Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study.
ABSTRACT To determine whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative.
A 2-year longitudinal study of participants enrolled in the Medical Research Council Cognitive Function and Ageing Study between 1991 and 1993.
Community-dwelling and institutionalized participants.
Thirteen thousand four participants aged 65 and older.
Baseline use of possible or definite anticholinergics determined according to the Anticholinergic Cognitive Burden Scale and cognition determined using the Mini-Mental State Examination (MMSE). The main outcome measure was decline in the MMSE score at 2 years.
At baseline, 47% of the population used a medication with possible anticholinergic properties, and 4% used a drug with definite anticholinergic properties. After adjusting for age, sex, educational level, social class, number of nonanticholinergic medications, number of comorbid health conditions, and cognitive performance at baseline, use of medication with definite anticholinergic effects was associated with a 0.33-point greater decline in MMSE score (95% confidence interval (CI)=0.03-0.64, P=.03) than not taking anticholinergics, whereas the use of possible anticholinergics at baseline was not associated with further decline (0.02, 95% CI=-0.14-0.11, P=.79). Two-year mortality was greater for those taking definite (OR=1.68; 95% CI=1.30-2.16; P<.001) and possible (OR=1.56; 95% CI=1.36-1.79; P<.001) anticholinergics.
The use of medications with anticholinergic activity increases the cumulative risk of cognitive impairment and mortality.
- SourceAvailable from: Danijela Gnjidic[Show abstract] [Hide abstract]
ABSTRACT: Anticholinergic and sedative medications are commonly used in older adults and are associated with adverse clinical outcomes. The Drug Burden Index was developed to measure the cumulative exposure to these medications in older adults and its impact on physical and cognitive function. This narrative review discusses the research and clinical applications of the Drug Burden Index, and its advantages and limitations, compared with other pharmacologically developed measures of high-risk prescribing.Clinical Interventions in Aging 01/2014; 9:1503-1515. · 2.65 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cognitive impairment is one of the side effects of using anticholinergic medicines for overactive bladder; however, its incidence has not been fully reported. We experienced two elderly Japanese patients with overactive bladder who had temporary cognitive impairment caused by anticholinergic medicines.BMC Research Notes 09/2014; 7(1):672.
- [Show abstract] [Hide abstract]
ABSTRACT: Anticholinergic drugs are associated with poor outcomes in older patients but no specific intervention strategies aimed at reducing anticholinergic drug exposure have been described.Therapeutic advances in drug safety. 06/2014; 5(3):121-8.
Anticholinergic Medication Use and Cognitive Impairment in the
Older Population: The Medical Research Council Cognitive
Function and Ageing Study
Chris Fox,?MD,aKathryn Richardson,?MSc,bIan D. Maidment, MA,cdGeorge M. Savva, PhD,e
Fiona E. Matthews, PhD,fDavid Smithard, MD,ghSimon Coulton, MSc,dCornelius Katona, MD,i
Malaz A. Boustani, MD, MPH,jklmand Carol Brayne, MDbe
OBJECTIVES: To determine whether the use of medica-
tions with possible and definite anticholinergic activity in-
creases the risk of cognitive impairment and mortality in
older people and whether risk is cumulative.
DESIGN: A 2-year longitudinal study of participants
enrolled in the Medical Research Council Cognitive Func-
tion and Ageing Study between 1991 and 1993.
PARTICIPANTS: Thirteen thousand four participants
aged 65 and older.
MEASUREMENTS: Baseline use of possible or definite
cholinergic Cognitive Burden Scale and cognition deter-
mined using the Mini-Mental State Examination (MMSE).
The main outcome measure was decline in the MMSE score
at 2 years.
RESULTS: At baseline, 47% of the population used a
medication with possible anticholinergic properties, and
4% used a drug with definite anticholinergic properties.
After adjusting for age, sex, educational level, social class,
number of nonanticholinergic medications, number of
comorbid health conditions, and cognitive performance at
baseline, use of medication with definite anticholinergic
effects was associated with a 0.33-point greater decline in
MMSE score (95% confidence interval (CI)50.03–0.64,
P5.03) than not taking anticholinergics, whereas the use of
possible anticholinergics at baseline was not associated with
further decline (0.02, 95% CI5 ?0.14–0.11, P5.79). Two-
year mortality was greater for those taking definite
(OR51.68; 95% CI51.30–2.16; Po.001) and possible
CONCLUSION: The use of medications with anti-
cholinergic activity increases the cumulative risk of cogni-
tive impairment and mortality. J Am Geriatr Soc 2011.
