Alzheimer disease: progress or profit?

Claire Mount & Christian Downton

Alzheimer disease is the most common cause

of dementia. According to the World Health
Organization, an estimated 37 million people
worldwide currently have dementia; Alzheimer
disease affects about 18 million of them1.
Increasing age is the greatest risk factor for
Alzheimer disease. Its prevalence approximately doubles every five years after the age
of 60one in 10 individuals over 65 years
and nearly half of those over 85 are affected by
the disease. So, although the incidence rate of
Alzheimer disease is not thought to be changing, Alzheimer disease poses one of the greatest threats to the future of healthcare systems,
owing to the anticipated demographic shift to
an aging populationthe number of people
worldwide above the age of 60 years is expected
to double over the next 25 years.
The Alzheimers Society (Alzheimers
Society Policy Positions PaperDemography,
http://www.alzheimers.org.uk/News_and_
campaigns/Policy_watch/demography.htm;
ref. 2) estimates that the number of individuals
with Alzheimer disease will almost double to
34 million by 2025, with just less than 1 million
new cases per year by 2050 (Fig. 1). Notably,
developing countries are expected to see the
biggest increase in population and life expectancy. According the Alzheimers Association3,
between 1990 and 2010 the number of people
aged 65 years or over in developing countries is
projected to increase by 78%from 183 million to 325 million.
Costs of Alzheimer disease
With the expected increase in the prevalence
of Alzheimer disease will come an increase
in the financial burden caused by this condition. Alzheimer disease already takes an enormous financial toll on society; the Alzheimers
Association and the National Institute on Aging
estimate that the current direct and indirect
The authors are at Wood Mackenzie, London, EC2N
1HN, UK. Correspondence should be addressed to
claire.mount@woodmac.com.

780

959

2050
2040

820
615

2030

Year

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591

2020
2010

454

2000

411
377

1995
0

200

400

600

800

1,000

1,200

Number of Alzheimer disease cases in thousands

Figure 1 Actual and estimated number of new Alzheimer disease cases in the US through the
year 2050 (ref. 2).

costs of caring for the 4.5 million Americans

with Alzheimer disease are at least $100 billion
annually4.
It is estimated that more than 70% of people
with Alzheimer disease live at home, where
family and friends provide the majority of care,
placing physical and emotional stress on caregivers. As a result, the caregivers are themselves
at risk of psychiatric and physical morbidity
and, according to the Alzheimers Association,
one in eight caregivers of individuals with
Alzheimer disease becomes ill or injured, and
one in three uses medication for problems
related to caregiving5.
By 2030, when the baby boom generation
is more than 65 years old, the number of
Americans with Alzheimer disease is expected
to soar to levels that may exceed the ability of the government to absorb the added
cost. According to a report commissioned by
the Alzheimers Association, Medicare costs
for beneficiaries with Alzheimer disease are
expected to increase 75% from $91 billion in
2005 to $160 billion in 2010. Furthermore,
Medicaid expenditures on residential dementia care were reportedly $21 billion in 2005 and
expected to increase by 14% to $24 billion in
2010 (Fig. 2)6. According to the Alzheimers

Association, however, the advent of effective

treatments that can delay the onset of Alzheimer
disease for just five years could save $50 billion
in annual healthcare costs. Hence, governments
and Alzheimer disease associations have made
it their goal to delay the disabling symptoms
of the disease and eventually prevent it. To
support this aim, the governments commitment to research has grown dramatically in
recent years. For example, in fiscal year 2005,
the American government estimates spending
of approximately $647 million for Alzheimer
disease research7.
Diagnosis and initial care
Diagnosis rates are generally low, averaging
around 60% in developed nations, but vary
widely according to healthcare policies and
guidelines in different countries. Definitive
diagnosis of Alzheimer disease can only be
performed by examining the neuropathological features of the diseaseamyloid plaques
and neurofibrillary tanglesat autopsy.
Nevertheless, in the day-to-day clinical setting,
a variety of methods are used, and research
has suggested that this can be considered 87%
effective compared with autopsy8. Early diagnosis is beneficial for the patients, as they can

