effect in 
improving memory at best in AD (0-5% improvement in memory test scores over a few months) and have 
not yet been shown to significantly improve memory in MCI, the clinical risk associated 
with discontinuation of any of these medications for two weeks is minimal. There is consistent evidence that 
reinstatement of these medications after a brief interval of a few weeks leads to the therapeutic effect being 
regained (if there has been a therapeutic effect in that patient to begin with). Although the wash-out period 
is unlikely to put subjects at risk, precautions will still be taken to minimize any possible risks. Patients that 
agree to undergo the wash-out will be instructed that if they feel marked worsening in memory or other 
cognitive abilities or develop other new symptoms during the wash-out they should call the clinic and they 
will be seen immediately by the study doctor to determine if they can complete the two-week wash-out 
safely. If it is determined at the visit that the patient cannot complete the wash-out safely, the cognitive 
enhancer (cholinesterase inhibitor or memantine) will immediately be reinstituted and the patient will not be 
enrolled in the study.
Atropine Nasal Spray: Atropine is routinely used in ENT offices and does not pose undue risk. In this 
study, a single acute dose of 1.0 mg spray to one nostril will be administered at baseline. The atropine dose 
is within the range used in ENT practice and systemic absorption is minimal so side effects are not expected 
(and have not been reported in the ENT literature). The only exclusion criterion for atropine administration 
will be the presence of nasal deformity or disease that makes it difficult to administer the atropine nasal 
spray reliably. Dryness of nose and throat are possible side effects; visual effects do not occur with nasal 
administration. It is usually mild and short-lived and will be expected to disappear before the study 
procedures are completed and before the patient leaves the clinic. If the patient experiences any adverse 
events after the atropine nasal spray is administered, the study doctor will examine the patient and 
appropriate clinical action will be taken.  
University of Pennsylvania Smell Identification Test (UPSIT). The UPSIT (odor identification test) uses 
mainly synthetic odors and there is little risk of an allergic reaction with this procedure. Patients with a 
history of severe allergies to odors will be excluded. The test has been administered to several hundred 
thousand subjects around the world and does not lead to any known side effects.
Neuropsychological Assessment. During neuropsychological testing, some subjects may find some 
questions upsetting. If so, they are not obliged to answer them.
 Blood Draw. The risks associated with blood draw include local tenderness, redness, bruising, infection 
and mild bruising at the puncture site. Also, a feeling of lightheadedness may occur.
 
Apolipoprotein E genotyping. In the informed consent form, we will state (1) the presence of specific 
subtypes of apolipoprotein may be associated with an increased risk of memory disorders, (2) the results 
will be kept strictly confidential and not released to the subject or to other parties. This approach, required 
by our IRB for all apolipoprotein genotyping studies, follows from the current ambiguities for clinical 
application of apolipoprotein E genotyping. Further, given that this involves genotyping, as per our NYSPI 
IRB requirements, a Certificate of Confidentiality has been obtained from NIA, as we have done in other 


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studies. Procedures to ensure that samples are stored without identifying information have already been 
described.
 