Key words: anticholinergic activity; cognitive impair-
tions to reduce the risk of developing Alzheimer’s disease.
Less physical, cognitive, andsocial activity andthe presence
of diabetes mellitus, hypertension, and hyperlipidemia have
been identified as potentially modifiable risk factors for
cognitive decline, including incident dementing illnesses
such as Alzheimer’s disease.1Use of anticholinergic medi-
cations has been associated with acute cognitive impair-
ment.2–7Animal models8–10link direct antagonism of the
muscarinic cholinergic receptor M1 to decline in cognitive
function, but there have been few studies evaluating the
long-term exposure to medications as a modifiable risk fac-
tor. Progression of Alzheimer’s-type pathology may be
dentifying risk factors for cognitive decline may lead
researchers to a better understanding of clinical interven-
Hon Consultant Psychiatrist, School of Medicine, Health Policy and Practice,
DeNDRoN Eastern Research Director and Dementia Research Group Chair,
University of East Anglia, Norwich, NR4 7TJ, UK. E-mail: chris.fox@uea.
?Joint first authors.
From theaDepartment of Psychiatry, School of Medicine, Health Policy and
Practice, University of East Anglia, Norwich, United Kingdom;bInstitute of
Public Health,eDepartment of Public Health and Primary Care, University of
Cambridge, Cambridge, United Kingdom;cKent and Medway National
Health Service and Social Care Partnership Trust, Kent, United Kingdom;
dCentre for Health Service Studies, University of Kent, Kent, United King-
dom;fMedical Research Council Biostatistics Unit, Cambridge, United
Kingdom;gKent Community Health National Health Services Trust, Ash-
ford, United KingdomhNational Institute for Health Research, Maidstone,
United Kingdom;iUniversity College London, London, United Kingdom;
jCenter for Aging Research andkDepartment of Medicine,lSchool of Med-
icine, Indiana University, Indianapolis, Indiana;mRegenstrief Institute Inc.,
r 2011, Copyright the Authors
Journal compilation r 2011, The American Geriatrics Society
cholinergic transmission through the M1receptor may re-
duce the deposits of Ab peptides.12,13
A recently published systematic review of the associa-
tion betweenthe anticholinergic activityof medications and
cognitive function found a strong link between acute cog-
nitive impairment and anticholinergic potency of medica-
tions as measured according to the serum anticholinergic
assay or through consensus opinion,14but the review did
not identify sufficient studies that examined the long-term
cognitive effects of anticholinergics.14Therefore, data from
an ongoing observational study (Medical Research Council
Cognitive Function and Ageing Study; MRC CFAS) were
examined to support or refute the hypothesis that the use of
medications with possible and definite anticholinergic
activity increases the risk of cognitive impairment and
death in older people and to determine whether there is a
Participants included in this analysis underwent the base-
line screening interview of the MRC CFASFa prospective
community-based epidemiological study of random sam-
ples of people aged 65 and older. The study has been
described elsewhere.15,16In summary, at each of the five
study centers in England and Wales, approximately 2,500
people agreed to a structured interview to collect sociode-
mographic information, cognitive measures (including the
activities of daily living. Participants were sampled from
general practice lists, and so are representative of the pop-
ulation aged 65 and older living at home and in institutions.
MRC CFAS has ethical approval from the Eastern Anglia
committees for the duration of the study (1990 to date).
Measurement of Cognition
Each participant was administered the MMSE at baseline
screening and at the follow-up assessment.
Ascertainment of Mortality
All participants in MRC CFAS were flagged on the UK
Office of National Statistics National Health Service Cen-
tral Register to enable routine collection of mortality
Measuring Exposure to Anticholinergics
For the purposes of this study, each participant’s anti-
cholinergic burden was calculated using the Anticholinergic
Cognitive Burden Scale (ACB).3The scale was developed
through a systematic review of the literature to identify
drugs with documented anticholinergic activity. Content
validity was tested by presenting the list to an expert inter-
disciplinary panel of geriatricians, pharmacists, geriatric
psychiatrists, general physicians, specialist geriatric nurses,
and aging brain researchers. Any disagreements were
resolved by consensus.
