Article

Does Donepezil Treatment Slow the Progression

of Hippocampal Atrophy in Patients
With Alzheimer’s Disease?

Mamoru Hashimoto, M.D., Ph.D.
Hiroaki Kazui, M.D., Ph.D.
Keiji Matsumoto, M.D.
Yoko Nakano, M.D., Ph.D.
Minoru Yasuda, M.D., Ph.D.
Etsuro Mori, M.D., Ph.D.
Objective: The only approved pharmaco-
logical approach for the symptomatic
treatment of Alzheimer’s disease in Japan
is the use of a cholinesterase inhibitor,
donepezil hydrochloride. Recent in vivo
and in vitro studies raise the possibility
that cholinesterase inhibitors can slow the
progression of Alzheimer’s disease. The
purpose of the present study was to deter-
mine whether donepezil has a neuropro-
tective effect in Alzheimer’s disease by us-
ing the rate of hippocampal atrophy as a
surrogate marker of disease progression.
Method: In a prospective cohort study,
54 patients with Alzheimer’s disease who
received donepezil treatment and 93 con-
trol patients with Alzheimer’s disease who
never received anti-Alzheimer drugs un-
derwent magnetic resonance imaging
(MRI) twice at a 1-year interval. The an-
nual rate of hippocampal atrophy of each
subject was determined by using an MRI-
based volumetric technique. Background
characteristics, age, sex, disease duration,
education, MRI interval, apolipoprotein E
(APOE) genotype, and baseline Alzheimer’s
Disease Assessment Scale score were com-
parable between the treated and control
groups.
Results: The mean annual rate of hippo-
campal volume loss among the treated pa-
tients (mean=3.82%, SD=2.84%) was signif-
icantly smaller than that among the
control patients (mean=5.04%, SD=2.54%).
Upon analysis of covariance, where those
confounding variables (age, sex, disease
duration, education, MRI interval, APOE
genotype, and baseline Alzheimer’s Dis-
ease Assessment Scale score) were entered
into the model as covariates, the effect of
donepezil treatment on hippocampal at-
rophy remained significant.
Conclusions: Donepezil treatment slows
the progression of hippocampal atrophy,
suggesting a neuroprotective effect of
donepezil in Alzheimer’s disease.

(Am J Psychiatry 2005; 162:676–682)

A t present, the only approved pharmacological ap-

proach for the symptomatic treatment of Alzheimer’s
disease in Japan is the use of cholinesterase inhibitors.
Donepezil hydrochloride has been demonstrated to have
significant effects in slowing symptomatic progression in
24-week placebo-controlled trials (1), and some long-term
studies have shown that there is no less benefit after 1 year
of treatment (2, 3). One observational study (4) showed
that cholinesterase inhibitor treatment alters the natural
history of Alzheimer’s disease, as indicated by the delay in
admission to nursing homes. Furthermore, a longitudinal
neuroimaging study using single photon emission com-
puted tomography (SPECT) demonstrated that treatment
of patients with Alzheimer’s disease with donepezil for 1
year reduced the decline in regional cerebral blood flow
(rCBF) (5), suggesting the preservation of functional brain
activity in donepezil-treated patients. Although these
studies appear to have demonstrated the efficacy of done-
pezil in slowing down clinical disease progression, it is not
clear whether donepezil treatment slows disease progres-
sion in Alzheimer’s disease.
Neuropathologically, Alzheimer’s disease is characterized
by the presence of neurofibrillary tangles and senile
plaques, impaired synaptic function, and cell loss (6).
Although these histological features cannot be examined
noninvasively, the cell loss that accompanies them can be
seen in vivo as atrophy with magnetic resonance imaging
(MRI). Among the characteristic neuropathological changes
in Alzheimer’s disease, the most prominent structural
changes at the initial stage occur in the hippocampal for-
mation (7, 8). MRI-based volumetry of the medial tempo-
ral lobe structures has been proposed as a useful tool for
the clinical diagnosis of Alzheimer’s disease (8). Serial MRI
studies permit calculation of rates of atrophy over time. It
has been proposed that measurement of the rate of atro-
phy could be used to monitor the effectiveness of antide-
mentia drugs for Alzheimer’s disease (9, 10). If an anti-Alz-
heimer drug can slow down the anatomic progression of
Alzheimer’s disease pathology, this should be detectable
as a decrease in the rate of hippocampal atrophy in treated
patients.

