Drugs Aging
DOI 10.1007/s40266-015-0266-9
SYSTEMATIC REVIEW
A Risk-Benefit Assessment of Dementia Medications: Systematic
Review of the Evidence
Jacob S. Buckley1 • Shelley R. Salpeter2,3
Ó Springer International Publishing Switzerland 2015
Abstract
Background There is no cure for dementia, and no
treatments exist to halt or reverse the course of the disease.
Treatments are aimed at improving cognitive and func-
tional outcomes.
Objective Our objective was to review the basis of
pharmacological treatments for dementia and to summarize
the benefits and risks of dementia treatments.
Methods We performed a systematic literature search of
MEDLINE through November 2014, for English-language
trials and observational studies on treatment of dementia
and mild cognitive impairment. Additional references were
identified by searching bibliographies of relevant publica-
tions. Whenever possible, pooled data from meta-analyses
or systematic reviews were obtained. Studies were included
for review if they were randomized trials or observational
studies on dementia or mild cognitive impairment that
evaluated efficacy outcomes or adverse outcomes associ-
ated with treatment. Studies were excluded if they
evaluated non-FDA approved treatments, or if they
evaluated treatment in disorders other than dementia and
mild cognitive impairment.
Results The literature search found 540 potentially rele-
vant studies, of which 257 were included in the systematic
& Shelley R. Salpeter
salpeter@stanford.edu
1
Brown University, Providence, RI, USA
2
Stanford University School of Medicine, Stanford, CA, USA
3
1670 Amphlett Blvd, Suite 300, San Mateo, CA 94402, USA
review. In pooled trial data, cholinesterase inhibitors
(ChEIs) produce small improvements in cognitive, func-
tional, and global benefits in patients with mild to moderate
Alzheimer’s and Lewy body dementia, but the clinical
significance of these effects are unclear. There is no sig-
nificant benefit seen for vascular dementia. The efficacy of
ChEI treatment appears to wane over time, with minimal
benefit seen after 1 year. There is no evidence for benefit
for those with advanced disease or those aged over
85 years. Adverse effects are significantly increased with
ChEIs, in a dose-dependent manner. A two- to fivefold
increased risk for gastrointestinal, neurological, and car-
diovascular side effects is related to cholinergic stimula-
tion, the most serious being weight loss, debility, and
syncope. Those aged over 85 years have double the risk of
adverse events compared with younger patients. Meman-
tine monotherapy may provide some cognitive benefit for
patients with moderate to severe Alzheimer’s and vascular
dementia, but the benefit is small and may wane over the
course of several months. Memantine exhibits no sig-
nificant benefit in mild dementia or Lewy body dementia or
as an add-on treatment with ChEIs. Memantine has a
relatively favorable side-effect profile, at least under con-
trolled trial conditions.
Conclusions ChEIs produce small, short-lived improve-
ments in cognitive function in mild to moderate dementia,
which may not translate into clinically meaningful effects.
Marginal benefits are seen with severe disease, long-term
treatment, and advanced age. Cholinergic side effects, in-
cluding weight loss, debility, and syncope, are clinically
significant and could be especially detrimental in the frail
elderly population, in which the risks of treatment out-
weigh the benefits. Memantine monotherapy may have
minimal benefits in moderate to severe dementia, balanced
by minimal adverse effects.

Key Points
Cholinesterase inhibitors produce small
improvements in cognitive function in mild to
moderate dementia, with marginal effects seen in
severe disease, long-term treatment, and advanced
age.
Cholinesterase inhibitors are associated with
significant cholinergic side effects, including weight
loss, debility, and syncope, which can be detrimental
in the frail elderly population.
The available evidence indicates that memantine
monotherapy produces small benefits in cognitive
function in moderate to severe dementia, without
significant adverse effects.
1 Introduction
Dementia is a clinical syndrome characterized by acquired
global cognitive deficits that interfere with social and oc-
cupational functioning [1]. It typically presents in elderly
individuals and involves a progressive decline in memory,
reasoning, language, and executive function [2, 3]. The
estimates for dementia prevalence vary based on geo-
graphic location and diagnostic criteria used, but it is
thought that at least 5 % of people over the age of 60 years
live with dementia, and the total number of these cases is
expected to double every 20 years [4]. Incidence of de-
mentia increases exponentially with advancing age, with
one population study observing it doubling every 5 years
[5]. Due to the rapid expansion of the elderly population,
dementia is a serious public health concern, with an esti-
mated worldwide cost of US$600 billion in 2010 [6].
Currently, there is no cure for dementia, and no treat-
ments exist to halt or reverse its progression, so therapeutic
interventions are targeted to treat symptoms or to improve
cognitive function [7–9]. The two treatments with mar-
keting approval for dementia are the cholinesterase in-
hibitors (ChEIs) donepezil, galantamine, and rivastigmine,
and the low-affinity N-methyl-D-aspartate (NMDA) an-
tagonist memantine [1, 10]. The vast majority of published
data available on dementia treatment are in short-term in-
dustry-sponsored trials of ChEIs [11]. The trials have
mostly been limited to patient populations with a mean age
of approximately 75 years, with relatively mild Alzhei-
mer’s dementia and few to no comorbidities [11, 12]. This
significantly decreases the clinical applicability of the re-
search to real-world cases of dementia, as the vast majority
of patients, such as those with severe disease, advanced
J. S. Buckley, S. R. Salpeter
age, or frailty, would have been ineligible for these trials,
and the benefit of long-term treatment is unclear [13–18]. It
is also important to distinguish between statistical and
clinical significance, as a small change in cognitive status
may not translate into a meaningful change for the patient
[1, 2, 19]. In addition, a risk–benefit assessment must in-
clude quantification of adverse effects, especially in old
frail individuals in whom side effects may have serious
consequences for survival and quality of life [2, 11, 20].
2 Methods
We performed a literature search of MEDLINE through
November 2014 for English-language studies evaluating
the risks and benefits of ChEIs and memantine in the
treatment of dementia and mild cognitive impairment
(MCI). Additional references were identified by reviewing
the bibliographies of relevant papers. Whenever possible,
pooled trial data from meta-analyses or systematic reviews
were obtained. Search terms for cognitive disorders in-
cluded dementia, mild cognitive impairment, cognition
disorder, Alzheimer, Parkinson’s dementia, Lewy
body dementia, and vascular dementia. Search terms for
treatment included cholinesterase inhibitor, acetyl-
cholinesterase inhibitor, donepezil, galantamine, rivastig-
mine, and memantine. Studies were included for review if
they were randomized trials or observational studies that
evaluated efficacy outcomes (cognitive, neuropsychiatric,
or global function, and disease progression) or adverse
outcomes associated with treatment. Studies were excluded
if they evaluated non-FDA approved treatments for de-
mentia, such as ginkgo biloba, vitamin E, and hormonal
treatments [2, 10]. In addition, studies were excluded if
they evaluated ChEIs or memantine in disorders other than
dementia and MCI.
Two independent reviewers (JSB, SRS) completed data
abstraction and evaluated the quality and risk of bias of
included studies. The results were then presented in a
systematic review, following PRISMA (preferred reporting
items for systematic reviews and meta-analyses) guide-
lines. The primary scales used to measure cognition deficits
were the mini-mental state examination (MMSE), the
Alzheimer’s Disease Assessment Scale (ADAS) cognitive
subscale (ADAS-cog), and the severe impairment battery
(SIB). Other domains assessed included the activities of
daily living (ADL), instrumental activities of daily living
(IADL), and the neuropsychiatric inventory (NPI). Global
function and disease progression were also assessed. Ad-
verse events assessed included abdominal pain, nausea,
vomiting, diarrhea, anorexia, headache, dizziness, insom-
nia, abnormal dreams, vertigo, agitation, muscle cramps,
tremor, bradycardia, syncope, pacemaker implantation,
Systematic Review of the Risks and Benefits of Dementia Medications