VOLUME 12 | NUMBER 7 | JULY 2006 NATURE MEDICINE

be treated early and any comorbidities can be

monitored, as well as for their families, who can
receive additional support.
In developed countries, primary care is the
point of initial diagnosis; individuals may
subsequently be referred to a neurologist to
confirm diagnosis and for treatment. Some
neurologists refer patients for a brain scan, but
the norm is for patients to be assessed against
standard clinical criteria that take into account
patient age, cognitive testing (such as the MiniMental State Exam (MMSE) or Mini-Cog), and
functional and behavioral testing (such as the
Dementia Severity Rating Scale). The National
Institute of Neurological and Communicative
Diseases and Stroke/Alzheimers Disease and
Related Disorders Association (NINCDADRDA) criteria use this information to give
a diagnosis of probable or possible Alzheimer
disease. Criteria from the Fourth Edition of the
Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) can also be used. In clinical trials, it is often the MMSE that is used as
a primary endpoint, although it is arguable
whether this endpoint is sensitive or robust
enough, as the test was not designed for
repeated use.
To proceed to treatment, individuals are
assigned to stages of Alzheimer disease, which
are most easily defined by their MMSE score.
Individuals rating with mild Alzheimer disease are able to perform activities of daily living
independently, have difficulty with memory
and learning, and have mild personality
changes. They then progress to moderate and
severe Alzheimer disease, which are characterized by increased dependence on a caregiver,
impairment of language and memory and a
short attention span. Profound and terminal
Alzheimer disease precede death as the disease
worsens.
Despite the evident insufficiencies in current Alzheimer disease diagnostic techniques,
we believe diagnosis is unlikely to change
profoundly in the future. Telephone- and selfdiagnosis technologies are available but are not
thought to be adequate or particularly useful.
Laboratory tests using urine or other patient
samples are also in their infancy, as clinically

useful and robust biomarkers for disease have

yet to be developed.
Current treatment of Alzheimer disease
Whereas diagnosis of Alzheimer disease can be
performed with some certainty, the underlying
pathophysiology is still not well understood. A
variety of pharmaceutical approaches, targeted
at several disease hypotheses, are now under
investigation. However, currently available
treatment options are limited and, when compared with other therapeutic areas, differentiation between these options in terms of efficacy
is minimal.
There are currently two classes of drugs
approved for the treatment of symptoms
of late-onset or sporadic Alzheimer disease
(Table 1). Acetylcholinesterase (AChE) inhibitors prolong the action of acetylcholine in the
synapse by preventing its breakdown. This
strategy results in improvements of cognition,
mood and behavior. N-methyl-D-aspartate
(NMDA) receptor antagonists are believed to
work by helping to regulate levels of the neurotransmitter glutamate.
AChE inhibitors. Treatment practices depend
on the patients age and stage of disease. The
AChE inhibitors are widely considered to be
first-line treatment for the cognitive symptoms of dementia associated with Alzheimer
disease and are indicated for the mild and
moderate stages. The AChE inhibitor class of
drugs is represented by donepezil (Aricept,
Eisai/Pfizer), rivastigmine (Exelon, Novartis)
and galantamine (Razadyne, Johnson &
Johnson). Multiple studies of AChE inhibitors
have shown that they are generally well tolerated. If side effects do occur, they commonly
include nausea, vomiting, loss of appetite, diarrhea and bradycardia. Nevertheless, they show
modest clinical benefits in the earlier stages of
Alzheimer disease9. On the other hand, there
is evidence that AChE inhibitors, in addition
to providing symptomatic relief, may slow
disease progression10. This, however, remains
controversial.
Tacrine (Cognex) was the first cholinesterase
inhibitor, approved in 1993, but is rarely prescribed today because of side effects, including a

Cost (in billions of US dollars)

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M A R K E T A N A LY S I S
200
180
160
140
120
100
80
60
40
20
0
2005