676 http://ajp.psychiatryonline.org Am J Psychiatry 162:4, April 2005


The purpose of the present study was to determine
whether a cholinesterase inhibitor, donepezil hydrochlo-
ride, has a neuroprotective effect on Alzheimer’s disease.
Using an MRI-based volumetric technique, we examined
the rates of hippocampal atrophy in donepezil-treated
Alzheimer’s disease patients and compared the results
with those in control patients.
Method
Subjects and Study Design
In the present study, a prospective cohort was compared with a
historical control cohort. All procedures followed the clinical
study guidelines of the ethics committee of Hyogo Institute for
Aging Brain and Cognitive Disorders, a research-oriented hospital,
and were approved by the institutional review board. Written in-
formed consent was obtained from the patients or their families.
The control group was selected among those who participated
in the annual follow-up program before donepezil was intro-
duced. Patients with Alzheimer’s disease who were examined at
the Hyogo Institute for Aging Brain and Cognitive Disorders were
invited to the Hyogo Institute’s Alzheimer’s disease annual follow-
up program starting in July 1993. The consent and availability of a
reliable caregiver and the absence of severe behavioral problems
impelling institutionalization were the requirements for partici-
pating in the program. At baseline, the patients were examined
comprehensively by both neurologists and psychiatrists under a
short-term admission to the infirmary and were given routine
laboratory tests, EEGs, and standardized neuropsychological ex-
aminations. The patients’ medical history was systematically col-
lected from reliable family members by using a database format.
Other imaging studies, such as MRIs of the brain, magnetic reso-
nance angiograms of the head and neck, and cerebral perfusion
or metabolism studies with positron emission tomography or
SPECT were performed at baseline. Neuropsychological tests and
MRIs were repeated at 1-year intervals. The clinical and investiga-
tive data collected prospectively in a standardized fashion were
all added to the database (11).
After donepezil hydrochloride was licensed and marketed in
November 1999 in Japan, the annual follow-up program was re-
vised to the donepezil follow-up program because most patients
with Alzheimer’s disease were treated with donepezil. The treated
group consisted of consecutive patients with mild to moderate
Alzheimer’s disease who received donepezil treatment and were
enrolled in a prospective longitudinal cohort study between No-
vember 1999 and June 2003. Treatment with donepezil was a pre-
requisite for participating in the revised program. After the same
baseline assessments as the annual follow-up program were eval-
uated, the patients received 3 mg/day of donepezil for 1 or 2 weeks
and then 5 mg/day (the approved maximum dose in Japan). Do-
nepezil hydrochloride was prescribed for the entire year after the
initial MRI, and compliance was monitored at every visit (every 3
months). Neuropsychological tests and MRIs were repeated at 1-
year intervals. The treated patients satisfied six inclusion criteria:
1. Meeting criteria of the National Institute of Neurological
Disease and Stroke/Alzheimer’s Disease and Related Disor-
ders Association for probable Alzheimer’s disease (12)
2. Having minimal to moderate functional severity (a score of 15
or more on the Mini-Mental State Examination (MMSE) (13)
3. Having no lifetime history of other neurological or mental
disorders
4. Taking no established and documented antidementia drugs
other than donepezil (agents with possible antidementia
Am J Psychiatry 162:4, April 2005
HASHIMOTO, KAZUI, MATSUMOTO, ET AL.
properties, such as nonsteroidal antiinflammatory drugs,
vitamins E, ginkgo biloba, and lecithin were allowed)