fatigue, asthenia, weight loss, falls, and drug–drug
interactions.
The search identified approximately 6800 potentially
relevant articles, of which 540 were retrieved and evaluated.
Of those, 257 studies were included in the systematic review.
Study inclusion is represented in a flow diagram (Fig. 1).
3 Results
3.1 Epidemiology and Assessment of Dementia
There are several types and causes of dementia, with
confusion related to variations in diagnostic criteria and the
fact that many forms of dementia exist concurrently [2, 21].
Alzheimer’s disease is the most common cause, accounting
for roughly 50–70 % of all dementia cases [22]. Another
large subgroup is vascular dementia, which is often ob-
served concurrently with other forms, resulting in preva-
lence estimates that vary considerably [23–28]. Mixed
Alzheimer’s disease and vascular dementia is common,
accounting for approximately 25 % of all dementia cases
[29]. Vascular dementia becomes increasingly prevalent
with advanced age, with at least 70 % of those over the age
of 90 years having some degree of vascular pathology [13].
Finally, Parkinson’s disease dementia and dementia with
Lewy bodies are two major types of dementia with similar
neuropathological presentations, indicating that they are
part of the same condition or exist within a spectrum of
disorders, often collectively called Lewy body dementia
[30]. Lewy body dementia may account for 10–20 % of
global dementia cases, with the risk increasing with age
and years since Parkinson’s disease onset [31–34]. Many
other forms of clinically relevant dementia exist, but this
review focusses on these three main subgroups.
MCI is classified as a cognitive decline that exceeds the
typical aging process yet does not meet the diagnostic
criteria of dementia [35]. This cognitive decline usually
manifests as a loss in memory that is not significant enough
to alter ADL [35]. The prevalence estimates for MCI range
from 5 to 20 % in older individuals, with up to one-third of
MCI cases progressing to dementia within 2 years [7].
Although MCI is a distinct entity, it is often considered to
be a pre-clinical stage of dementia [7]. Studies have
evaluated whether pharmacological interventions are ca-
pable of delaying the progression to dementia or improving
the quality of life of individuals with MCI.
Various assessment tools are available to measure cog-
nitive function, which have been used to determine the
presence and severity of dementia as well as the progres-
sion of the disease [36]. One standard measurement is the
MMSE, which is easy to administer in the clinical setting
and measures cognitive function on a 30-point scale, with
higher scores corresponding to higher cognitive function
[37, 38]. Although the MMSE has its limitations, including
decreased utility for detecting dementia in patients with
minimal cognitive deficits or those with low education
levels, it has been widely used and validated globally, and

Fig.1 Flow chart of studies

Literature search of studies on
search
treatment of dementia (n = 6800)

Studies excluded: Not potentially

relevant (n = 6260)

Potentially relevant studies of

benefits or risks of medications
for cognition disorders (n = 540)

Studies excluded from systematic review:

On non-FDA approved dementia
treatments (n = 52)
Not on treatments for dementia or mild
cognitive impairment (n = 72)
No relevant information provided
(n = 159)