Describe procedures for minimizing risks
There are three areas in which safeguards to protect subjects from undue risk require discussion. These 
include the procedures used to obtain informed consent, the procedures used to ensure confidentiality of 
subjects’ responses and findings on tests, and the procedures used to minimize possible risks associated with 
the research procedures.
Informed Consent. Informed consent is obtained and documented with a signed consent statement giving 
full information about the study. In the consent form and in discussion with an investigator, subjects are 
advised fully of the procedures to be used, the amount of time required of them, the fact that this is a 
longitudinal treatment study with repeated assessment at specified time points, the possible risks and 
benefits of the procedures and the treatment conditions, their right to refuse participation in the study 
without prejudice, their right to terminate participation at any moment without prejudice, and the name and 
telephone number of the Principal Investigator.
Capacity to Consent. Based on IRB requirements, patients will be recruited by a study physician who signs 
the consent form in addition to the patient and informant. As described earlier, the inclusion/exclusion 
criteria are such that essentially all patients at the time of study entry should have the capacity to consent to 
the protocol. All patients with MCI will have the capacity to consent to the study. In the rare instance that a 
patient with mild AD lacks the capacity to consent based on the patient’s inability to understand the protocol 
as elicited by interview, the patient will not be recruited into the protocol. We will follow the procedures 
required by the NYSPI IRB (based on New York State regulations) regarding assessment of capacity to 
consent.
Confidentiality of Subjects’ Responses. In the informed consent form, subjects are told that the 
information they provide and all findings will be kept strictly confidential, with access limited to the 
research staff with the possible exception of State or Federal regulatory personnel for audits. All records are 
kept in locked files. Each subject is given a code number for database purposes, and the patient’s name does 
not reside in the database. Computer files will be stored in a database which is password protected and 
behind an institute and department firewall. No one but the project staff has access to the master list linking 
subjects’ names to code numbers, and all information obtained is coded. The master list is kept under strict 
lock and key. The research data on specific predictors are not released to the patients, and this is specified in 
the consent form. This applies particularly to the apolipoprotein E genotyping, because of uncertainty as to 
what these results really mean and the risk of misinterpretation.
Research Procedures. We have described above the potential risks of the research procedures and the 
safeguards that will be used to minimize risks. These include termination of subjects from research 
participation if it is believed that such participation endangers their welfare. Monitoring procedures are used 


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to evaluate potential side effects of research procedures. The protocol stipulates an extensive medical, 
neurological, and psychiatric evaluation of all subjects as a condition for research participation.
 
Procedures for minimizing risk for donepezil, medication washout, atropine nasal spray, UPSIT, 
neuropsychological assessment, and APOE genotyping are included in the above discussion of 'Risks that 
could be encountered during the study period'.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
Confidentiality of Subjects’ Responses. In the informed consent form, subjects are told that the information 
they provide and all findings will be kept strictly confidential, with access limited to the research staff with 
the possible exception of State or Federal regulatory personnel for audits. All records are kept in locked 
files. Each subject is given a code number for database purposes, and the patient’s name does not reside in 
the database. Computer files will be stored in a database which is password protected and behind an institute 
and department firewall. No one but the project staff has access to the master list linking subjects’ names to 
code numbers, and all information obtained is coded. The master list is kept under strict lock and key. The 
research data on specific predictors are not released to the patients, and this is specified in the consent form. 
This applies particularly to the apolipoprotein E genotyping, because of uncertainty as to what these results 
really mean and the risk of misinterpretation.
In addition to the confidentiality protections described, a Federal law called the Genetic Information 
Nondiscrimination Act (GINA) generally makes it illegal for health insurance companies, group health 
plans, and most employers to discriminate against the patient based on his/her genetic information. GINA 
does not protect a patient against genetic discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance or by adoption agencies. GINA also does not protect a patient against 
discrimination based on an already diagnosed genetic condition or disease. If a patient would like to know 
more about it, he /she can discuss this with the principal investigator of this study or can go to the following 
website: http://ww.genome.gov/24519851.
 
Research records will be stored in a confidential manner so as to protect the confidentiality of subject 
information.
Will the study be conducted under a certificate of confidentiality?
Yes, we have already received a Certificate of Confidentiality
Direct Benefits to Subjects  
Direct Benefits to Subjects


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Patients will obtain free clinical evaluation, neuropsychological testing, and will receive open clinical 
treatment with donepezil. The treatment is clinically consistent with treatment typically received by patients 
with AD (Study 2), and is used in a significant proportion of patients with MCI clinically. For Study 1, even 
though ACheI, including donepezil, are not FDA-approved for treatment of patients with MCI, there is 
considerable evidence that a sizeable proportion of patients with MCI do improve on donepezil as reviewed 
in the Approach section.
Potential benefits to society may be considerable.  If the hypotheses in both studies are supported by the 
results, the use of an odor identification test like the UPSIT, which is very inexpensive compared to 
MRI/PET imaging and CSF measures and is easy to administer, may have clinical utility to predict and 
monitor treatment with ACheI like donepezil, and potentially other treatments in the future. Further, if a 
patient is being treated with an ACheI but is having side effects, the change in odor identification deficits 
may prove to be a useful adjunct in determining whether the patient is indeed benefiting from treatment and 
whether to continue or discontinue the medication. The aging of the population means that more patients 
will develop MCI and AD and require treatment. Even though donepezil and other ACheIs are now generic, 
the costs of prolonged treatment are considerable and the development of a method to identify patients 
likely to benefit from treatment is of great public health importance.
 