5. Having no evidence of focal brain lesions on a MRI
6. There being informed consent from patients and their rela-
tives for determination of their apolipoprotein E (APOE)
genotype
The control group was selected among those who participated
in the annual follow-up program between July 1993 and October
1999. Requirements for inclusion in the present study were the
same as those for the donepezil follow-up participants except for
the use of donepezil. Those who received anti-Alzheimer drugs
other than donepezil were not included in the present study. In
this study, only baseline and 1-year follow-up data were used.
Cognitive Functions
The status of global cognitive function was assessed with the
MMSE and the Alzheimer’s Disease Assessment Scale (14). The Alz-
heimer’s Disease Assessment Scale was administrated by neuro-
psychologists (along with the MRI examination) who were not in-
volved in managing the patients at a 1-year interval (10–14 months).
MRI Volumetry
We directly measured the volume of the hippocampal forma-
tion on high spatial resolution three-dimensional spoiled-gradi-
ent echo images (15). The images were generated perpendicular to
the anterior-posterior commissure plane that covers the whole
calvaria with a 1.5-T MRI unit (Sign Advantage 5.x, General Elec-
tric Medical Systems, Milwaukee). The operating parameters were
as follows: field of view=220 mm, matrix=256×256, 124×1.5 mm
contiguous sections, TR=14 msec, TE=3 msec, and flip angle=20°.
The detailed hippocampal MRI volumetric procedure is de-
scribed elsewhere (15). In brief, the MRI data set was transmitted
to a computer from the MRI unit, and after an appropriate data
conversion, it was analyzed by using the public domain Image
version 1.62 program (developed at the National Institutes of
Health and available on the Internet at http://rsb.info.nih.gov/
nih-image/) with residential macro programs developed in our
institute. Hippocampal formation volume in all subjects was
measured by a single investigator (M.H.) who was blinded to 1) all
clinical information, 2) the order (initial and follow-up) of MRIs,
and 3) the time of enrollment. Before starting the measurement,
the rater inspected the suitability of MRIs for hippocampal volu-
metry. If either one of the two MRIs obtained for a subject was un-
suitable for volumetry because of motion artifacts or for any other
technical reason, the subject was excluded from the study.
For volumetry, we used a combination of semiautomatic seg-
mentation-through-density thresholding and manual tracing,
thereby lowering partial voluming and the observer’s bias. The re-
liability and validity of volumetry have been established and de-
scribed elsewhere (9, 15). The hippocampal formation was de-
fined to include the pes hippocampi, digitationes hippocampi,
alveus hippocampi, dentate gyrus, and subiculum (16–18). The
boundary of the hippocampal formation was defined from the
entire head of the hippocampus to the slice where the crus of the
fornix was seen in full profile. The outline of the hippocampal for-
mation together with the surrounding white matter and CSF was
first traced with a manually guided mouse cursor, and subse-
quently, the gray matter of each structure was extracted by den-
sity thresholding set at a range between minimum and maximum
pixel values. The maximum value was defined as the largest value
for any pixel of the gray matter (represented by the caudate head).
The minimum value was defined as one-half the sum of the mean
pixel value of the gray matter and the mean value of CSF (repre-
sented by the lateral ventricle) (16). The slice volume of the hip-
pocampal formation was obtained by automatically counting the
number of pixels within the segmented regions and then multi-
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DONEPEZIL AND HIPPOCAMPAL ATROPHY