Medications wereidentified to have absent, possible, or
definite anticholinergic properties based on the ACB.3,14
Drugs with possible anticholinergic effects were defined as
those with serum anticholinergic activity or in vitro affinity
to muscarinic receptors but with no known clinically rel-
evant negative cognitive effects (ACB score51). Drugs
with established and clinically relevant cognitive anti-
cholinergic effects were considered to be definite anti-
cholinergics (ACB score 2–3).3,14Using the ACB, a team
of a pharmacist (IM), a physician (DS), and a geriatric
psychiatrist (CF) independently reviewed all medications
used by the study population and categorized medications
into three categories: absent anticholinergic activity
(ACB score50), possible anticholinergic activity (ACB
score51), ordefinite anticholinergic
score52 or 3). The scores were then compared to reach a
consensus agreement on the ACB of each medication that
participants in the CFAS had taken. An additional variable
was structured to capture the total burden of anti-
cholinergic per participant by adding the score of each pos-
sible or definite anticholinergic.
Measurement of Medication Use and Covariates
Details of prescription and over-the-counter medication
reporting and associations at baseline have been described
previously.17In brief, trained interviewers assessed the par-
ticipants’ current use of medication with the question: ‘‘Do
you take any medicine, tablets or injections of any kind,
either that you buy yourself or that are prescribed by your
doctor?’’ Drug name, dose, frequency, and quantity were
recorded for each reported medication. To improve data
accuracy, interviewers were required when possible to see
the medicines or consult the matron in nursing homes and
to check exactly which medication was taken before enter-
ing the data. The medication data were coded according to
the Read Codes Drug and Appliance Dictionary, Version
2.18Using this coding, medications were also grouped into
the following classes for analysis: gastrointestinal, cardio-
vascular, respiratory, central nervous system excluding an-
tipsychotics, antipsychotics, urinary tract infection, and
Covariates investigated from the baseline survey were
sex, age, institutionalization (residential care including
nursing homes and long-stay hospitals), social class (high-
est occupation class achieved during working life or that of
the husband in the case of housewivesFprofessional or
managerial, skilled, or partly skilled or unskilled), years of
full-time education, smoking status (never, past, current),
and alcohol drinker (ever, never). The number of self-re-
ported health conditions from the following was also ex-
amined: angina pectoris, arthritis, asthma, bronchitis,
depression, diabetes mellitus, epilepsy, heart attack, high
blood pressure, Parkinson’s disease, pernicious anemia,
stroke, and thyroid problems.
Logistic regression was used to estimate odds ratios (ORs)
and 95% confidence intervals (CIs) for factors predicting
anticholinergic medication use at baseline. Backward step-
wise regression, retaining variables with Po.15, was used
to build a multivariable logistic model to identify indepen-
dent predictors of anticholinergic medication use. After this
regression, all subsequent analyses were adjusted for age,
FOX ET AL.
sex, education, social class, number of self-reported health
conditions, and nonanticholinergic medications.
Analysis of Cognition
Baseline MMSE score and change in MMSE by 2-year fol-
low-up were modeled using linear regression. For each
analysis, the relationship with ACB score was included in
three ways: categorical sum of ACB (P-value given for trend
test), continuous sum of ACB, and any definite or possible
anticholinergic medications. Owing to the ceiling effects,
baseline MMSE scores were adjusted for in the longitudinal
analysis. To test whether the effect varied with varying lev-
els of cognitive impairment, results were further stratified
according to MMSE score at baseline (0–21, 22–25, and
Loss to Follow-Up
Logistic regression was also used to measure the association
between ACB score and loss to follow-up through dropout
and mortality by 2 years after adjusting for the potential
covariates and baseline MMSE score.
Version 8.3 of the MRC CFAS data was used, and
STATA 10 (StataCorp., College Station, TX) was used for
Of the 13,004 participants at baseline in MRC CFAS,
12,423 (96%) provided data on medication use. Sixty per-
cent of the population with medication data were women,
and mean age at baseline was 75.2 ? 6.8. MMSE at base-
line was complete for 12,250 (99%) participants. The mean
score was 25.9 ? 3.5 (median 27, interquartile range 24–
28). Ten percent of participantshad a MMSE score of 0–21,
25% of 22–25, and 65% of 26–30. Of the 12,250 partic-
ipants with complete medication data and MMSE score at
baseline, by 2-year follow-up, 1,223 (10%) had died, 2,493
(20%) had dropped out, and 8,534 had completed the 2-
year follow-up survey (8,334 with complete MMSE).
