Nursing Practice

Review
Older people

Keywords: Alzheimers disease/

Dementia/Drug therapy
This

article has been double-blind

peer reviewed

No new drugs have been approved to treat Alzheimers disease since the late 1990s;
this article discusses the problems this poses and the efficacy of these drugs

Drug treatments for

Alzheimers disease
In this article...
 ow drugs work in the treatment of Alzheimers symptoms
H
NICE guidelines on use of medication and dementia
How Alzheimers treatment is likely to change in the future
Author Graham A Jackson is professor of
dementia care, Alzheimer Scotland Centre
for Policy and Practice, Research,
University of the West of Scotland.
Abstract Jackson GA (2014) Drug
treatments for Alzheimers disease.
Nursing Times; 110: 9, 24-26.
This article discusses the development and
progress of treatment for Alzheimers
disease. Medical treatments have not
changed since the late 1990s and have
limited effects. They treat the symptoms
patients experience but do not reverse the
effects or repair neurological damage
caused by Alzheimers disease.
Updated NICE guidance and likely
future advances in treatment are also
discussed.

n the mid-1990s, drugs became available that improved cognitive function

in Alzheimers disease (AD), leading to
a sense of optimism that finally something could be done to help people with
the disease. However, the treatments have
limited efficacy (Langtot et al, 2003), and
no new drugs have been licensed for over
10 years.
The promise of improvements in cognitive functioning has helped reduce the
negativity around the diagnosis and management of Alzheimers, contributed to
more people being diagnosed early and
changed the direction of service development. However, the availability of these
drugs may have resulted in AD treatment
being prioritised over that for other forms
of dementia and over the later stages of
dementia, where the drugs are less useful
(Pelosi et al, 2006). Many memory clinics
provide a different, less supportive
pathway for people with other types of

dementia, particularly vascular.

More recently, national dementia strategies have increased the emphasis on early
recognition and diagnosis of dementia,
leading to these drugs being more widely
prescribed.

Drugs licensed for Alzheimers

The first drug licensed for the treatment of

the cognitive symptoms of AD in the UK
was the cholinesterase inhibitor donepezil
(Aricept), which was licensed in 1997.
Donepezil was closely followed by two
more cholinesterase inhibitors, rivastigmine (Exelon) and galantamine (Reminyl).
These drugs were developed based on
the theory that cognitive deficits associated with AD are due to reduced production of acetylcholine, a neurotransmitter.
Cholinesterase inhibitors work by slowing
down the breakdown of acetylcholine,
leading to higher levels in the brain (Fig 1).
Memantine (Ebixa), an N-methyl-Daspartate (NMDA) receptor antagonist,
was approved in 2002 for the treatment of
more severe AD. It appears to work
through a different neural pathway, by
blocking glutamate receptors, preventing
excessive levels of glutamate from further
damaging brain cells (Fig 2).

Guidelines

When these drugs were first made available, many areas were reluctant to fund
them as the benefits were thought not to
justify the cost.
Reviewing the evidence for the use of
cognitive enhancers, the National Institute for Health and Care Excellence (2006)
found little difference between cholinesterase inhibitors and recommended they
were used only in the treatment of

24 Nursing Times 26.02.14 / Vol 110 No 9 / www.nursingtimes.net

5 key
points

Existing
treatments for
Alzheimers
disease have
limited beneficial
effects
Cholinesterase
inhibitors work
by increasing the
amount of
acetylcholine in
thebrain
Although
no one
cholinesterase
inhibitor is more
effective than
another, method of
administration
might influence
prescribing
decisions
There is no
clear guidance
or evidence on
how long these
medications should
be prescribed for
Current
treatments
reduce symptoms
but do not reverse
the neurological
effects of
Alzheimers
disease

2
3

4
5

For a Nursing Times Learning unit on

Drug Calculations in Practice, go to
www.nursingtimes.net/drugcalculations

moderate AD. NICE did not recommend

the use of memantine other than in
research.
However, an updated guideline recommended donepezil, galantamine and rivastigmine for mild as well as moderate AD;
memantine was recommended for moderate AD in people unable to take cholinesterase inhibitors, and as an option for
severe AD (NICE, 2011).
A Cochrane review concluded that,
despite slight variations in the actions of
the different cholinesterase inhibitors,
there was no evidence of any differences in
efficacy (Birks, 2006). The drugs do differ
in how and when they are administered;
for example, rivastigmine can be given by
a skin patch that is changed once a day or
as an oral suspension as an alternative to
twice-daily tablets for people who have
difficulty swallowing. Galantamine is usually prescribed twice daily though there is
now a modified-release form, which is
taken once a day. Donepezil has a longer
half-life, so is given only once daily.

fig 1. action of cholinesterase inhibitor

Nerve

CoA

CoA

ACh

Choline
carrier

Choline
AChE

ACh
receptor

Acetate

How effective is ongoing

treatment?