TABLE 1. Demographic and Clinical Characteristics of Patients With Alzheimer’s Disease

Donepezil-Treated Group
One or Two Control Group
Apolipoprotein One or Two
E (APOE) ε4 APOE ε4 APOE ε4 APOE ε4
Allele(s) Present Allele Absent Total Allele(s) Present Allele Absent Total
Characteristic (N=35) (N=19) (N=54) (N=50) (N=43) (N=93)
N N N N N N
Sex
Male 6 6 12 13 5 18
Female 29 13 42 37 38 75

Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD

Age (years) 69.3 9.0 69.9 10.5 69.5 9.5 71.2 7.9 69.8 10.5 70.5 9.1
Education (years) 9.8 2.0 9.9 3.3 9.8 2.5 9.2 2.0 9.7 2.2 9.5 2.1
Duration of disease (months) 31.8 19.3 36.1 19.8 33.3 19.4 35.0 23.8 27.8 18.3 31.7 21.6
Magnetic resonance imaging
interval (days) 389 25 386 35 388 29 395 35 389 35 392 35
Baseline score on Mini-Mental
State Examination 21.9 3.8 21.6 4.2 21.8 3.9 21.5 2.7 21.7 2.9 21.6 2.8

plying the number by the voxel size: 9([220/256]2 × [1.5=1.1078 Results

mm 3]). The average volume of the right and left hippocampal
formations was used for the analysis. The test-retest reliability
(kappa=0.98) was measured as an intraclass correlation coeffi-
cient derived from three repeated measurements by a single rater
under blinded conditions in 10 randomly selected subjects. Co-
efficients of variation (standard deviation/mean, where standard
deviation indicates square root value of the arithmetic mean of 10
variance estimates) were 2.84% and 2.78% for the right and left
hippocampal formations, respectively.
Determination of APOE Genotype
The detailed method for APOE genotyping is described else-
where (19). In brief, genomic DNA was extracted from peripheral
blood with a Genomix DNA extraction kit (Talent Corp., Trieste,
Italy) according to the manufacturer’s protocol. The APOE geno-
type was determined by using polymerase chain reaction restric-
tion fragment length polymorphism, according to the procedure
described by Wenham and colleagues (20).
Statistical Analysis
The annual rate of hippocampal atrophy was defined as the
percentage change, which was computed as baseline hippocam-
pal formation volume minus 1-year hippocampal formation vol-
ume divided by baseline hippocampal formation volume (×100).
The change in cognitive decline was expressed as the difference
(points) between the baseline and 1-year Alzheimer’s Disease As-
sessment Scale scores. Because the APOE ε4 allele is known to be
specifically related to hippocampal atrophy in Alzheimer’s dis-
ease (9, 21), the effect of donepezil on hippocampal atrophy is
possibly influenced by the APOE genotype. Therefore, we used
two-way analysis of variance, which included the effects of done-
pezil treatment (i.e., treated and untreated), APOE type (i.e., pres-
ence and absence of the APOE ε4 allele), and their interaction.
When the interaction term was not significant, the effects of the
donepezil treatment were examined with a t test. When signifi-
cant effects were found, they were further examined with analysis
of covariance (ANCOVA) in which age, sex, disease duration, edu-
cation, interval between the two MRI studies (days), APOE geno-
type, and baseline MMSE score were entered into the model as
covariates. The level of significance was set at p<0.05 for all statis-
tical analyses.
Twelve of 77 patients who were initially enrolled in the
donepezil follow-up program were dropped from the
study. Seven withdrew their consent, two were institution-
alized, and the remaining three withdrew for other rea-
sons. Of the 65 patients who completed the entire proce-
dure of the study, 11 were excluded because the quality of
one of their two MRIs was unsuitable for volumetry. Thus,
54 patients remained in the treated group. Two patients
did not receive the full, 1-year dosage of donepezil. One
patient discontinued donepezil after 3 weeks because of
adverse effects, and the other took the drug irregularly (re-
ceiving about 60% of the full dose). However, these pa-
tients were included in the primary analyses.
Of the 108 patients who completed the entire procedure
of the annual follow-up study, 15 patients were excluded
because their MRIs were of poor quality. Thus, 93 patients
remained in the control group. The background character-
istics of both groups are summarized in Table 1. The
treated and control groups were not significantly different
in age, sex, education, disease duration, intervals between
the first and second MRI, or baseline MMSE scores.
Hippocampal volumes and Alzheimer’s Disease Assess-
ment Scale scores are summarized in Table 2. The effect of
donepezil treatment on the change in Alzheimer’s Disease
Assessment Scale scores was significant (F=5.55, df=143,
p<0.02), but neither the effect of the APOE ε4 allele (F=3.64,
df=143, p<0.06) nor the interaction term (F=0.32, df=143,
p=0.57) was significant. The effects of donepezil treatment
and the APOE ε4 allele on the rate of hippocampal atrophy
were significant (F=8.19, df=143, p=0.005, and F=5.29, df=
143, p<0.03, respectively), but the interaction term was not
significant (F=0.08, df=143, p=0.78). In a further analysis,
the mean annual rate of hippocampal atrophy in the
treated group (mean=3.82%, SD=2.84%) was significantly
lower than in the control group (mean=5.04%, SD=2.54%)
(t=–2.7, df=145, p=0.008). In a one-way ANCOVA, where

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 HASHIMOTO, KAZUI, MATSUMOTO, ET AL.