If the atropine challenge test is shown to be useful, this can be used clinically to select patients likely to 
improve with ACheI. Further, research using this challenge strategy can be expanded to sequential challenge 
tests to monitor change with ACheI treatment at more than one time-point. Overall, our approach can be 
used to stratify patients who are likely to respond in intervention studies of patients with MCI or AD, and 
potentially support the clinical use of odor identification tests for predicting likely improvement and 
monitoring treatment for symptomatic treatments like ACheI. 
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Patients will be given $50 for participating in the study at study entry and for each of the visits at weeks 8, 
26 and 52) for a total of $200 for each participant.  This will be paid upon completion of each study visit.  
This amount is commensurate with the amount of compensation paid by other protocols in our center. There 
are no bonus payments.
References
References


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disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on 
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SAP_001.pdf: 
 
 
Olfactory Deficits and Donepezil Treatment in Cognitively Impaired 
Elderly 
NCT01951118 
Document Date: 03/05/2012 


Pfeffer Functional Activities Questionnaire (FAQ) is a widely used 10-item instrument that takes 3 minutes to 
administer and focuses on instrumental, social and cognitive functioning80.  We published the first report showing 
that informant-reported, but not self-reported, FAQ deficits strongly predicted conversion from MCI to AD102.  We 
recently showed that specific FAQ items, particularly financial items and remembering appointments or to take 
medications, strongly distinguished patients with AD, MCI and healthy controls in baseline ADNI data7.  The FAQ 
also showed improvement in an MCI trial using the ACheI galantamine50.  The FAQ may be less sensitive than the 
E-cog because it is short and does not tap into a wide range of functions.  The FAQ is part of NACC and will be 
the secondary function measure.  The informant is now required in all cases for study entry; some patients living 
alone without any available informant will not be eligible.  The informant completes the FAQ19,102 and the E-Cog36. 
Treatment Emergent Symptom Scale (TESS) is widely used to evaluate somatic side effects.  For each item, a 
rating is made on a 3-point scale, with an additional rating on the likelihood that the medication caused the side 
effect.  The total score with this safety assessment of possible ACheI side effects will be an ancillary measure.   
Apolipoprotein E genotype.  In 501 elderly subjects, poor odor identification ability in combination with older 
age and the apolipoprotein E ε4 allele predicted greater global cognitive decline during follow-up.76  This effect 
was not seen with a vocabulary test that used a multiple choice format similar to the odor identification test76.  
A similar association between the shorter 12-item CCSIT version of the UPSIT and the apolipoprotein E ε4 
allele was reported in an epidemiological study40.  Odor identification deficits characterize subjects with familial 
and genetic risk factors for AD42 and predict episodic verbal memory decline over time in elderly subjects42,101, 
112.  Therefore, we will evaluate family history in detail (NACC assessment) and apolipoprotein E genotype. 
Apolipoprotein-E genotype will be examined as a potential moderator of UPSIT prediction of donepezil 
response.  Blood obtained will be stored at the Human Genetics Resources Core (HGRC) at Columbia 
University and annually sent in a batch to Prevention Genetics for identification of apolipoprotein E genotype.  
Using a standard protocol, DNA is amplified by the polymerase chase reaction (PCR).  The genotypes are 
determined by the sizes of DNA fragments present.  Recent evidence suggests that other genes, including 
clusterin, complement receptor 1 and phosphatidylinositol binding clathrin are associated with AD91, but their 
effects are not as strong as apolipoprotein E and their associations with olfaction are unknown.  Therefore, we 
will not study them and will not bank DNA because of the relatively small sample size for genetic analyses. 
STATISTICS.  General considerations and approach to multiple comparisons.  In this proof-of-concept study, 
we do not consider it essential or even important to control for making one or more Type I errors between the 
two different study samples (MCI, AD) or between any of the cognitive or global clinical endpoints (SRT, 
ADAS-cog, CIBIC-plus).  Testing this study’s hypothesis (do changes in UPSIT predict outcome?) in these 
different samples with these different measures represents very different research questions, such that a 
positive finding from one sample or with one outcome cannot be claimed to support a positive result in a 
different sample or with a different outcome.  However, for a given patient sample and a given outcome, our 
analysis will consider four parameters of interest, any one of which could be used as evidence supporting the 
scientific hypothesis that changes in UPSIT predict the given outcome in the given sample.  This creates a 
four-dimensional parameter space and a corresponding family of hypotheses within which we will control the 
probability of making one or more Type I errors at 5%.  Therefore, we will repeat the analyses described below 
for each study sample and for each endpoint, controlling the family-wise type I error rate in each repetition at 
the 0.05 level.  Any positive findings will be viewed as hypothesis-generating for a subsequent, larger 
confirmatory study in the given sample and with the given cognitive or overall clinical endpoint. 
Notation and statistical analysis model.  Let Yit denote the value for subject i at time index t for a given outcome 
measure for patients in a given study sample.  Here i = 1,...,N and the time index t takes values t=0 for 
baseline, t=1 for the measurement at week 26, and t=2 for the measurement at week 52.  For t =1 and 2, 
define the change-score ∆Yit = Yit –Yi0.  Let Uit denote the UPSIT value for subject i at time index t, where now 
t=0 corresponds to the pre-atropine challenge measurement, t=1 to the post-challenge measurement, and t=2 
to the week-eight measurement.  Define the change-score ∆Uit = Uit –Ui0.  Thus ∆Ui1 is the change (typically a 
decrease) in the UPSIT due to the atropine challenge and ∆Ui2 is the change (typically an increase) from 
baseline to week eight.  The statistical model we will use is a bivariate multiple regression model:   
∆Y = β'X + E, where ∆Y is the 2 x 1 response vector (∆Yi1, ∆Yi2)', β is a 7 x 2 matrix of multivariate regression 
coefficients, X is the 7 x 1 vector of explanatory factors (∆Ui1, ∆Ui2, age, sex=female, education ≥ 8 yrs, 
baseline MMSE, and an intercept dummy), and E is a 2 x 1 vector of errors terms which we will assume has a 
bivariate normal distribution with mean 0 and 2 x 2 variance-covariance matrix Σ for each given X.  [If there is 
an unexpected departure from normality in any outcome measure, as evidenced by visual inspection of 
residual histograms and a formal Kolmogorov-Smirnov goodness of fit statistic at p<.10, we will use a 