Anticholinergic Medication Use
Of the baseline sample, 9,850 (79%) participants reported
taking any medication and 6,010 (48%) were taking med-
ications with possible or definite anticholinergic properties
(ACB score?1), of whom 508 were taking medication with
definite anticholinergic properties (ACB score?2). The
most frequently reported anticholinergic medications were
furosemide (n51,384), dextropropoxyphene (n5955),
atenolol (n5922), and nifedipine (n5752). Each of these
was rated as having possible anticholinergic properties
(ACB score51). The most frequent medication with mod-
erate activity (ACB52) was carbamazepine (n569), and
the most frequentmedication
(ACB53) was amitriptyline (n5136). For those taking
anticholinergic medications, mean total ACB score was
1.8 ? 1.1 (maximum 12).
Exposure to any anticholinergic medication was inde-
pendently associated with older age, lower social class, for-
mer smoking, and more health conditions (Table 1).
Women were more likely to report taking anticholinergic
medications, but the greater number of health conditions
that women reported explained this. Participants living in
with severe activity
institutions were more likely to report taking anti-
cholinergic medications, but their older age explained this.
Association Between Anticholinergic Medication Use and
Cognition at Baseline
A dose-response relationship was observed between greater
total ACB score and lower MMSE, with those who scored 5
or higher on the ACB having a mean MMSE score of
25.0 ? 3.7, compared with 26.1 ? 3.5 in those taking no
anticholinergic medications (Table 2). In multivariable
analysis, this relationship was largely unaltered, with a
total ACB score of 5 or higher associated with an MMSE
score of 0.70 points lower (95% CI50.25–1.16) than for
no anticholinergics (Po.001). Taking any definite anti-
cholinergic medication was also associated with an MMSE
score 0.82 points lower (95% CI50.55–1.10) than for no
possible anticholinergic medications and MMSE score at
baseline was observed.
Association Between Anticholinergic Medication and
For the 8,334 participants with an MMSE score recorded at
the 2-year follow-up, the average baseline and 2-year
MMSEscoreswere26.5 ? 3.1and25.8 ? 4.0,respectively.
The change in scores were approximately normally distrib-
uted, with participants dropping on average 0.8 ? 2.9
points in the 2 years. Table 3 shows the effect of anti-
cholinergic medication use on decline in MMSE at 2 years
stratified according to MMSE severity group at baseline
adjusted for age, sex, baseline MMSE score, education, so-
cial class, number of nonanticholinergic medications, and
number of health conditions. A dose-response relation was
observed between greater total ACB score and MMSE de-
cline, with those who scored 4 or greater on the ACB de-
clining by 0.34 (95% CI50.01–0.67) more points on the
MMSE than those not taking anticholinergics. Taking any
definite anticholinergics was also associated with declining
by 0.33 (95% CI 0.03–0.64) more points on the MMSE
than those taking no anticholinergics.
The greatest effect on cognitive decline was seen in the
group with a baseline MMSE score of 26 to 30. Taking any
definite anticholinergic medication was associated with a
decline of 0.52 (95% CI50.21–0.83) more points on the
MMSE than those not taking definite anticholinergics in
this group. Similar effects were seen in the group with a
baseline MMSE score of 22 to 25 but not in the group with
a baseline MMSE score of 0 to 21, although the numbers in
this group were small (Table 3).
Association Between Anticholinergic Medication Use and
Mortality and Attrition
After adjusting for age, sex, baseline MMSE score,
education, social class, number of nonanticholinergic
medications, and number of health conditions, taking
anticholinergic medications was associated with death at
2 years, with a dose-response effect on ACB score. Ninety-
eight (20%) of those who scored 4 or greater on the ACB
and 436 (7%) of those not taking anticholinergics had died
during the 2-year follow-up. For every additional point
scored on the ACB, the odds of dying increased by 26%
ANTICHOLINERGIC ACTIVITY AND COGNITION
(OR51.26, 95% CI51.20–1.32). The effect was present
for the use of definite (OR51.68, 95% CI51.30–2.16)
and possible (OR51.56, 95% CI51.36–1.79) anti-
cholinergics. Results were also found not to vary accord-
ing tobaselineMMSEgroup(results notshown).Therewas
no association between dropout rate and ACB (results not
In this large prospective study, 48% of patients reported
taking medications with anticholinergic properties. Over-
all, the results in participants with normal or mildly
impaired cognitive function at baseline support the hypoth-
esis that medications with a definite anticholinergic effect
are independently associated with greater risk of cognitive
decline and mortality over 2 years. Although no evidence of
an association between anticholinergic use and cognitive
decline in those with already significantly impaired cogni-
tion (MMSE scoreo22) was found, 24% of this group died
before follow-up assessment, and mortality was strongly
related to ACB.It istherefore possiblethat cognitivedecline
associated with anticholinergic medication use occurred in
this group before death but was not captured in the study.