TABLE 2. Annual Change in Alzheimer’s Disease Assessment Scale Score and Rate of Hippocampal Atrophy Among Patients
With Alzheimer’s Disease
Donepezil-Treated Group
One or Two Control Group
Apolipoprotein E One or Two
(APOE) ε4 APOE ε4 APOE ε4 APOE ε4
Allele(s) Present Allele Absent Total Allele(s) Present Allele Absent Total
(N=35) (N=19) (N=54) (N=50) (N=43) (N=93)
Variable Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD
Baseline Alzheimer’s
Disease Assessment Scale
score 14.0 4.8 16.3 5.6 14.8 5.2 15.9 4.9 16.9 5.0 16.4 4.9
Annual change in
Alzheimer’s Disease
Assessment Scalea –0.2 3.8 2.5 4.9 0.8 4.4 3.0 6.4 4.4 7.6 3.6 7.0
Baseline hippocampal
formation volume (mm3) 2496 428 2514 496 2502 449 2391 461 2585 435 2481 457
Annual hippocampal
atrophy rate (%)a,b 4.15 2.32 3.21 3.60 3.82 2.84 5.59 2.15 4.40 2.81 5.04 2.54
a Significant effect of treatment.
b Significant effect of APOE ε4 allele.

age, sex, disease duration, education, MRI interval, APOE
genotype, and baseline Alzheimer’s Disease Assessment
Scale score were entered into the model as covariates, the
effect of donepezil on hippocampal atrophy remained sig-
nificant (F=10.34, df=138, p=0.002).
Even if the two patients who did not receive the full 1-
year dosage of donepezil were excluded from the analyses,
the results remained unchanged; donepezil treatment had
significant effects on Alzheimer’s Disease Assessment
Scale score (F=4.37, df=141, p<0.04) and the rate of hip-
pocampal atrophy (F=6.53, df=141, p<0.02), and the APOE
ε4 allele had a significant effect on the rate of hippocampal
atrophy (F=4.14, df=142, p<0.05). The mean annual rate of
hippocampal atrophy in the treated group (mean=3.93%,
SD=2.76%) was significantly lower than in the control
group (mean=5.04%, SD=2.54%) (t=–2.4, df=143, p<0.02).
Discussion
In the present study, the mean annual decline in the
Alzheimer’s Disease Assessment Scale score in the control
group (3.6 points) was significantly larger than in the
treated group (0.8 points). Thus, these results are consis-
tent with the results of previous long-term studies of do-
nepezil (2, 3), and suggest that treatment with donepezil
for 1 year was associated with a cognitive benefit. More-
over, donepezil seemingly slows the rate of hippocampal
atrophy. The decrease in hippocampal volume in the
treated patients (3.82%) was about 24% less than in the
control patients (5.04%). The present results suggest that
donepezil has both symptomatic and disease-progression
slowing effects. The mean annual rate of hippocampal at-
rophy was significantly higher in the patients with the
APOE ε4 allele than in those without the APOE ε4 allele,
replicating our previous observation that the APOE ε4 al-
lele is specifically related to accelerated hippocampal pa-
thology in Alzheimer’s disease (9). On the other hand, for
the rate of hippocampal atrophy and for the change in Alz-
heimer’s Disease Assessment Scale, no significant interac-
tion was noted between donepezil treatment and the APOE
genotype. In a previous study, the effect of donepezil treat-
ment did not appear to be affected by the APOE genotype
(22). Our data are consistent with this observation.
In recent studies, long-term donepezil treatment has
been demonstrated to slow the decline in cognition and
functional activities (2, 3), delay the admission to a nurs-
ing home (4), and reduce the decline in rCBF (5). However,
these studies do not answer the question of whether the
beneficial effects of donepezil are due to symptomatic
suppression, which leaves the underlying disease process
unaltered, or to neuroprotection modifying the disease
process. Recently, one randomized, double-blind, pla-
cebo-controlled pilot study in patients with Alzheimer’s
disease demonstrated that donepezil-treated patients had
significantly smaller mean decreases in total hippocampal
volumes compared with placebo-treated patients. Al-
though that study had limitations in that it included a rel-
atively small number of patients and the period of drug
treatment was short, our data are consistent with the re-
sults (23). Furthermore, two clinical trials, both open-la-
bel, placebo-controlled extension studies, have raised the
possibility that cholinesterase inhibitors have slowing ef-
fects on both symptomatic and disease progression in
Alzheimer’s disease patients. In one study (24), the level of
cognitive function in patients who were treated with pla-
cebo for 3 months, followed by 12 months of donepezil
treatment, was lower than in patients who were treated
with donepezil for all 15 months. In the other study (25),
the level of cognitive function of the patients who were
treated with placebo for 26 weeks, followed by 26 weeks of
rivastigmine treatment, was lower than that in patients
who were treated with rivastigmine for all 52 weeks. The
inability to catch up in those in whom the treatment with

