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and currently the only agent approved for moderately severe to severe AD in

Europe and for moderate to severe AD in the United States. Consistent reduc-

tion of the deterioration rate on global, cognitive, functional, and behavioral

measurements was shown in the memantine treatment group compared to the

usual care group in a recent clinical trial (Bullock, 2006). In the meta-analysis

of clinical trials for memantine treatment, improvements versus the placebo

were seen in individual activities of daily living and behavior, particularly ag-

itation and cognitive function (McShane, Areosa Sastre, & Minakaran, 2006).

Efficacy of memantine was demonstrated in patients with newly diagnosed

AD, patients previously or currently receiving ChEIs, and both institutional-

ized and community-dwelling AD patients. Increased dependency and institu-

tionalization are significant cost drivers in AD. Memantine is able to reduce

dependency and caregiver time required. This effect is important from the

point of view that AD progression, caregiver burden, and health care costs are

interrelated.

UTURE

UTLOOK FOR

LZHEIMER

’

ISEASE

RUGS

XTRAPOLATION FROM

RIALS OF

ATIENTS

WITH

ILD

OGNITIVE

MPAIRMENT

It has been shown that several subtypes of mild cognitive impairment exist, and

there is still a lack of consensus on whether or not to consider MCI to be a precur-

sor state of AD. However, there is general agreement that MCI is a risk factor for

the onset of dementia. Not everyone who has MCI will develop AD, and some pa-

tients who do not have MCI will develop AD (Knopman et al., 2003; Snowdon,

2003). Recently, several studies have been conducted on subjects with amnestic

MCI, which is believed to exhibit the most typical clinical picture, course, and

outcome among the various subtypes of MCI. It is known that neuropathological

changes exist prior to the onset of clinical symptoms of AD. Thus, if we assume

that MCI is an precursor state of AD as demonstrated by existing neuropatholog-

ical changes (Kordower et al., 2001; Mitchell et al., 2002; Mufson et al., 2002) or

images, or neuropsychological test results (Arnaiz & Almkvist, 2003), then it is

indeed appropriate to conduct a treatment trial of MCI, whose objective is to

delay, even if only slightly, the onset of the clinical symptoms of AD. Although

satisfactory results have not been obtained, we have reviewed the results re-

ported thus far and here attempt to discuss them. The need for a disease modifier

such as ChEI will increase in the future. Important information may be obtained

from discussion about a study design of ChEIs. The ChEI studies conducted thus

far are summarized in Table 13.2.

As is clear in Table 13.2, there were no study results that successfully

achieved the initial objective, although the efficacy of a ChEI as symptomatic

therapy was confirmed for donepezil when the study period was 6 months and

in a study whose objective was 3-year secondary prevention. It can be seen that

very similar selection criteria were used for the subjects of the studies in Table

13.2. However, if we consider that there was a large range in the conversion rate

to AD, that is, from 4.5% and 6.4% per year for rofecoxib to 16% for donepezil +

vitamin E, it is possible that the subjects selected were extremely heteroge-

neous. Visser, Scheltens, and Verhey (2005) retrospectively examined the accu-

Alzheimer’s Disease 357

racy of the diagnostic criteria used in MCI studies and pointed out that there

were large discrepancies in the definitions of cognitive impairment. Rubinsztein

and Easton (1999) performed a meta-analysis of the frequency of apoE4 in 42 re-

ports and found it to be 32% in patients at least 65 years old with sporadic AD

and 41% in those less than 65. Taking this into consideration, the criteria for

cognitive impairment in donepezil + vitamin E studies were strict. The subjects

were selected using those criteria with a high predictive value and they showed

high conversion rates. This resulted in the selection of subjects with relatively

high degrees of impairment compared to other studies because of the high per-

centage of apoE4.

Even with respect to the diagnostic criteria for AD, there have been several re-

ports dealing with the interrater reliability in multicenter studies, as well as clin-

ical neuropathological reports. If we consider that the results of MCI were not

satisfactory and there is no consensus concerning the clinical diagnostic criteria

for MCI, it may be necessary to add some types of biological markers as criteria

for MCI. Visser and colleagues (2002) used the Preclinical AD Scale (PAS), which

combines age, MMSE score, degree of functional impairment, neuropsychological

test results, medial temporal lobe atrophy, and apoE subtype; they reported that

it has high levels of detection and specificity for the precursor state of AD. Al-

though the PAS is an important tool for MCI detection, further studies are ur-

gently needed.

The primary end points (outcome measures) for treatment of MCI also need to

be considered. The primary outcome measures used in these MCI studies were

revised or modified versions of conventional test batteries and scales such as

Alzheimer’s Disease Assessment Scale (ADAS) and Clinician Interview Based

Impression of Change (CIBIC), which are initially designed according to Food

and Drug Administration guidelines for AD. With respect to ADAS, much knowl-

edge has been obtained regarding the changes in cognitive impairment over time,

and it is known that the rate of change is related to the baseline severity (Mohs,

1996). Such information for the change in cognitive function would be very useful

for distinguishing between changes in MCI and changes due to normal aging, be-

cause there is almost no knowledge or information like this for healthy individu-

als (Graham, Cully, Snow, Massman, & Doody, 2004).