Randomized trials or observational

studies on acetylcholinesterase
inhibitors or memantine for dementia
or mild cognitive impairment (n = 257)

is quite accurate for diagnosing and tracking mild to
moderate dementia [39–42]. Another common tool is the
ADAS-cog, a 70-question scale with higher scores indi-
cating worse cognitive performance, which was designed
to detect and follow clinical changes in cognition [43, 44].
The ADAS-cog is most sensitive to changes in mild to
moderate dementia [44–48]. Another cognitive assessment
tool is the SIB, which is most helpful for those with severe
dementia [49].
Other tests are commonly used to measure outcomes
other than cognition in patients with dementia. An impor-
tant measure in the determination of quality of life and
degree of disability is the assessment of ADL, such as
feeding and dressing, and IADL, such as handling money,
preparing food, or using the telephone [36, 50, 51]. In
addition, behavioral and psychological symptoms can be
assessed with the NPI, which focuses on behavioral dis-
turbances such as delusions, anxiety, and disinhibition [51,
52]. Another research tool is the measurement of global
dementia status, which integrates in-depth clinical assess-
ments of patients with caregiver input to derive a basic
quantitative measure of change [53].
There are no universally accepted cut-offs for defining
dementia severity, but it is reasonable to use MMSE scores to
divide dementia severity into mild (20–23), moderate
(10–19), severe (1–9), and end-stage (0) [40, 41, 54–59].
MCI corresponds to an MMSE score of 24–27, although this
is not sufficient as a sole diagnostic criterion [58, 60–62].
Mild dementia can be detected by basic clinical assessment
and is characterized by decreased memory of personal and
current events and slightly diminished executive function
[41]. In moderate dementia, the individual begins to lose
independence and conversational skills and may forget sig-
nificant personal information [56, 63]. By the stage of severe
dementia, there is a complete loss of independence in per-
forming ADLs associated with lack of orientation, but with
some maintained ambulatory and verbal functioning [63,
64]. End-stage dementia, in which the individual no longer
has the ability to walk or speak, is an important clinical stage
that may persist for years before death [63, 64].
3.2 Pathophysiological Basis of Dementia
with Rationale for Treatment
Cognitive decline in dementia is due in part to deficient
cholinergic activity in the basal ganglia and neocortex
caused by destruction of cholinergic neurons. ChEIs
function by inhibiting acetylcholinesterase, thereby in-
creasing available acetylcholine [65–67]. Another cause of
cognitive decline common to various types of dementia is
excitatory neurotoxicity caused by overstimulation of
NMDA-glutamate receptors, and memantine could serve
by blocking NMDA activity at a low enough affinity to
J. S. Buckley, S. R. Salpeter
prevent excitotoxicity without interfering with necessary
functions of glutamate in learning and memory [68–71].
Despite very different pathogenic mechanisms, there are
key similarities in the pathophysiology of Alzheimer’s
dementia, Lewy body dementia, and vascular dementia that
result in cognitive decline, and these may indicate ChEIs
and memantine as possible treatment options.
In Alzheimer’s disease, the initiating event is thought to
be the accumulation of amyloid beta-protein (Ab) plaques,
which in turn trigger hyperphosphorylation of tau protein
and neuronal degeneration [72]. The Ab plaques cause a
decrease in acetylcholine release and synthesis, along with
increased activity of acetylcholinesterase, impaired mus-
carinic acetylcholine signaling pathways, and a decrease in
cholinergic signaling and function; these changes in turn
indirectly result in disrupted NMDA-receptor activity and
glutamate neurotoxicity [73, 74]. Since the plaques are
concentrated in areas related to memory and executive
function, such as the basal ganglia and parts of the tem-
poral lobe and neocortex, the neural damage caused by
cholinergic impairment and glutamate neurotoxicity is re-
lated to a loss of these cognitive functions [65].
Vascular dementia results from varied cerebrovascular
events such as ischemia, infarct, or hemorrhage, so its
pathogenesis is multifactorial and poorly defined [75]. The
cognitive deficits involved resemble those found in Alz-
heimer’s disease and other dementia types, as they involve
cerebrovascular damage to similar neural regions, such as
the temporal lobe, basal ganglia, and neocortex [75]. These
vascular changes in the brain are associated with inflam-
mation, atrophy, and decreased cerebral perfusion, as well
as decreased inhibition of NMDA channels, leading to
chronic overstimulation of glutamate receptors [71, 75].
There is also some evidence that these changes may result
in impaired cholinergic transmission [67, 76].
Lewy body dementia is a multisystem disease with
various presentations along a spectrum; if the parkinsonian
extrapyramidal symptoms precede dementia, it is consid-
ered to be Parkinson’s disease dementia, but if the order of
presentation is reversed it is typically diagnosed as de-
mentia with Lewy bodies [77]. Both disorders eventually
involve the production of proteinaceous cytoplasmic in-
clusions throughout the brain, called Lewy bodies, with
neurodegeneration of dopaminergic neurons in the sub-
stantia nigra and denervation of cholinergic neurons in the
basal forebrain and cerebral cortex [77–79]. There is some
evidence that these conditions may also induce glutamate
hyperactivity by altering the expression of glutamate re-
ceptors, and this is often worsened by chronic L-dopa ad-
ministration, which is commonly used in the treatment of