normalizing transformation for ∆Y in an attempt to restore the normality of the residuals.]  The first two rows of 
β are our parameters of interest: slope coefficient βrs is the expected change in mean ∆Yis per unit change in 
∆Uir (for r,s=1,2).  They will be estimated by ordinary least squares (OLS) with 95% confidence intervals.  We 
will test the global null hypothesis of no ability of UPSIT to predict the cognitive or clinical outcome by testing 
H0: β11=β12=β21=β22=0, at level alpha=0.05, using an F test with 4 and N–14 degrees of freedom.  Simultaneous 
95% confidence intervals for each coefficient, and for linear contrasts between coefficients will be prepared 
using the standard union-intersection principle for multivariate analysis. 
Secondary analyses.  (i) All measures other than the hypothesized predictor and outcome variables will be 
evaluated in secondary analyses, e.g., E-cog and FAQ as functional outcomes.  Pearson correlation 
coefficients will be used to examine the associations between these measures and UPSIT, other cognitive 
measures, and continuous baseline demographic variables.  Student’s t test will compare differences for 
dichotomous variables (e.g., sex).  The statistical analytic approach will be similar for testing the primary 
hypotheses.  (ii) In another secondary analysis we will attempt to confirm the findings of the British study108 
using their choice of dichotomization at 4 or more points change in week eight UPSIT for predicting outcome.  
We will not use that (or any other) dichotomization for our primary analysis in order to retain full power.  We 
will, however, be able to evaluate whether the four-point change in 8-week UPSIT cut-point is better or worse 
than other cut-points in predicting outcomes.  For this we will use ROC methods for predicting a good clinical 
outcome, such as a 4-point improvement in SRT or ADAS-cog, or a 2-point improvement in CIBIC-plus.  (iii) In 
other secondary analyses we will determine the robustness of our findings by preparing completers-only 
analyses (see Handling of Missing Data below) and comparing the results to the primary analyses. 
Exploratory analyses.  We will not assume any time-evolution curve for the responses at 26 and 52 weeks.  
The response-curve is unlikely to be linear over the year of follow-up, as evidence shows a plateau or a small 
decline in cognitive and global measures after an initial positive response to donepezil.  In exploratory analyses 
we will check if a simple parametric model in time with subject-specific parameters can parsimoniously fit the 
response data and if the findings relating to UPSIT persist.  We will check for interactions between the slope 
parameters β11, β12, β21, β22 and the other covariates of age, sex, education, and baseline MMSE, each at the 
alpha = 0.10 level given reduced power to detect interactions compared with main effects.  For exploratory 
hypothesis with baseline UPSIT as a significant predictor in both the MCI and AD samples, we will conduct 
separate simple regression analyses with covariates as appropriate.  We will also explore the relative utility of 
the baseline UPSIT compared to the change scores by entering them in the same regression model and 
examining which has a larger standardized coefficient (i.e., the regression coefficient times the ratio of 
standard deviations of the predictor and dependent variables).  For the exploratory hypothesis on prediction of 
conversion to AD (MCI sample only), logistic regression analyses will be conducted.  For variables that may 
impact outcome, e.g., incident depression, stroke, in secondary analyses we will check for the effect of any 
such potential confounders as individual terms in a bivariate multiple regression model.  Apolipoprotein-E 
genotype will be examined as a potential moderator of UPSIT prediction of donepezil response.   
Missing data and handling of dropouts.  All due diligence will be done to minimize the occurrence of losses to 
follow-up, as the best first-line defense of study validity.  Close-out due to death from any cause is not a loss to 
follow-up as we will use worst-possible scores for patients who die.  Dropout due to withdrawal of consent, 
moving away, and other forms of loss to follow-up will be handled as follows.  Patients who drop out prior to 
their week eight visit will be omitted from the analysis, as one of the two key predictor variables will be 
unobservable as will every outcome change-score.  In each study, we expect 5% attrition before the week 
eight visit.  Other patients dropping out after week eight (estimated additional 10%, i.e., total 15% dropout in 
MCI, and an additional 15% or total 20% dropout in AD) will be included in the analysis by using their last 
observations carried forward.  While this may underestimate the change in cognitive and clinical outcomes at 
26 and 52 weeks, these measures are not expected to change much after the point of dropout, especially if the 
patient discontinues donepezil treatment.  Patients switched from donepezil to another ACheI during the 52 
weeks will be considered as completers assuming they remain in the study.  All patients who discontinue 
donepezil, whether or not they switch to another ACheI, will still be followed for the entire 52 weeks (whenever 
possible) for the primary intent-to-treat analyses. 
Power and sample size considerations.  In the multivariate regression model the ordinary least squares estimate 
of the vectorized regression coefficient β* = βV , has variance-covariance matrix  Σ
(X'X)–1 where 
 is the 
Kronecker product, and the estimates of the four regression coefficients of interest, β = (β11, β21, β12, β22)', has 
variance-covariance matrix Σ
D, where D is the 2 x 2 submatrix of (X'X)–1 corresponding to (∆Ui1, ∆Ui2).  For 
purposes of the power calculation we assume D will be approximately equal to   