These results confirm the suggestion that anti-
cholinergics adversely affect cognitive abilities.6,7,19–25
Most of the other similar population-based data support a
link between cognitive decline and use of anticholinergics.
One of the largest other studies, involving 6,912 partici-
pants aged 65 and older, found greater risk of cognitive
decline and dementia, which decreased if anticholinergics
were discontinued.7In a longitudinal study involving 372
Table 1. Predictors of Anticholinergic Medication Use (N512,423)
Univariable Results Multivariable Results
Predictor Anticholinergic Use (n)Odds Ratio (95% CI)
P-ValueOdds Ratio (95% CI)
Professional or managerial
Partly skilled or unskilled
Number of comorbiditiesw
1.15 (1.07 to 1.23)
1.20 (1.09 to 1.33)
1.47 (1.33 to 1.63)
1.62 (1.47 to 1.78)
1.18 (1.06 to 1.31)
1.45 (1.30 to 1.62)
1.67 (1.49 to 1.86)
1.02 (0.88 to 1.17)
0.88 (0.75 to 1.02)
0.79 (0.52 to 1.19) 44
1.22 (1.12 to 1.32)
1.26 (1.14 to 1.39)
1.08 (0.80 to 1.47)
1.17 (1.07 to 1.28)
1.17 (1.05 to 1.31)
1.13 (0.79 to 1.61)81
1.13 (1.04 to 1.22)
0.79 (0.72 to 0.88)
1.11 (1.02 to 1.21)
0.88 (0.79 to 0.99)
0.89 (0.80 to 0.99).04
1.19 (1.00 to 1.42) .05
2.66 (2.36 to 2.99)
5.36 (4.74 to 6.06)
11.07 (9.72 to 12.60)
2.63 (2.34 to 2.97)
5.36 (4.73 to 6.06)
10.96 (9.61 to 12.48)
?Defined according to the highest occupation class achieved during working life of the head of household.
wNumber of self-reported comorbidities: heart attack, diabetes mellitus, bronchitis, stroke, arthritis, asthma, angina pectoris, hypertension, epilepsy, thyroid
problems, Parkinson’s disease, pernicious anemia, and depression.
FOX ET AL.
elderly people, after adjustment for other causes of cogni-
tiveimpairment, anticholinergicuse was a highlysignificant
predictor of mild cognitive impairment (MCI) (OR55.12,
95% CI51.94–13.51).23Consistent anticholinergic users
were significantly more likely to develop MCI at 1 year
(80%) than consistent nonusers (35%); there were no
differences in overall dementia rates (16% vs 14%) at 8
years.23A study of 836 older people found that participants
with dementia who were taking donepezil were more likely
to use anticholinergics than matched controls not taking
Table 2. Association Between Anticholinergic Medication Use and Mini-Mental State Examination (MMSE) Score at
MMSE Adjusted MMSE Difference?
Mean ? Standard
(95% Confidence Interval)
Sum of ACB score
Sum of ACB (per point)
Any anticholinergic drugs
26.1 ? 3.5
25.8 ? 3.4
25.6 ? 3.6
25.6 ? 3.6
25.1 ? 3.9
25.0 ? 3.7
?0.03 (?0.11 to 0.16)
0.09 (?0.27 to 0.10)
0.10 (?0.35 to 0.14)
0.55 (?0.91 to ?0.19)
0.70 (?1.16 to ?0.25)
12,250 10025.9 ? 3.5 27 (24–28)
?0.09 (?0.14 to ?0.04)
26.1 ? 3.5
25.7 ? 3.5
0.02 (?0.10 to 0.14)
9625.9 ? 3.5
24.9 ? 3.9
?0.82 (?1.10 to ?0.55)
?Adjusted for age, sex, education, social class, number of nonanticholinergic medications, and number of comorbidities.