Parkinson’s disease [69, 80, 81].
Ultimately, the use of ChEIs may serve to compensate
for decreased cholinergic activity by increasing the
Systematic Review of the Risks and Benefits of Dementia Medications
availability of acetylcholine released from limited cholin-
ergic neurons, and memantine may offer neuroprotective
effects from excitotoxic stimulation of overexpressed
NMDA pathways, but neither medication can reverse or
slow the underlying pathophysiological progression of the
disease. Therefore, the target of these therapies is to at-
tempt to reduce symptoms related to the disease, rather
than address the neurodegenerative processes themselves.
3.3 Cholinesterase Inhibitors
3.3.1 Benefits of Cholinesterase Inhibitors for Mild
Cognitive Impairment
No medication has marketing approval for the treatment of
MCI, but many investigators have evaluated whether
ChEIs could delay the progression to dementia or provide
clinically significant improvements in cognition for indi-
viduals with MCI. A few small studies have shown some
minimal cognitive benefits of ChEIs in the treatment of
MCI [56, 82–84], but pooled data analyses of the trials
show that there is no significant difference in progression
to dementia, nor in global, cognitive, or neuropsychiatric
outcomes [7, 85, 86]. A significant increase in adverse
events was observed for MCI patients treated with ChEIs,
mainly gastrointestinal side effects such as nausea, diar-
rhea, and vomiting, as well as cardiac syncope and head-
aches [7, 54, 84, 85, 87, 88]. Therefore, ChEIs are not
recommended for the treatment of MCI [89, 90].
3.3.2 Benefits of Cholinesterase Inhibitors for Dementia
Numerous studies have investigated the efficacy of differ-
ent treatments for cognitive function in dementia, and
several systematic reviews and meta-analyses have worked
to pool the data and summarize the results (Table 1) [1, 2,
11, 20, 30, 56, 91–96]. The three commercially available
ChEIs, donepezil, galantamine, and rivastigmine, have
marketing approval for the treatment of mild to moderate
dementia in most countries [10, 56]. The first-generation
ChEI, tacrine, was removed from the US market due to
poor efficacy and high incidence of serious adverse events,
and is not evaluated here [2, 20]. The available ChEIs
differ slightly in their pharmacological properties, but they
share the main mechanism of acetylcholinesterase inhibi-
tion [2, 97]. Studies have shown similar efficacies with
these medications so the data will be pooled for this review
[2, 91, 98, 99]. A meta-analysis also concluded that results
in efficacy for low and high doses of ChEIs were compa-
rable, so results from studies using different doses will also
be pooled [20].
Essentially all of the published trials on ChEI use in
dementia were industry sponsored, with the exception of
one long-term trial by the Alzheimer’s Disease Col-
laborative Group [100, 101]. This raises the possibility of
publication bias or selective reporting of the results. One
study evaluating the potential bias in reporting adverse
events found that most of the randomized trials stated that
they examined harm, but many did not report mortality
data or provide clear definitions and detailed analyses of
harm [102].
A recent clinical practice guideline by the American
College of Physicians and the American Academy of
Family Physicians presented the available evidence on
ChEI treatments based on systematic evidence reviews
sponsored by the Agency for Healthcare Research and
Quality [1, 11, 93]. They concluded that ChEI treatment for
dementia results in a small statistically significant im-
provement in cognitive function that was not considered to
be clinically important [1]. Pooled data from ChEI trials in
Alzheimer’s disease, Lewy body dementia, and vascular
dementia show average improvements in the MMSE
ranging from 0.8 to 1.6 points on a 30-point scale, while 3
points or more was generally considered to be clinically
significant [1, 12, 30, 93, 94, 103]. Pooled data also showed
an average improvement in ADAS-cog of approximately
1.4–2.7 points on a 70-point scale, while several studies
have used a change of 4 points or more to indicate clinical
relevance [1, 12, 93, 94, 103].
The majority of available data has been in mild to
moderate Alzheimer’s disease, with limited data on Lewy
body dementia and vascular dementia [11]. The pooled
data from meta-analyses on ChEIs have shown relatively
similar results for cognitive outcomes in Alzheimer’s de-
mentia and Lewy body dementia, with improvements on
the order of 1.5 points in MMSE and 2.5 points in ADAS-
cog compared with placebo [12, 30]. In comparison, trials
on vascular dementia show marginal cognitive effects of
ChEIs (0.8 points in MMSE and 1.5 points in ADAS-cog),
with some studies finding no improvements at all [94].
In addition to cognitive assessment, many studies also
assessed global and functional outcomes of ChEI treat-
ment. The results from studies on global outcomes have
been mixed, with some studies concluding that there is no
significant change and others finding slight improvements
[12, 30, 93, 94]. Pooled data show a mean improvement of
0.4–0.5 for treatment in Alzheimer’s and Lewy body de-
mentia in a 7-point interview-based global assessment of
change scale [30, 93, 104]. Functional measures of ADL
showed similarly mixed results for the treatment of Alz-
heimer’s and Lewy body dementia, with studies achieving
improvements on the order of 0.1 standard deviations
compared with placebo, which was not considered to be
clinically significant. [1, 28, 87, 89, 93] Studies on ChEIs
for vascular dementia have found negligible improvements
in global and functional measures [94]. A secondary
 J. S. Buckley, S. R. Salpeter