Year

2010

Figure 2 Actual and estimated financial costs

of Alzheimer disease in the US6. Purple bars,
Medicare costs; yellow bars, Medicaid costs.

risk of liver damage. In contrast, one of the first

AChE products to enter the market, Aricept has
performed exceptionally well and, despite competition from Razadyne and Exelon, Aricept is
expected to remain the leading product by sales
in this class, owing to a more convenient dosing
schedule (once daily) and continued strong comarketing support from Pfizer. We predict that
Aricept will maintain a global market share of
more than 40% until 2010 (Box 1).
Like Aricept, Exelon is an AChE inhibitor
indicated for the treatment of mild to moderate Alzheimer disease. Exelon has performed
well in this fast-growing market. To drive future
growth, Novartis has instigated an extensive
clinical development program including a
head-to-head trial against Aricept, and is
also looking to expand the indication base to
include mild cognitive impairment, vascular
dementia, Lewy body dementia, moderate to
severe Alzheimer disease and Parkinson disease. US sales are expected to enter a steady
decline when the key US patent expires in
2007. We predict sales in the rest of the world
to grow, however, driven by line extension programs. In January 2006, the European Unions
Committee for Medicinal Products for Human
Use gave a positive opinion for the use of
Exelon for dementia associated with Parkinson
disease, following an appeal by Novartis against
an earlier negative opinion.
Reminyl, re-branded Razadyne in 2005, was
co-developed by Johnson & Johnson and Shire,

Table 1 Current drugs on the market for the treatment of Alzheimer disease
Drug

Company

Mechanism

Indication

Aricept (donepezil)

Eisai / Pfizer

Acetylcholinesterase inhibitor

Mild to moderate Alzheimer disease

Exelon (rivastigmine)

Novartis

Acetylcholinesterase inhibitor

Mild to moderate Alzheimer disease

Razadyne (galantamine)

Johnson & Johnson

Acetylcholinesterase inhibitor

Mild to moderate Alzheimer disease

Namenda / Ebixa (memantine)

Lundbeck / Forest

N-methyl-D-aspartate receptor antagonist

Moderate to severe Alzheimer disease

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781

and was the third AChE inhibitor to enter the

market for the treatment of mild to moderate
Alzheimer disease. Despite few differentiating
features and a relatively late entry, uptake has
been impressive, aided by Johnson & Johnsons
marketing skills. In the future, Razadyne is
expected to generate sustained growth in the
short term. We predict, however, that sales of
Razadyne will decline steadily once US patent
protection is lost in 2008.
Despite the phenomenal growth of AChE
inhibitors, some concerns remain over the relatively modest efficacy of the class as a whole,
and little evidence exists to support continued
use into advanced stages11. In this regard, the
UKs National Institute of Clinical Excellence
(NICE) is due to publish its final recommendation on the use of Alzheimer disease drugs
this summer. It is anticipated that the institute
will only recommend the use of AChE inhibitors for individuals with moderate Alzheimer
disease and will state that there is not sufficient
evidence to advocate the prescription of mematine (see below). NICEs concerns echo those of
many experts that, when considered rationally,
these drugs are simply not effective enough to
warrant widespread prescription.
Nevertheless, AChE inhibitors continue to
be investigated in Alzheimer disease clinical
trials with a view to expanding their labels
to encompass mild cognitive impairment,
and milder and/or more severe forms of
Alzheimer disease. Furthermore, uptake
of the AChE inhibitors continues to grow
steadily year on year, primarily through
expanded market volume driven by the lack
of alternative treatments, the increase in the
elderly population and earlier initiation of
treatment.
For people with mild to moderate Alzheimer
disease, antioxidants such as vitamin E are often
recommended in combination with AChE
inhibitors, and their use is often continued into