, 
where Sj
2 is the variance of ∆Uij (j=1,2) and
is the correlation between ∆Ui1 and ∆Ui2.  The approximation 
consists of ignoring the effects of the other covariates and assuming that the distribution of (∆Ui1, ∆Ui2) we will 
observe in the study will have variances and correlation given by S1
2, S2
2, and 
.  Then the quadratic form 
 has a non-central F distribution on four and N–14 degrees of freedom with non-centrality 
parameter 
, and the probability that a non-central F variable with non-centrality parameter  
will exceed the critical value cutting off 5% in the upper tail of the F distribution on four and N–14 
degrees of freedom will approximate the power of the F test.  Since Cov(∆Y) = β'Cov(∆U) β + 
, we could 
estimate 
 by Cov(∆Y) - β'Cov(∆U)β with assumptions about the marginal variances and covariance of ∆Y and 
the same about ∆U.  However, to be conservative, we will simply assume that 
 is given by the marginal 
parameters listed below and not reduce them by the assumed regression effects.  We assume the following 
standard deviations and within-variable correlation parameters (between times t=1 and t=2). 
MCI sample parameters 
UPSIT change score 
SRT change score 
ADAS-cog change score 
CIBIC-plus change score 
Standard deviation (t=1) 
3.75 (S1) 
2.0 (
) 
2.0 (
) 
1.0 (
) 
Standard deviation (t=2) 
3.75 (S2) 
2.0 (
) 
2.0 (
) 
1.0 (
) 
Correlation (t=1, t=2) 
0.80 (
) 
0.85 (
) 
0.85 (
) 
0.70 (
) 
AD sample parameters 
 