Table 1 Benefit assessment of cholinesterase inhibitors for dementia by type

Condition The evidence Comments

Mild cognitive impairment

Mild cognitive Minimal cognitive benefits and possible delay of Pooled data show no significant delay in dementia
impairment progression to dementia suggested by a few small studies progression or in cognitive and global benefits
Dementia
Mild-moderate Improvements on the order of 1.5 MMSE (30-point scale), The most evidence exists for otherwise relatively young and
AD 2.5 ADAS-cog (70-point scale), 0.5 in interview-based healthy individuals with this dementia type. While these
global assessment of change (7-point scale), 2 points in improvements are statistically significant, they fall short
NPI (144-point scale), and 0.1 standard deviations of ADL of many standards of clinical significance, and most do
scales not assess for longer than 1 year
Mild–moderate Similar outcomes in cognitive, neuropsychiatric, and global While there is slightly less evidence available for Lewy
Lewy body domains as with mild–moderate AD body dementia than AD, pooled evidence indicates the
dementia benefit of ChEIs is similar for both conditions in the short
term
Mild–moderate Some small studies have shown more marginal benefit than Fewer large and long-term studies have been conducted on
vascular for AD and Lewy body dementia—on the order of 0.8 vascular dementia than on other dementia types, but
dementia MMSE, 1.5 ADAS-cog, and negligible improvements in pooled evidence indicates that benefits are small or
other domains nonexistent
Advanced and end- What limited evidence exists is mostly for AD, and shows A huge paucity of evidence for severe dementia of any type
stage dementia of only small benefits to cognition—4 to 7 points SIB (133- and separately for dementia patients with advanced age
any type point scale) and little to no benefits in other domains makes assessing data difficult. Limited pooled data
indicate that the effectiveness of ChEIs decreases with
increasing dementia severity, age, and duration of
treatment
AD Alzheimer’s dementia, ADAS-cog Alzheimer’s Disease Assessment Scale-cognitive subscale, ADL activities of daily living, ChEI choli-
nesterase inhibitors, MMSE mini-mental state examination, NPI neuropsychiatric inventory, SIB severe impairment battery