the severe stage of Alzheimer disease. The use

of vitamin E is controversial, however, as there
is no robust clinical evidence to support its use
in this setting. Furthermore, there is growing
concern regarding the potential risk of mortality associated vitamin E supplementation,
particularly by individuals with cardiovascular disease and those already being prescribed
anticoagulants agents such as warfarin12,13.
NMDA antagonists. Although AChE inhibitors have been somewhat effective at improving cognition, they have little impact on the
progression of the disease. The approval of
the NMDA antagonist memantine in Europe
in May 2002 and in the US in October 2003
has transformed the treatment of moderate to
severe Alzheimer disease. Memantine (licensed
by Lundbeck from Merz for Europe, Canada,
Australia and South Africa as Ebixa, and
licensed by Forest for the US as Namenda) is the
first drug approved for the treatment of moderate to severe Alzheimer disease. By targeting
this indication, Lundbeck and Forest have
avoided direct competition with giants such as
Johnson & Johnson, Pfizer and Novartis.
Although memantine is indicated for
the later stages of the disease, there is evidence that there is significant off-label use,
particularly in combination with an AChE
inhibitor for mild and moderate Alzheimer
disease in the US. Clinical trials designed
to seek approval for mild to moderate
Alzheimer disease are ongoing, and a successful approval would give the product a
broad label covering mild to severe disease
states. In addition, the potential for combination therapy is being explored, and
preliminary data suggest that memantine
in combination with Aricept is superior to
Aricept alone in the treatment of moderate
to severe Alzheimer disease14. Furthermore,
Daiichi-Sankyo is developing memantine for
the Japanese market, where it is currently in

phase 3 clinical development for the treatment of severe Alzheimer disease.

Emerging therapies
AChE inhibitors and NMDA antagonists will
continue to form the backbone of symptomatic relief of dementia in Alzheimer disease for
the near term. However, none of the currently
approved drugs stops the underlying degeneration of brain cells or reverses the progression of
Alzheimer disease. Furthermore, about 3040%
of individuals with Alzheimer disease do not
respond to AChE inhibitors, and approximately 29% of individuals treated with AChE
inhibitors leave clinical trials because of adverse
events, compared to 18% of those from the placebo group15. Reflecting the dissatisfaction with
current treatment options, current research and
development efforts are aimed at addressing the
etiology of the disease, and a significant number
of candidates are currently in development for
treatment of Alzheimer disease.
The molecules and processes being
explored as targets of potential new therapies for Alzheimer disease reflect several leading hypotheses on the underlying causes of
the disorder. They include amyloid plaque
deposition, formation of neurofibrillary
tangles and neuroinflammation. The variety
of therapeutic approaches being researched
may foretell a market in which individuals
are treated optimally with drug combination
therapy (Table 2).
Arguably, the most exciting drugs in development are targeted at the amyloid- peptide,
the main component of amyloid plaques. It is
thought that if this type of drug can work early
in the disease, it could act as a disease modifier
and delay or prevent progression to later stages.
If these drugs can deliver on their promise, they
will be highly valuable. Although the amyloid
hypothesis is well supported, some controversy
persists regarding the existence of a clinical link

BOX 1 HISTORICAL AND FORECASTED GROWTH OF THE GLOBAL ALZHEIMER DISEASE

TREATMENT MARKET
The existing global Alzheimer disease treatment market
reached an estimated value of $4.07 billion in 2005 and
is forecast to reach $5.74 billion in 2010, a compound
annual growth rate (20052010) of 7.1%. We expect this
growth to come primarily through an expanded market
volume, offset by the US patent expirations of two of
the key brandsRazadyne (patent expires in 2008)
and Exelon (patent expires in 2007). The US market is
expected to continue to dominate, reflecting this markets
more aggressive approach to treatment of Alzheimer
disease. In contrast, a more gradual, evidence-based
uptake is expected in the European markets
(Source: Wood Mackenzies Productview March 2006).