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DONEPEZIL AND HIPPOCAMPAL ATROPHY
cholinesterase inhibitors was postponed reminds us of a
potential disease-modifying effect.
A recent long-term randomized, double-blind trial (26)
showed that no significant benefits were seen with done-
pezil compared with placebo in the institutionalization
and progression of disability. In the study, there were no
significant differences in behavioral symptoms, caregiver
well-being, and caregiver time costs. On the other hand,
statistically significant cognitive and functional effects
were maintained over at least 2 years. Because many of the
outcomes are influenced by the interaction of complex bi-
ological, social, and environmental factors, they might be
inappropriate for assessing the neuroprotective effects of
donepezil.
To explain the neuroprotective effect of cholinesterase
inhibitors, mechanisms based on beta-amyloid metabo-
lism have been postulated. Accumulation of amyloid is
one of the earliest changes in Alzheimer’s disease pathol-
ogy (27, 28) and may cause neuronal death in the CNS (29,
30). In vitro studies have demonstrated a link between
cholinergic activation and beta-amyloid precursor protein
metabolism. Wallace et al. (31) found evidence that lesions
of the cholinergic nucleus basalis of Meynert increased
the synthesis of beta-amyloid precursor protein in the ce-
rebral cortex of rats. Wolf et al. (32), using human CNS
neurons, found increased amyloid precursor protein se-
cretion and decreased beta-amyloid protein production
with carbachol stimulation of muscarinic receptors (32).
These studies support a beneficial alteration in amyloid
processing associated with cholinergic stimulation. Ki-
hara et al. (33) examined the effects of nicotinic receptor
agonists on amyloid beta cytotoxicity in cultured rat corti-
cal neurons and found that nicotinic receptor stimulation
may be able to protect neurons from degeneration in-
duced by amyloid beta. Svensson and Nordberg (34) dem-
onstrated that tacrine and donepezil at clinically relevant
concentrations attenuated amyloid beta (25-35)-induced
toxicity in rat pheochromocytoma PC12 cells. The neuro-
protective effect was blocked by the presence of the nico-
tinic antagonists mecamylamine and tubocurarine, sug-
gesting an intervention through nicotinic receptors.
Our study has some limitations. First, because it was a
comparative study with a historical control group rather
than a randomized study, it suffers from several sources of
bias. The groups are not comparable because of the selec-
tion of subjects who received the intervention (selection
bias), the cointerventions and other medical management
being received by the two groups were different (perfor-
mance bias), and the methods of outcome measurement
being used in the two groups were different (detection
bias). Although there was no intention to select subjects
for the control and treatment groups, patients who could
not tolerate the initial doses of donepezil were not in-
cluded in the donepezil follow-up program. This could
have been a source of selection bias. However, we are un-
aware of any evidence that donepezil tolerance predicts
680 http://ajp.psychiatryonline.org
disease progression. Because the control group in the
present study was not concurrent but historical, there was
a generation difference of several years between the
groups. Although the generation difference was a possible
source of selection and performance bias, the difference
in the patients’ generation was not likely to affect the vol-
umetric results, and the cointerventions and other medi-
cal management did not change throughout the first and
second halves of the study period. Second, it has been rec-
ognized that open-label studies are not optimal. The fact