ACB5Anticholinergic Cognitive Burden Scale.
Table 3. Association Between Anticholinergic Medication Use and Additional Decline on the Mini-Mental State
Examination (MMSE) at 2 Years Stratified According to MMSE Score at Baseline
26–30 (n56,041)22–25 (n51,769) 0–21 (n5524) Overall
Sum of ACB score
Sum of ACB score
Any anticholinergic drugs
Definite (2–3) ?0.52 (?0.83 to ?0.21) o.001 ?0.32 (?1.10 to 0.46)
0.00.02 0.00.030.00 .11 0.00 .09
0.05 (?0.08 to 0.19)
0.01 (?0.19 to 0.21)
?0.21 (?0.47 to 0.05)
?0.51 (?0.84 to ?0.18)
?0.06 (?0.45 to 0.32)
0.01 (?0.53 to 0.54)
?0.28 (?1.00 to 0.45)
?0.44 (?1.24 to 0.36)
0.33 (?0.60 to 1.27)
?0.09 (?1.31 to 1.14)
0.97 (?0.70 to 2.65)
1.85 (?0.18 to 3.87)
0.03 (?0.11 to 0.17)
0.01 (?0.20 to 0.21)
?0.15 (?0.42 to 0.12)
?0.34 (?0.67 to ?0.01)
?0.07 (?0.13 to ?0.02) .01
?0.07 (?0.21 to 0.07).320.32 (?0.02 to 0.65).07
?0.05 (?0.10 to 0.01) .10
0.02 (?0.10 to 0.14) .75
?0.05 (?0.39 to 0.29).77
0.38 (?0.43 to 1.20)
1.10 (?0.61 to 2.82)
0.02 (?0.11 to 0.14)
?0.33 (?0.64 to ?0.03)
Models adjusted for age, sex, baseline MMSE, education, social class, number of non-anticholinergic medications, and number of comorbidities.
ANTICHOLINERGIC ACTIVITY AND COGNITION
donepezil (33.0% vs 23.4%; P5.001).24Definite anti-
cholinergic use increased the risk of cognitive impairment,
but not dementia, in a cohort of African Americans with
normal cognitive functionat baseline.6A longitudinalstudy
of an elderly cohort found that anticholinergic use did not
accelerate the rate of decline in cognitive status,25although
this study used a binary independent variableFreceiving or
not receiving anticholinergicsFand did not consider the
effect of exposure to multiple anticholinergics, potentially
underestimating the effect.25
The current study adds to the existing work evaluating
anticholinergic exposure and cognitive impairment; in par-
ticular a dose-response effect for anticholinergic load and
MMSE errors was demonstrated. Clinicians, therefore,
need to review cumulative anticholinergic burden in people
presenting with cognitive impairment. Also, as far as the
authors are aware, this is the first team to identify a link
between mortality and anticholinergic burden, although
this finding should be treated with caution, because med-
ications with possible anticholinergic effects are used for
many diseases, such as hypertension26and congestive heart
failure.27Therefore, the finding may simply reflect the
prevalence of anticholinergic prescribing in disease states
with significant morbidity.
The study has four important strengths. First, thepopulation
was large (N513,004) and representative of the older pop-
ulation of England and Wales. Second, the great majority of
respondents reported medication data (96%), and detailed
assessments of medication use allowed for accurate cross-
sectional collection of medications that a participant may
have in their home, including over-the-counter, herbal, and
supplement products. Third, the comprehensive interview
included cognitive assessment and ascertainment of many
sociodemographic and health-related factors, allowing the
independent effect of anticholinergic medications to be fully
explored. Fourth, the use of the ACB has been validated
elsewhere,6,14making the assessment of anticholinergic
burden robust and clinically relevant.
A limitation of the study is that it is unknown whether
participants continued to take their medication with anti-
cholinergic activity over the 2-year period, although it was
possible to examine ACB score at 2-year follow-up in the
main arm of the study (n56,685), which indicated that the
ACB scores were stable over that period; for those not tak-
ing anticholinergics at baseline, 21% were incident users 2
years later, and for those taking anticholinergics at baseline,
17% were no longer users by the 2 year follow-up. The
issues of compliance, duration, interrupted use, and the
effect of different doses also require consideration, and
there is, therefore, need for further work in this area. A
future study should investigate the relationship between
longitudinal cumulative actual anticholinergic exposure
and cognitive decline. The medication from the database
should be compared with potentially more-comprehensive
methods of measuring medication utilization, such as dis-
pensing records, that may better assess long-term exposure
to anticholinergic medications. Adherence should be
assessed in interviews and a random subsample of pill
counts to validate the interviews.