 
 
 
Standard deviation (t=1) 
3.75 (S1) 
3.0 (
) 
3.0 (
) 
1.0 (
) 
Standard deviation (t=2) 
3.75 (S2) 
3.0 (
) 
3.0 (
) 
1.0 (
) 
Correlation (t=1, t=2) 
0.80 (
) 
0.85 (
) 
0.85 (
) 
0.70 (
) 
It would be clinically meaningful if a four-point change in UPSIT either at the atropine challenge test or the week 
eight observation were to predict a four-point change in either the SRT or the ADAS-cog endpoint, or a one-point 
change in CIBIC-plus, at week 26.  Similarly, the scientific hypothesis implies that no change in UPSIT predicts no 
change in the cognitive or clinical endpoint, and this would imply that the slope coefficients β12 = β22 = 1.0 for SRT 
and ADAS-cog and β12 = β22 = 0.25 for CIBIC-plus.  However, this assumes perfect correlation between UPSIT 
and the outcome measures, which we do not expect.  A set of smaller regression coefficients are expected, and 
the next table presents the magnitudes of regression coefficients that can be detected with 90% power with a 
proposed sample size of N=100 in the AD sample.  Regarding effect sizes at 52 weeks, we assume equal effects 
or, alternatively, half the effect size, compared to 26 weeks.   
Effect sizes (θ) detectable at 90% (with alpha=.05 two-tailed). 
Primary Hypothesis Test 
SRT 
change score 
ADAS-cog** 
change score 
CIBIC-plus 
change-score*** 
β11 = β12 = β21 = β22 = θ 
(equal effect size at 26 & 52 weeks and for both UPSIT scores)  
0.165 
–0.165 
0.053 
β11 = β12 = θ  with  β21 = β22 = 0 
(equal effect size for the atropine challenge measure at 26 and 
52 weeks, but no effect of UPSIT at 8 weeks)* 
0.312 
–0.312 
0.100 
β11 = 2β12 = β21 = 2β22 = θ   
(effect size at week 52 equal to half that at week 26; same for 
both UPSIT measures) 
0.143 
–0.143 
0.055 
β11 = 2β12 = θ  with  β21 = β22 = 0 
(effect size at week 52 equal to half that at week 26 for 
atropine challenge, but no effect of UPSIT at 8 weeks)* 
0.271 
–0.271 
0.105 
Test of H0: β11 = β12 
 
 
 
|β11 - β12| = θ 
(difference of UPSIT effect between weeks 26 and 52) 
0.241 
0.241 
0.114 
*  Note that because of the assumed symmetries, results assuming effects for UPSIT at atropine challenge and no effect for UPSIT at week 8 are the 
same as for the reverse.  **The signs are reversed for ADAS-cog since ADAS-cog is an inverse scale.  *** The non-monotonicities in the table reflect the 
effect of the different correlation structure assumed for SRT or ADAS-cog versus CIBIC-plus.   
The table shows power is at least 90% to declare a slope coefficient 0.312 or greater significant at the 5% level.  
We have greater power for the MCI sample since the standard deviations are smaller for SRT and ADAS-cog.