that the investigators were not blinded to treatment might
increase the donepezil effect. However, neither hippo-
campal volume nor the Alzheimer’s Disease Assessment
Scale score was a subjective outcome measure. Further-
more, in the present study, the Alzheimer’s Disease Assess-
ment Scale was administered by neuropsychologists who
were unblinded but not involved in managing the pa-
tients, and MRI volumetry was made by an investigator
who was blinded to all clinical information. Therefore, it
was unlikely that detection bias affected the results of the
rate of hippocampal atrophy or the Alzheimer’s Disease
Assessment Scale score in favor of the donepezil-treated
group. Third, dropouts are a problem for this type of de-
sign and a possible source of exclusion bias. Simply ignor-
ing everyone who has withdrawn from a clinical trial may
bias the results, usually in favor of the intervention. There-
fore, it is standard practice to analyze the results of com-
parative studies on an intention-to-treat basis. In the
present study, two patients who did not take the full 1-year
dosage of donepezil because of adverse events or poor
compliance were included in the primary analyses.
As a result, the patients’ background characteristics,
such as age, sex, education, disease duration, disease se-
verity, and MRI interval, were comparable between the
two groups, and even after we controlled for these vari-
ables, the effect of donepezil on hippocampal atrophy re-
mained unchanged. In any case, the significant difference
of the rate of hippocampal atrophy was likely to be due to
the intervention with donepezil. Although our findings
should be confirmed by a randomized, controlled long-
term trial in patients with Alzheimer’s disease, it would be
unethical to conduct such a study to extend the knowl-
edge of donepezil.
The present results suggest that donepezil has not only
a symptomatic effect but also a neuroprotective effect. If
donepezil does, in fact, influence disease progression, we
need to modify our treatment strategies; donepezil is not
an optional but rather a mandatory treatment for Alzhe-
imer’s disease and should be started in the prodromal or
very early stage of the disease. Mild cognitive impairment
is a condition that frequently progresses to Alzheimer’s
disease, which requires early diagnostic and therapeutic
interventions. Donepezil, through its neuroprotective ef-
fect, could possibly inhibit progression from mild cognitive
impairment to Alzheimer’s disease. Further studies are
needed to determine whether donepezil slows the progres-
Am J Psychiatry 162:4, April 2005

sion from mild cognitive impairment to Alzheimer’s dis-
ease. Hippocampal atrophy could be used as a surrogate
marker of disease progression in such studies. Further-
more, the potential neuroprotective mechanism should be
refined and exploited to enhance the drug’s effectiveness in
treating Alzheimer’s disease. A better understanding of this
mechanism may suggest strategies for designing improved
drugs.
Received June 11, 2004; revision received Sept. 1, 2004; accepted
Sept. 10, 2004. From the Hyogo Institute for Aging Brain and Cogni-
tive Disorders, Hyogo, Japan; Sawa Hospital at Toyonaka; the Depart-
ment of Psychiatry and Behavior Science, Osaka University Graduate
School of Medicine, Osaka, Japan; the Department of Psychiatry and
Neurology, Kobe Graduate University School of Medicine, Hyogo, Ja-
pan; and the Department of Behavioral Neurology and Cognitive
Neuroscience, Tohoku University Graduate School of Medicine, Sen-
dai, Japan. Address correspondence and reprint requests to Dr. Ha-
shimoto, Sawa Hospital, 1-9-1 Shiroyamacho, Toyonaka, Osaka, 561-
8691, Japan; qq257xk9@minos.ocn.ne.jp (e-mail).
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