Other products
Memantine (Daiichi-Sankyo)
Sermion (Tanabe)
Razadyne (Johnson & Johnson)
Namenda (Forest)
Exelon (Novartis)
Ebixa (Lundbeck)

6,000

Sales (in millions of US dollars)

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5,000
4,000
3,000

Aricept (Pfizer)

2,000
1,000

Aricept (Eisai)

0
2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Year

782

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M A R K E T A N A LY S I S

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Table 2 Selected candidates for the treatment of Alzheimer disease in late-stage development
Drug

Company

Mechanism

Status

Alzhemed (tramiprosate)

Neurochem

Inhibits formation of amyloid plaques

Phase 3

Flurizan (R-flurbiprofen)

Myriad Genetics

Nonsteroidal anti-inflammatory drug; lowers levels of amyloid-

Phase 3

Memryte (leuprolide acetate)

Voyager Pharmaceuticals

Implantable leuprolide

Phase 3

Neramexane

Merz & Co

NMDA receptor antagonist

Phase 3

Xaliproden

Sanofi-Aventis

5-HT1a agonist

Phase 3

Lecozotan

Wyeth

5-HT1a agonist

Phase 3

Ispronicline

Targacept/AstraZeneca

Nicotinic acetylcholine agonist

Phase 2

Bapineuzumab (AAB-001)

Wyeth/Elan

Amyloid-specific monoclonal antibody

Phase 2

between reduction in amyloid- and symptom

improvement (see page 723), and certain evidence suggests alternative processes as the
prime cause of Alzheimer disease.
The most advanced drug targeting amyloid- is tramiprosate (Alzhemed), being
developed by Neurochem. This small molecule, which can be taken orally, binds soluble
amyloid-, preventing it from aggregating
into plaques. Currently in phase 2 clinical
trials, the drug seemed to have a good safety
profile, showed moderate evidence of efficacy and reduced amyloid- levels. Phase 3
trials in Europe and North America are now
ongoing, with more than 1,000 participants
with mild to moderate Alzheimer disease
currently taking AChE inhibitors. The trial
will track participants for 18 months, and
subjects completing this part of the trial will
be asked to continue in an open-label section
of the study. This is noteworthy, as evidence
of disease modification (such as changes in
brain volume) may require a longer time
frame compared with trials using cognitive
measures as endpoint. Initial results from
this trial are expected early in 2007.
An amyloid-lowering agent named
R-flurbiprofen (Flurizan), developed by
Myriad Genetics, is in phase 3 trials involving participants with mild Alzheimer disease.
Its mechanism of action is not well understood and, although the racemic mixture of
flurbiprofen is an established nonsteroidal
anti-inflammatory drug (NSAID), the R isomer is not thought to have cyclooxygenase
activity. In phase 2 trials, Flurizan was well
tolerated but it did not meet its primary endpoint using ADAS-Cog (Alzheimers Disease
Assessment ScaleCognitive), ADCS-ADL
(Alzheimers Disease Cooperative Study
Activities of Daily Living) and CDRSB

(Clinical Dementia Rating Sum of Boxes)

scores, although a subset of participants
with mild manifestations of the disease
(MMSE > 20) showed a treatment benefit. So, some 1,600 individuals with mild
Alzheimer disease are being enrolled in the
phase 3 trial, and initial results are expected
in the second half of 2007.
Voyager Pharmaceuticals is developing extended-release leuprolide acetate
(Memryte) for mild to moderate Alzheimer
disease, which is currently in phase 3 trials. Leuprolide affects levels of luteinizing
hormone, which modulate cognition and
amyloid- deposition. Results from phase
2 trials in female participants with mild to
moderate Alzheimer disease did not meet
the primary endpoint efficacy measurements
of ADAS-Cog and ADCSCGIC (Alzheimers
Disease Cooperative Study Clinical Global
Impression of Change), but did show an
effect in participants receiving high-dose
leuprolide and additional AChE inhibitors.
Results from phase 2 trials in male participants are expected later this year, and
phase 3 results from two 56-week trials are
expected in 2007.
As a follow up to memantine (Namenda),
Merz and Forest Labs are developing neramexane, another NMDA receptor antagonist. Like Namenda, neramexane is being
studied in individuals with moderate to
severe Alzheimer disease, but it did not meet
its primary endpoint efficacy measurements
of SIB (Severe Impairment Battery) and
ADCS-ADLsev (ADCS-ADL severe subset)
when tested in phase 3 trials in combination
with AChE inhibitors (although Namenda
did not work in individuals with mild to
moderate disease). A second phase 3 trial as
monotherapy showed statistical significance