outcome often studied in dementia trials is the incidence
and severity of neuropsychiatric symptoms, including be-
havioral and psychiatric disturbances, common in patients
with dementia [104]. As with global and functional scores,
pooled data showed a marginal improvement of about 2 of
144 points in NPI for Alzheimer’s and Lewy body de-
mentia, and no improvement for vascular dementia [91, 94,
103].
Very few studies have evaluated severe dementia
(MMSE 1–9), and none have looked at end-stage dementia
(MMSE 0). In fact, only one published study with 248
participants examined monotherapy of ChEIs in patients
with severe dementia (MMSE 1–10) [105]. If the criteria
were expanded to define severe dementia as MMSE 1–12,
and then post hoc subgroup analyses of larger studies were
included, that would allow for the inclusion of a few more
small trials of short duration [106–109]. One other study
evaluated severe dementia but did not classify patients
according to MMSE [110]. These trials had variable results
using the SIB, with some showing minimal cognitive
benefit (4–7 points of the 133-point SIB compared with
placebo) and others showing a trend to worse scores
compared with placebo [105–111]. Treatment of severe
dementia resulted in minimal to no benefit in ADLs or in
NPI scores [105–109].
There is also limited evidence for efficacy of ChEIs in
long-term treatment, with most randomized trials lasting
only 3–6 months despite the fact that patients often con-
tinue therapy indefinitely [12, 112]. Only four trials have
lasted 1 year or longer, all in mild to moderate Alzheimer’s
disease, and they provide some evidence for a waning of
effect over time [100, 113–115]. One 1-year trial of
donepezil found an improvement in MMSE of 1.5 points
by 1 year [113], while another trial showed improvement at
6 months but no significant effect by 1 year [114]. One
2-year trial of galantamine found an improvement in
MMSE of 0.7 points by 2 years [115]. However, another
2-year trial of donepezil, which had a complicated protocol
with two randomization periods, found an improvement in
MMSE of 0.9 points by 12 weeks that did not significantly
change in the second randomization period for the duration
of the trial [100]. The two primary outcomes of that trial,
time to institutionalization and loss of critical ADLs, did
not significantly differ between treatment and placebo by
2 years [100].
Finally, a paucity of data exist for the effectiveness of
ChEIs in the treatment of those with advanced age; in
pooled trial data, the mean age was approximately
75 years, with few participants included over the age of
85 years [11, 12, 94, 116, 117]. A single trial examined the
Systematic Review of the Risks and Benefits of Dementia Medications

effectiveness of donepezil in a population of nursing home In addition, similar effects have been seen with Alzhei-
residents with a mean age of 85 years and found no sig- mer’s disease, vascular dementia, Lewy body dementia,
nificant improvement in MMSE or neuropsychiatric out- and MCI [7, 11, 12, 30, 94].
comes at 24 weeks [118]. Pooled data from dementia trials show that ChEI treat-
ment is associated with a twofold increase in drop-outs due
3.3.3 Risks of Cholinesterase Inhibitors to adverse events compared with placebo [12, 103]. The
absolute increase in risk is 10 %, indicating that the
ChEIs can cause adverse effects due to increased cholin- number needed to treat over 3–6 months to cause one
ergic stimulation, both centrally and peripherally [119, significant drug reaction is 10 [12]. For patients with ad-
120]. Acetylcholine-containing neurons exist in the brain, vanced age, frailty, and comorbidities, and those using
mainly in the cerebral cortex, and in the periphery, both in concomitant medications, there is heightened concern for
the autonomic parasympathetic nervous system and skele- clinically relevant adverse effects associated with ChEIs.
tal muscle [121]. The central effects result in gastroin- These patients, in general, have not been included in the
testinal and neurological disturbances, while peripheral trial data, as less than 10 % of patients treated in clinical
cholinergic activity related to vagal stimulation results in practice would have been eligible for the published trials
cardiovascular and gastrointestinal events, as well as gen- [15]. Therefore, the exact magnitude of risk for real-world
eral effects such as weakness or fatigue (Table 2). The patients is uncertain. Another major difficulty in evaluating
ChEIs donepezil, galantamine, and rivastigmine have the risks of treatment is that the vast majority of random-
slightly different mechanisms of action but they share the ized trials are industry sponsored [102]. One study
common effect of reversible acetylcholinesterase inhibition evaluated 27 ChEI trials that stated they reported on the
with relative selectivity for central nervous system effects; safety and tolerability of the medication; however, 90 % of
they have been found to have similar adverse effects, so the these trials did not report standard regulatory agency-de-
data for these drugs will be reported together [2, 121, 122]. fined serious adverse events, making interpretation of the
data very difficult [102]. We provide best estimates from
randomized trial data as well as real-world experiences.
Table 2 Adverse effects of cholinesterase inhibitors compared with
placebo in Alzheimer’s disease
3.3.4 Risks of Cholinesterase Inhibitors: Gastrointestinal
Adverse outcome OR (95 % CI)
Effects
Gastrointestinal
Abdominal pain 1.95 (1.46–2.61) Procholinergic drugs such as ChEIs significantly increase
Anorexia 3.75 (2.89–4.87) gastrointestinal side effects, which can be attributed to both
Diarrhea 1.91 (1.59–2.3) central and peripheral cholinergic pathways [119, 122].
Nausea 4.87 (4.13–5.74) Abdominal pain, nausea, vomiting, diarrhea, and anorexia
Vomiting 4.82 (3.91–5.94) are all increased by two- to fivefold compared with placebo
Neurological in pooled data of Alzheimer’s trials lasting at least
Abnormal dreams 5.38 (1.34–21.55) 6 months (Table 2) [12]. These effects may be particularly
Dizziness 1.99 (1.64–2.42) prominent in the initial dose escalation phase but can re-
Headache 1.56 (1.27–1.91) main throughout long-term treatment, often resulting in
Insomnia 1.49 (1.12–2.00)
discontinuation of the drug [12, 119]. The degree of ad-
Tremor 6.82 (1.99–23.37)
verse gastrointestinal side effects appears to be dose de-
Vertigo 3.95 (1.08–14.46)
pendent [122].
In a meta-analysis of ChEI treatment of Alzheimer’s
Cardiovascular
dementia, a threefold increase in clinically significant
Syncope 1.90 (1.09–3.33)
weight loss compared with placebo was observed, related
Edema 2.08 (1.01–4.28)
at least in part to these gastrointestinal side effects [12].
General
Little inter-study heterogeneity was observed in the results,
Asthenia 2.47 (1.27–4.81)
indicating a consistent class effect on weight loss for all
Fatigue 4.39 (1.21–15.85)
ChEIs [12]. Evaluation of trial data indicates a dose de-
Muscle cramps 13.32 (1.71–103.74)
pendence related to weight loss, with a loss of C7 % of
Weight loss 2.99 (1.89–4.75)
body weight occurring in 10–25 % of patients receiving
At least one adverse event 2.51 (2.14–2.95)
high-dose ChEIs [122–125]. In one randomized trial of
Based on Birks [12] ChEI use in nursing home patients with dementia, a two-
CI confidence interval, OR odds ratio fold increase in significant weight loss was observed for