The ACB has not been validated against in vitro mea-
sures of anticholinergic activity, although it is uncertain
whether assays reflect actual in vivo anticholinergic activity
in the human brain, and not all relevant drugs have been
assayed in vitro, in particular drug metabolites, which may
possess anticholinergic effects.3,14,28,29
Participants, who did not report their medications
(4%) and those who could not complete the MMSE at
baseline (1%) were excluded, but these numbers were small
and unlikely to have affected the results. In addition no
association was observed between baseline ACB score and
dropout or missing 2-year MMSE.
This study could not consider subclinical disease,
which may confound any associations, but medication use
is associated with health status, so despite adjusting for
many health-related factors, the possibility of residual con-
founding between health status and cognitive function can-
not be excluded. Indication bias may have limited this study
in that participants with cognitive impairment may have
been more likely to be exposed to anticholinergic medica-
tions because of the presence of cognitive impairment.
This large population-based study showed that the use of
medications with anticholinergic activity increased the risk
of cognitive decline, as measured by the MMSE, and mor-
tality over 2 years in participants with normal or mildly
impaired cognition. With a growing prevalence of cognitive
impairment in the older adult population, prescribers
should be aware of the potential effect that anticholinergics
have on the development of cognitive and executive dys-
function and mortality. Further research is needed to con-
firm and extend these findings, in particular the effect on
medicines with anticholinergic activity.
We are grateful to the respondents, their families, and their
family practices for all their help in the study.
The CFAS is funded by the MRC, UK (Grant
Conflicts of Interest: Dr. Fox and Professor Katona
have received research grants and honoraria from Eisai,
Lundbeck, Lilly, Pfizers, Novartis, and Shires. Ian Maid-
menthas received research grantsand honoraria fromEisai,
Lundbeck, Pfizers, Novartis, Schwarz, and Shires. Dr. Bou-
stani has received research grants and honoraria from
Lundbeck, Novartis, Pfizers, and Forest. No authors hold
stock or shares in pharmaceutical companies.
accessto allofthe data inthestudy andtake responsibility for
the integrity of the data and the accuracy of the data analysis.
Dr. Fox: design, interpretation, and manuscript preparation.
Miss Richardson: analysis, manuscript preparation, and set-
ting up the CFAS ACB medication database. Ian Maidment:
project delivery, manuscript design, writing, drafting, and
editing. Dr. Savva and Dr. Matthews: analysis and manu-
script preparation. Dr. Smithard: medication review and
manuscript preparation. Professor Coulton: study design
FOX ET AL.
and manuscript preparation. Professor Katona and Profes-
sor Brayne: interpretation of findings and manuscript pre-
paration. Dr. Boustani: medication review and manuscript
Sponsor’s Role: None.
1. Boustani M, Ham RJ. Alzheimer disease and other dementias. In: Ham RJ,
Sloane PD, Warshaw GA, Bernard MA, Flaherty E, editors. Primary Care
Geriatrics, a Case-Based Approach, 5th Ed. Philadelphia: Mosby Elsevier,
2007, pp 219–236.
2. Hanlon JT, Schamder KE, Boult C et al. Use of inappropriate prescription
drugs by older people. J Am Geriatr Soc 2002;50:26–34.
3. Boustani MA, Campbell NL, Munger S et al. Impact of anticholinergics on the
aging brain: A review and practical application. Aging Health 2008;4:311–320.
4. Boustani M, Hall KS, Lane KA et al. The association between cognition and
histamine-2 receptor antagonists in African Americans. J Am Geriatr Soc
5. Castelino RL, Bajorek BV, Chen TF. Targeting suboptimal prescribing in the
elderly: A review of the impact of pharmacy services. Ann Pharmacother
6. Campbell NL, Boustani MA, Lane KA et al. Use of anticholinergics and the
risk of cognitive impairment in an African American population. Neurology
7. Carriere I, Fourrier-Reglat A, Dartigues JF et al. Drugs with anticholinergic
properties, cognitive decline, dementia in an elderly general population-the 3-
City study. Arch Intern Med 2009;169:1317–1324.