There are no clear guidelines on how long

cholinesterase inhibitors should be continued as well as a lack of any long-term
trials. Statements from NICE and other
sources tend to rely on cognitive testing
(NICE, 2011), but the benefits of treatment
should be based on quality of life, which is
more difficult to measure.
Although medication is less likely to be
of benefit when impairments are more
advanced, discontinuing treatment has
been linked with a decline in mental state
(Rainer et al, 2001).
A Cochrane review concluded that
memantine has a definite but small beneficial effect after six months in later-stage
AD, but no effect in mild to moderate disease (McShane et al, 2006).
While cognitive enhancers have led to
improvements that can be measured in
cognitive testing, their benefits in terms of
global functioning are less clear. There is
evidence of improvements in general functioning and behaviour as well as in cognitive benefits in some patients, but it is difficult to predict who will respond in this
way, and average improvements tend to be
small (Raina et al, 2008). Claims that cognitive enhancers lead to later admission into
institutional care have not been consistent
(AD2000 Collaborative Group, 2004).
Ongoing studies are looking into the
effects of combining treatments. Early evidence shows no convincing benefit of
combining memantine with a cholinest-

Choline acetyl
transferase

Post-synaptic membrane

fig 2. action of memantine

Memantine selectively blocks pathological activation of NMDA
receptors
Pathological activation of
NMDA receptors

Rest

neuroprotection by
memantine

Memantine does not

impair neurotransmission
or plastic processes

Cognitive
activity

Rest
Ca2+

Ca2+

Noise
Noise

Ca2+

Signal Noise

Glutamate
Magnesium
Memantine

erase inhibitor (Howard et al, 2012).

Cholinesterase inhibitors may also be
useful in the management of dementia
associated with Parkinsons disease.

Although only rivastigmine is licensed for

this purpose, the benefits are likely to be
due to the class effect of this group of
drugs, so donepezil and galantamine are

www.nursingtimes.net / Vol 110 No 9 / Nursing Times 26.02.14 25

Nursing Practice
Review
likely to have similar effects. Similarly,
anecdotal evidence suggests cholinesterase inhibitors reduce some symptoms
associated with Lewy body disease, such
as hallucinations, although this use is
unlicensed.
Various other drugs and supplements
have been assessed as possible treatments
for AD, including gingko biloba, indometacin, vitamins E and B12, folic acid,
selegiline and metrifonate; there is no convincing evidence of benefit for any of them.
To date, licensed treatments for AD
treat only symptoms; they can help with
the cognitive, behavioural and functional
aspects of the condition but do not alter
the disease process. The evidence that
treatments also help with other symptoms
associated with AD, including aggressive
or agitated behaviour and hallucinations,
is inconsistent, although there appears to
be little doubt in clinical practice that
some patients show benefit.
NICE (2011) recommends that treatment
with cognitive enhancers should be started
by a specialist, but does not define what
this means. At present this is usually a psychiatrist, and it takes place almost entirely
in secondary care. This may need to be
reviewed due to increasing numbers of
people being diagnosed with AD and a
rising number of older people.
As these drugs are coming off licence,
cheaper generic production is likely to
reduce costs, so the benefits are more
likely to outweigh financial implications.
Side-effects
Although cholinesterase inhibitors are
largely well tolerated, they have a range of
side-effects. Some, such as restlessness
and gastrointestinal symptoms, are largely
transient; others, such as syncope, agitation, insomnia, bradycardia, persistent
rhinitis and muscle cramps, can be more
debilitating and lead to the medication
being stopped.
Gill at al (2009) reviewed the risk these
drugs pose in relation to more serious
effects such as syncope, bradycardia, the
need for pacemaker insertion and hip fracture. Although these are uncommon
events, the authors suggest that as these
drugs provide only a modest benefit, practitioners should think carefully about
whether the benefits outweigh the risks
before prescribing them. Some authorities
advocate the use of ECGs before prescribing; however, a review of the evidence
concluded this was of no benefit (Rowland
et al, 2007).
Memantine has generally been found to
be well tolerated, although reported

side-effects include agitation, hypertension, headaches and constipation.

Future treatment

The drugs available for the treatment of

AD are of limited clinical benefit and more
effective treatments that change the
course of the illness are needed. Research
focuses largely on two areas:
Reducing the amount of abnormal
amyloid in the brain (which leads to
amyloid plaques);
Reducing the deposition of tau protein,
which is a substantial part of the
neurofibrillary tangles also seen in the
illness.
In theory, statins might be useful in
slowing down the progress of AD. However, research has shown no benefits in
cognitive impairment despite some
changes in amyloid deposition (McGuinness et al, 2013). There have been some suggestions that statins might delay or prevent the onset of AD, but the evidence is
unclear (McGuinness et al, 2009).
One promising line of research was the
use of monoclonal antibody bapineuzumab, which reduces the amount of
abnormal amyloid in the brain. However,
two large trials were aborted in 2012 due to
participants already having substantial
damage that could not be reversed.
Future studies are likely to involve
patients in the early stages of the disease.
In 2008, optimistic claims were made on a
website not subject to peer review following a trial of Rember, a derivative of the
dye methylene blue. At the time of writing,
there have been no reports in peerreviewed journals, but phase 3 trials in
frontotemporal dementia are about to
start.
More recently, there have been promising results from the use of an intravenous immunoglobulin (Relkin et al, 2009),
but trials have been small. If this does
prove to be effective, the logistics of giving
this intravenous treatment will present a
major challenge.

Conclusion

For any breakthrough in the treatment of

AD, disease-modifying drugs are needed.
However, the biological causes that lead to
neuronal loss in AD are not fully understood. We also lack an understanding of
when the disease process starts, who will
develop it, and how it will progress in different people.
Further research is also needed into the
relationships between normal cognitive
ageing, mild cognitive impairment and AD.
The process that causes cognitive

26 Nursing Times 26.02.14 / Vol 110 No 9 / www.nursingtimes.net

impairment in AD is likely to start years or

even decades before deficits are noticed.
Effective treatments will therefore depend
on being able to recognise people at high
risk. While genetic studies may help with
this, particularly in cases where dementia
develops at an early age, the development
of this type of pre-emptive treatment relies
on recognition of detectable biomarkers
(Galimberti and Scarpini, 2013; Dubois et
al, 2010). NT
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