treatment compared with placebo, with those aged over
85 years having almost twice the risk of those aged under
85 years [118]. Weight loss can be quite detrimental in the
frail elderly population and has been associated with de-
creased quality of life, functional decline, institutionaliza-
tion, and increased mortality [126–130]. Observational
studies have indicated that subsequent weight gain can
occur when ChEIs are discontinued [131, 132].
3.3.5 Risks of Cholinesterase Inhibitors: Neurological
Effects
Central nervous system effects are frequently reported with
ChEIs [119]. In pooled data from Alzheimer’s trials, a
statistically significant increase, on the order of two- to
fivefold, was observed for headache, dizziness, insomnia,
abnormal dreams, and vertigo (Table 2) [12]. Observa-
tional evidence also exists that agitation may be increased
with ChEI use [119, 133]. Muscle cramps with ChEI use,
which may be related to direct cholinergic stimulation at
the neuromuscular junction, is increased 13-fold for ChEIs
compared with placebo, and could result in muscle weak-
ness or falls [12, 119].
Tremor and Parkinsonian symptoms are also sig-
nificantly increased by ChEIs, in those with and without
Parkinson’s disease, related to central cholinergic activa-
tion [12, 30, 103, 122]. Tremor is increased sevenfold with
ChEI treatment in patients with Alzheimer’s dementia,
while tremor and Parkinsonian symptoms increase two- to
threefold in patients with Parkinson’s disease being treated
with dopamine antagonists compared with placebo [12,
103, 117].
3.3.6 Risks of Cholinesterase Inhibitors: Cardiovascular
Effects
Procholinergic medications such as ChEIs can produce
bradycardia through vagal stimulation of the heart [119].
The degree of bradycardia is not an outcome generally
measured in randomized trials of ChEIs. Only one trial
reported this outcome and found a statistically significant
50 % increase in bradycardia in patients with MCI [84].
Several large observational studies have assessed the risk
for bradycardia and found a significant association between
ChEI use and hospital visits for symptomatic bradycardia,
with higher doses of medication associated with higher risk
[134–136]. Those with symptomatic bradycardia were
significantly more likely to fall, experience syncope, or
need a pacemaker implantation [134–136].
Pooled data from randomized trials in dementia have
found a statistically significant increase, by approximately
twofold, in the risk of syncope for ChEI treatment com-
pared with placebo (Table 2) [12, 54]. A meta-analysis of
J. S. Buckley, S. R. Salpeter
ChEIs in patients with MCI also found a twofold increase
in risk of syncope [7]. Inter-study heterogeneity in these
pooled analyses was low, indicating a consistent increased
risk for syncope associated with ChEIs [7, 12]. Similar
results have been found in a large population-based ob-
servational study of community-dwelling subjects with
dementia, which, after adjusting for potential confounding
variables, found that ChEI use was associated with a sig-
nificantly increased risk for hospital visits for syncope and
for syncope-related events such as pacemaker insertion and
falls with hip fracture [136]. The absolute increase in risk
for syncope in the study was 13 per 1000 person-years,
indicating that the number needed to treat for 1 year to
cause one hospitalization for syncope was 76 [136]. The
absolute increase in hip fracture was 3 per 1000 person-
years, indicating a number needed to treat of 333 patients
for 1 year to cause one hip fracture [136].
3.3.7 Risks of Cholinesterase Inhibitors: General Effects
Acetylcholinesterase inhibitors can also cause some gen-
eral adverse effects through cholinergic stimulation of
central and peripheral pathways [122]. These include fa-
tigue and asthenia, each of which have been shown to be
increased two- to fourfold compared with placebo. Weight
loss is also increased threefold; this is discussed above
under gastrointestinal effects but is probably also related to
general effects of ChEIs on fatigue and debility [12, 122].
In older patients with frailty, these effects can be quite
serious and may precipitate further decline. As mentioned
above, the risk for significant weight loss with ChEIs
essentially doubles for those aged over 85 years compared
with younger patients [118]. Data from pharmacovigilance
studies have also suggested the risk for adverse drug re-
actions related to ChEIs are twofold higher for those aged
over 85 years than for younger individuals with dementia
[137].
The effect of ChEIs on falls is unclear, as the definition
of what constitutes a fall varies considerably among studies
and fall-related events are significantly under-reported
[54]. As mentioned above, ChEIs are associated with an
increased risk for syncopal episodes, with some evidence
for an increase in syncope-related injuries such as hip
fractures [12, 54, 136]. However, most falls are not due to
syncope and many do not result in injury [138–140]. One
meta-analysis of randomized ChEI trials found no sig-
nificant effect on falls, despite a 50 % increase in syncopal
episodes compared with placebo [54]. Some observational
studies of dementia populations have found ChEIs to be
associated with an increased risk for syncope, falls, and
fall-related injuries such as hip fractures [136, 141], while
other studies have found no effect or reduced risk
[142–144].
Systematic Review of the Risks and Benefits of Dementia Medications
3.3.8 Risks of Cholinesterase Inhibitors: Drug–Drug
Interactions
Cholinesterase inhibitors could be involved in several
drug–drug interactions, both because of their complex
pharmacodynamic and pharmacokinetic properties, and
also because elderly patients with dementia are typically
receiving multiple concomitant medications [2, 119, 145–
147]. The use of medications with anticholinergic proper-
ties, such as some antidepressants, antipsychotics, antihis-
tamines, and bronchodilators, is quite common in the
elderly, and the action of either the ChEI or the anti-
cholinergic agent could be inhibited [145, 146]. In addition,
medications with anticholinergic effects could cause cog-
nitive worsening or delirium in patients with dementia
[147]. Observational studies indicate that over one-third of
patients on ChEIs also receive at least one anticholinergic
drug [148, 149]. Drugs with additional cholinesterase in-
hibitory activity, such as ranitidine, could theoretically
enhance cholinergic activity and cause greater adverse
toxicity [145, 146]. The use of ChEIs together with an-
tiparkinsonian medications could limit the efficacy of ei-
ther drug when treating Parkinson’s disease and dementia
[147]. In addition, as mentioned above, ChEIs have been
shown to increase tremor in patients with Parkinson’s
disease two- to threefold [12, 103, 119]. Medications with
bradycardic effects, such as beta-blockers, digoxin, amio-
darone, and calcium-channel blockers, cause vagal
stimulation or sympathetic blockade, and may increase the
risk for syncope or heart block [145–147, 150].
3.4 Memantine
3.4.1 Benefits of Memantine
Memantine has marketing approval for the treatment of
moderate to severe Alzheimer’s dementia in most countries
[10, 56, 151, 152]. Studies that have assessed memantine,
either as monotherapy or combination therapy with ChEIs,
are limited and all are short-term (3–6 months) industry-
sponsored trials [56, 95]. A recent meta-analysis from the
UK National Institute for Health and Care Excellence
pooled data on trials of memantine monotherapy versus
placebo in moderate to severe Alzheimer’s dementia and
found a small benefit at 3 months of treatment (4 points on
the 133-point SIB scale), but no significant change was
seen by 6 months of treatment [56]. In addition, memantine
monotherapy was found to produce a small improvement
of 0.3 points in a 7-point global assessment of change scale
at 24–28 weeks of treatment [56]. However, pooled data
from the meta-analysis showed no significant benefit in
functional outcomes as measured by ADL, or by the
Functional Assessment Staging instrument [56]. In
addition, no statistically significant gain from memantine
monotherapy on behavioral outcomes in moderate to sev-
ere dementia was observed as measured by the NPI at
24–28 weeks [56]. When the meta-analysis pooled data on
combination therapy with memantine and ChEIs, no sta-
tistically significant benefit on cognitive, functional, be-
havioral, or global outcomes was observed when
memantine was added to ChEI treatment [56].
Data on the effect of memantine in the treatment of mild
to moderate Alzheimer’s dementia are minimal. Two meta-
analyses found that memantine treatment for up to
6 months in moderate Alzheimer’s disease produced a
marginal benefit in cognitive function (1 point on the
70-point ADAS-cog scale) and in global outcomes (0.1
points on a 7-point global assessment of change scale) but
had no effect on mood and behavior [95, 153]. However,
when evaluating trials of mild Alzheimer’s disease, no
significant effect of memantine on any outcome was ob-
served, either in any single trial or when the trial data were
pooled together [153].
Data on the effect of memantine on vascular and Lewy
body dementia are even more scarce [1, 30, 93–95, 154–
156]. Memantine treatment in vascular dementia for
6 months showed minimal improvement in cognitive status
(approximately 2 points on the ADAS-cog scale) without a
significant effect on global outcomes or neuropsychiatric
scores [94, 154, 155]. Pooled trial data of memantine
treatment in Lewy body dementia found no statistically
significant effect on cognition, global outcome, or behav-
ioral symptoms [30, 156–158].
3.4.2 Risks of Memantine
In pooled trial data of memantine, the most common side
effects seen were constipation, dizziness, headache, hy-
pertension, and somnolence, but there was no statistically
significant difference in the number of withdrawals or pa-
tients with at least one adverse event between memantine
and placebo [93, 95, 159, 160]. A small reduction was
observed in the incidence of agitation recorded as an ad-
verse event, with a number needed to treat of 17 patients
for 6 months to prevent one occurrence of agitation [95].
Agitation was not a primary outcome for efficacy of me-
mantine in these trials, and there was no evidence that
agitation or other behavioral problems could be treated
with memantine [95]. Memantine had no significant effect
on falls, weight loss, or confusion [95, 159, 160]. One trial
found a threefold increase in hypertension for memantine
compared with placebo, but other studies did not evaluate
this effect [95].
Minimal drug–drug interactions have been seen with
memantine use [160]. However, little is known about the
use of memantine with other NMDA antagonists, such as