8. Aigner TG, Mishkin M. The effects of physostigmine and scopolamine on
recognition memory in monkeys. Behav Neural Biol 1986;45:81–87.
9. Fibiger HC, Damsma G, Day JC. Behavioral pharmacology and biochemistry
of central cholinergic neurotransmission. Adv Exp Med Biol 1991;295:399–
10. Miller EK, Desimone R. Scopolamine affects short-term memory but not in-
ferior temporal neurons. Neuroreport 1993;4:81–84.
11. Haroutunian V, Greig N, Pei XF et al. Pharmacological modulation of Alz-
cholinergic system lesions. Brain Res Mol Brain Res 1997;46:161–168.
12. Haring R, Fisher A, Marciano D et al. Mitogen-activated protein kinase-de-
pendent and protein kinase C-dependent pathways link the m1 muscarinic
receptor to b-amyloid protein secretion. J Neurochem 1998;71:2094–2103.
13. Allinson TM, Parkin ET, Turner AJ et al. ADAMs family members as amyloid
precursor protein a-secretases. J Neurosci Res 2003;74:342–352.
14. Campbell N, Boustani M, Limbil T et al. The cognitive impact of anti-
cholinergics: A clinical review. Clin Interv Aging 2009;4:225–233.
15. MRC CFAS Pathological correlates of late-onset dementia in a multicentre,
community-based population in England and Wales. Neuropathology Group
of the Medical Research Council Cognitive Function and Ageing study (MRC
CFAS). Lancet 2001;357:169–175.
16. MRC CFAS. Cognitive function and dementia in six areas of England and
Wales: The distribution of MMSE and prevalence of GMS organicity level in
the MRC CFA Study. The Medical Research Council Cognitive Function and
Ageing Study (MRC CFAS). Psychol Med 1998;28:319–335.
17. Chen YF, Dewey ME, Avery AJ. Self-reported medication use for older people
in England and Wales. J Clin Pharm Ther 2001;26:129–140.
18. NHS Centre for Coding and Classification The Read Codes: Drug and Ap-
pliance Dictionary General Information. Loughborough, UK: NHS Centre for
Coding and Classification, 1998.
19. Tune LE, Egeli S. Acetylcholine and delirium. Dement Geriatr Cogn Dis
20. Broks P, Preston GC, Traub M et al. Modeling dementia: Effects of scopola-
mine on memory and attention. Neuropsychologia 1988;26:685–700.
21. Beatty WW, Butters N, Janowsky DS. Patterns of memory failure after
scopolamine treatment: Implications for cholinergic hypotheses of dementia.
Behav Neur Biol 1986;45:196–211.
22. Itil T, Fink M. Anticholinergic drug-induced delirium: Experimental modifi-
cation, quantitative EEG, and behavioral correlations. J Nerv Ment Dis
23. Ancelin ML, Artero S, Portet F et al. Non-degenerative mild cognitive
impairment in elderly people and use of anticholinergic drugs: Longitudinal
cohort study. BMJ 2006;332:455–459.
24. Roe C, Anderson M, Spivack B. Use of anticholinergic medications by older
adults with dementia. J Am Geriatr Soc 2002;50:836–842.
25. Bottigi KA, Salazar JC, Yu L et al. Long-term cognitive impact of anti-
cholinergic medications in older adults. Am J Geriatr Psychiatry 2006;14:980–
26. Murray MD, Lane KA, Gao S et al. Preservation of cognitive function with
antihypertensive medications: A longitudinal analysis of a community-based
sample of African Americans. Arch Intern Med 2002;162:2090–2096.
27. Cacciatore F, Abete P, Ferrara N et al. Congestive heart failure and cognitive
impairment in an older population. Osservatorio Geriatrico Campano Study
Group. J Am Geriatr Soc 1998;46:1343–1348.
28. Chew ML, Mulsant BH, Pollock BG et al. Anticholinergic activity of 107
medications commonly used by older adults. J Am Geriatr Soc 2008;56:1333–
29. Thomas C, Hesterman U, Kopitz J et al. Serum anticholinergic activity and
cerebral cholinergic dysfunction: An EEG study in frail elderly with and with-
out delirium. BMC Neurosci 2008;9:1–10.
ANTICHOLINERGIC ACTIVITY AND COGNITION