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for neramexane in individuals with moderate to severe disease; the primary endpoint
of this trial was efficacy measurement of
ADCS-ADL, and further phase 3 studies are
planned. As Namendas patent is expected
to expire in 2010, neramexane may be an
early follow-on product and must show a
level of differentiation over Namenda if it is
to succeed. Nonetheless, with a number of
other indications also in development for
neramexane (including neuropathic pain,
tinnitus and alcohol dependence), it is clear
there is commitment from Forest and Merz
behind it.
Two 5-HT1A agonists are in phase 3 trials
for Alzheimer disease. Targeting serotonin
receptors in Alzheimer disease may alleviate some symptoms of Alzheimer disease
because a decline in serotonin function is
associated with cognitive decline in people
with the disease16. Lecozotan (Wyeth) is
under investigation for treatment of symptoms associated with cognitive deficits in
individuals with mild to moderate Alzheimer
disease, and Xaliproden (Sanofi-Aventis) is
being investigated in a large trial of individuals with mild to moderate Alzheimer
disease, although it has had a checkered history, with a number of already-failed indications such as anxiety, multiple sclerosis and
neuropathy.
Developing drugs for Alzheimer disease
is fraught with difficulties in predicting
efficacy in large-scale trials. Interestingly,
Targacept and its new licensee AstraZeneca
chose to initially gather evidence for their
nicotinic acetylcholine agonist ispronicline for indications such as age-associated
memory impairment and mild cognitive
impairment, for which trials can be easier
to perform and which are often considered

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M A R K E T A N A LY S I S
precursors to Alzheimer disease. It is then
their intention to test the drug, now in
phase 2 clinical trials, in Alzheimer disease
itself, following proof of concept in these
initial indications.
In our opinion, the most exciting drug in
development is Elan and Wyeths bapineuzumab (AAB-001), a humanized monoclonal antibody against amyloid-, which is in
phase 2 trials. As part of an alliance investigating a number of opportunities including the
amyloid- vaccine ACC-001, Elan and Wyeth
are concentrating on immunotherapeutic
strategies for Alzheimer disease in the hope
that they will lead to a truly disease-modifying drug. Evidence of efficacy with AAB-001
has already been obtained (Black, R.S. et al.,
presented at 9th Annual Geneva Springfield
Symposium on Advances in Alzheimer's
Therapy in Geneva, Switzerland). These
drug candidates may also carry the highest
risk, however; the highest dose of AAB-001
has now been discontinued owing to transient abnormalities observed through brain
imaging (Black, R.S. et al., presented at 9th
Annual Geneva Springfield Symposium on
Advances in Alzheimers Therapy in Geneva,
Switzerland). An earlier candidate drug developed to trigger an immune response against
amyloid-, AN-1792, was also discontinued
owing to cases of encephalitis.17

784

Conclusion
As population demographics shift and the
number of individuals with Alzheimer disease continues to increase, the challenge to
develop targeted, effective treatments and
our ability to recognize early symptoms
and intervene to prevent disease progression
will become more crucial. Although current
treatments for Alzheimer disease have witnessed phenomenal sales growth and will
continue to do so, they have provided only
modest symptomatic relief, and much of
their success appears to be borne of the significant unmet need, as highlighted by the
UKs NICE appraisal. Over the past 15 years,
research on Alzheimer disease has increased
our understanding of the underlying mechanisms of disease progression and provided
new targets for drug validation, generating
new hope for the future. It remains to be
seen, however, whether any of the new drugs
in clinical trials will truly modify disease.
Furthermore, clinical development in this
field is particularly complex, expensive and
highly uncertain in terms of predicting success early in development, choosing appropriate clinical measurements and obtaining
results for successful approval. Nevertheless,
given the unmet need, we anticipate that
there are considerable opportunities within
the Alzheimer disease market, and truly dis-

ease-modifying drugs have the potential to

expand it further.
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