amantadine, ketamine, and dextromethorphan, so caution is
recommended [160, 161].
4 Conclusions
This systematic review summarizes the available data on
the risks and benefits of dementia treatments in the elderly.
Treatment with ChEIs for mild to moderate Alzheimer’s
and Lewy body dementia for durations of up to 1 year
produces small statistically-significant improvements in
cognitive, functional, and global outcomes, but whether
these improvements result in clinically relevant effects is
unclear. The three available ChEIs have similar efficacy,
with minimal differences seen between low and high doses
of these agents. Evidence exists that the beneficial effects
of ChEIs wane over the course of 1–2 years, and essen-
tially no data is available to evaluate treatment beyond
2 years. No evidence exists for any beneficial effect of
ChEIs in the treatment of vascular dementia, and their use
is not recommended for this disease [94].
Trial data on ChEI treatment for severe Alzheimer’s
dementia are limited and have variable results, and no
studies have evaluated severe end-stage dementia. This
lack of data may indicate a publication bias on the part of
the pharmaceutical industry, with the assumption that pa-
tients with more severe dementia are less likely to benefit
from treatment [11]. Over half of community-dwelling and
roughly 90 % of institutionalized Alzheimer’s patients
have dementia rated as moderate to severe, so further re-
search on this population is clearly needed [55, 162]. The
present evidence indicates that ChEIs have minimal benefit
in patients with severe dementia, and discontinuation of
treatment should be considered once the disease becomes
severe [163, 164].
The limited trial data indicate that ChEIs do not sig-
nificantly improve cognitive or neuropsychiatric outcomes in
patients aged over 85 years. Of note, the prevalence of vas-
cular dementia increases with advancing age, with 70–90 %
of those aged over 90 years showing vascular pathology at
autopsy [13]. As ChEIs showed marginal efficacy for the
treatment of vascular dementia, this could explain why ChEIs
have decreased efficacy in older populations.
ChEIs produce side effects through increased choliner-
gic stimulation of central and peripheral neural pathways.
Pooled trial data show a twofold increase in withdrawals
due to adverse effects compared with placebo, with a
number needed to harm of ten. Individuals aged over
85 years have almost double the risk for an adverse event
compared with younger patients. For this older population,
with decreased efficacy of treatment and increased occur-
rence of adverse effects, we believe the risks of treatment
outweigh the benefits.
J. S. Buckley, S. R. Salpeter
Gastrointestinal effects are common with ChEI treat-
ment, with a significant increased risk for abdominal
pain, nausea, vomiting, diarrhea, and anorexia, and
clinically significant weight loss. In addition, the rate of
headache, dizziness, tremor, insomnia, abnormal dreams,
fatigue, asthenia, vertigo, and muscle cramps are higher
than with placebo. Finally, hospitalization for bradycar-
dia and syncope is doubled, and is associated with an
increased risk for syncope-related conditions such as hip
fracture. There appears to be a dose-dependence related
to adverse effects but not efficacy, so treatment with
lower doses may be preferable. It is clear that real-world
conditions are quite different from the controlled trial
environment, involving an older, frailer population with
more severe disease.
Memantine monotherapy in moderate to severe Alz-
heimer’s and vascular dementia has been shown to have
small beneficial effects on cognitive and global function
in trials of 3–6 months duration, with some waning of
effect by 6 months. In limited pooled trial data, me-
mantine has not been shown to be effective in the
treatment of mild dementia or Lewy body dementia, or
as an add-on treatment to ChEIs. From the available
evidence, memantine seems to have a favorable side-
effect profile.
In summary, ChEIs may provide some cognitive, func-
tional, and global benefits in mild to moderate Alzheimer’s
and Lewy body dementia, but at the risk of significant
cholinergic side effects, the most serious being weight loss,
debility, and syncope. These effects could be especially
detrimental in the frail elderly population, in which the
risks of treatment outweigh the benefits. The effectiveness
of ChEI treatment may be short lived, with minimal evi-
dence for benefit over 1 year or in those with more ad-
vanced disease. No significant efficacy of treatment is seen
for those with vascular dementia or for those aged over
85 years. Memantine monotherapy may provide some
benefit for patients with moderate to severe Alzheimer’s
and vascular dementia, but the benefit is small and may
wane over the course of several months. Memantine has a
relatively favorable side-effect profile, at least under con-
trolled trial conditions.
This systematic review provides the available evidence
on efficacy and risk of dementia treatments, but leaves a lot
of uncertainty on how to use these drugs in clinical prac-
tice. Good diagnostic criteria for identifying various de-
mentia types are lacking, and no well-defined markers for
evaluating therapeutic response across the spectrum of
memory disorders exists. How efficacy should be assessed
for individual patients in order to understand whether
treatment is providing continued benefit or should be
stopped is unclear. These decisions will need to be made on
a case-by-case basis.
Systematic Review of the Risks and Benefits of Dementia Medications
Compliance with ethical standards No outside funding was used
to complete this research. The authors, Jacob Buckley and Shelley
Salpeter, have no conflicts of interest that are directly relevant to the
content of this study.
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