Clinical trials conducted to date on ChEIs in the treatment of MCI have

studied amnestic MCI; this is understandable, as it makes the control group

homogeneous, but it is doubtful whether that aim was adequately achieved in

light of the differences in the rate of conversion to AD (see Table 13.10). This

means that conclusions concerning the effects of ChEIs on the progression of

MCI cannot be drawn on the basis of past results. Recently, Hashimoto and

colleagues (2005) used MRI and showed that atrophy of the hippocampus was

delayed in a group of subjects treated with donepezil compared with a non-

treatment group. The results of their study are in agreement with those of a

longitudinal study (Gron, Brandenburg, Wunderlich, & Riepe, 2006), that

used a neuropsychological test to examine hippocampal function in MCI be-

fore and after galantamine administration. If we assume that donepezil has an

effect not only on the symptoms of AD but also on the pathogenesis of the dis-

ease, then it is possible to rationalize therapy and studies on MCI using ChEIs,

including donepezil.

358

Table 13.10

Clinical Trials of Subjects with Mild Cognitive Impairment (MCI)

Donepezil +

Vitamin E Donepezil Rivastigmine Galantamine 1 Galantamine 2 Rofecoxib Piracetam

Affiliation (year at

trial)

69 sites, United

States and

Canada (1999)

Multicenter,

United States

69 centers, 14

countries (1999)

Multicenter in 8

European coun-

tries, United

States, and

Canada (2001)

Multicenter in 4

European coun-

tries, United

States, Canada,

Argentina, and

Australia (2001)

Multicenter 69 sites in 16

European coun-

tries (2000)

Design RCT, PCDB, 3

groups

RCT, PCDB, Par-

allel design

RCT, PCDB, Par-

allel design

RCT, PCDB, Par-

allel design

RCT, PCDB, Par-

allel design

RCT, PCDB, Par-

allel design

RCT, PCDB, 3

groups

Dosage/day Vitamine E,

donepezil: 10mg

10 mg/day 3–12 mg/day 16 or 24 mg/day

flexible dose

16 or 24 mg/day

flexible dose

25 mg/day 4,800 mg/day,

9,600 mg/day

Trial period 3 years 24 weeks 3 years + 1 year

extension

24 months 24 months 2–3 years + 1

year extension

12 months

Subject selection Amnestic MCI,

HDRS < 13,

CDR 0.5

Amnestic MCI,

CDR 0.5,

MMSE > 25

Amnestic MCI,

CDR 0.5,

HDRS < 13

Amnestic MCI,

CDR 0.5

Amnestic MCI,

CDR 0.5

Amnestic MCI,

CDR 0.5,

MMSE > 23,

BDRS < 4,

HDRS < 13

Amnestic MCI,

CDR 0.5,

HDRS < 18, etc.

Subjects 769 269 1,018 995 1,062 1,457 675

Age (years) 55–90 (mean:

72.9)

Mean 73 Mean 70.5 >50 >50 ≥65 50–89 (mean: 68)

ApoE e4 58% donepezil

55% vitamin E

53% placebo

Not available

41% (49% of all

subjects were

clarified)

26.4% galantamine

29.5% placebo

24.4% galantamine

23.5% placebo

35% rofecoxib

36% placebo

43% (60% of the

subjects were

clarified)

359

Primary measure Time to clinical

diagnosis of AD

Delayed recall

test, ADAS-cog,

CGIC-MCI

Time to clinical

diagnosis of AD,

Change on cogni-

tive function

Incident dementia,

CDR-SB

Incident dementia,

CDR-SB

Incident AD Symptom change,

CBCS

Conversion rate 16%/year Not available 19.4%/3–4 years 13% galantamine,

18% placebo/2

years

17% galantamine

and 21%

placebo/2 years

6.4% rofecoxib

4.5% placebo

Not available

Drop-out rate 12%/ year 20% 43% Not available Not available 45% rofecoxib

45% placebo

27% 4,800mg

21% 9,600mg

24% placebo

Adverse events Not available 88% donepezil

73% placebo

96% rivastigmine

93% placebo

90% galantamine

86% placebo

90% galantamine

86% placebo

90% rofecoxib

92% placebo

72% 4,800mg

68% 9,600mg

76% placebo

Results Significant effects

for conversion

rate and cognitive

function in the

first 18 months.

Significant effects

for 36 months in

the subjects with

ApoE4.

Significant effects

for ADAS-cog,

Immediate and

delayed recall

tests and digit

symbol backward,

and patient global

assessment were

significant for all

subjects.

No significant

results for primary

measures.

No effects on

conversion rate

and ADAS-cog,

positive effects on

CDR-SB and

attention, atrophy

rate on brain

volume.

No effects on

conversion rate,

ADAS-cog or

CDR-SB. Positive

effects on

attention.

No significant

improvements for

primary and sec-

ondary measures.

No significant dif-

ference for primary

and secondary

measures.

Note:

ADAS-cog = Alzheimer’s Disease Assessment Scale, Cognitive subscale; BDRS = Blessed Dementia Rating Scale; CBCS = Cognitive Battery Composite Score; CDR =

Clinical Dementia Rating Scale—Sum of Boxes; CGIC = Clinical Global Impression of Change Scale; HDRS = Hamilton Depression Rating Scale; PCDB = placebo-controled dou-

ble blind study; RCT = Randomized control study.

Source:

“Clinical Trials in Mild Cognitive Impairment: Lessons for the Future,” by Jelic V., M. Kivipelto, and B. Winblad, 2006,

Journal of Neurology, Neurosurgery, and Psy-

chiatry, 77,

pp. 429–438. Reprinted with permission.

360 E

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We have attempted to summarize the efficacies of three ChEIs that are presently

being used around the world, as well as introduce and comment on interesting re-

ports that have appeared recently. We have also summarized the results of recent

studies that used ChEIs to treat MCI and discussed future directions.

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