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JAMA Intern Med. Author manuscript; available in PMC 2015 March 13.
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Published in final edited form as:

JAMA Intern Med. 2015 March 1; 175(3): 401–407. doi:10.1001/jamainternmed.2014.7663.

Cumulative Use of Strong Anticholinergic Medications and

Incident Dementia
Shelly L. Gray, PharmD, MS1, Melissa L. Anderson, MS2, Sascha Dublin, MD, PhD2,3,
Joseph T. Hanlon, PharmD, MS4, Rebecca Hubbard, PhD2,5, Rod Walker, MS2, Onchee Yu,
MS2, Paul Crane, MD, MPH6, and Eric B. Larson, MD, MPH2,6
1School of Pharmacy, University of Washington, Seattle, Washington
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2Group Health Research Institute, Seattle Washington

3Department of Epidemiology, University of Washington, Seattle, Washington
4Division of Geriatric Medicine, University of Pittsburgh
5Department of Biostatistics, University of Washington, Seattle, Washington
6Division of General Internal Medicine, University of Washington, Seattle, Washington

Abstract
IMPORTANCE—Many medications have anticholinergic effects. The general view is that
anticholinergic-induced cognitive impairment is reversible upon medication discontinuation.
However, a few studies suggest that anticholinergic medications may be associated with increased
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dementia risk.

OBJECTIVE—To examine whether cumulative anticholinergic medication use is associated with

a higher risk of incident dementia.

DESIGN—Prospective population-based cohort study using data from the Adult Changes in
Thought Study.

SETTING—Group Health, an integrated health-care delivery system, Seattle, Washington

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Corresponding Author: Shelly Gray, University of Washington, Box 357630, Seattle, WA 98195-7630. Phone: 206.616.5061; FAX
206.543.3835; [email protected]. Alternate Author: Eric Larson, [email protected]; FAX 206 287 2871.
Authors’ contributions: SLG, MLA, SD, JH, RLW, RAH, OY and EBL contributed to study conception and design; all authors
contributed to acquisition, analysis, or interpretation of data; SG and MLA drafted the manuscript; all authors revised the manuscript
for critical intellectual content; MLA conducted statistical analyses; and SG, EBL and PKC obtained funding.
Prior Presentation: This paper was presented at the 2014 Annual American Geriatrics Society Meeting in Orlando, Florida on May
16, 2014
Disclosures: Dr. Dublin received a Merck/American Geriatrics Society New Investigator Award. Dr. Larson receives royalties from
UpToDate. Rod Walker has received funding as a biostatistician from a research grant awarded to Group Health Research Institute
from Pfizer. Onchee Yu has received funding as a biostatistician from a research grant awarded to Group Health Research Institute
from Amgen. All other authors have no conflicts to disclose.
Access to data: Dr. Gray and Ms. Anderson had full access to all the data in the study and take responsibility for the integrity of the
data and the accuracy of the data analysis. Ms. Anderson conducted and was responsible for the data analysis.
 Gray et al. Page 2

PARTICIPANTS—3,434 participants aged 65 and older with no dementia at study entry. Initial
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recruitment occurred between 1994 and 1996 or 2000 and 2003. Beginning in 2004, continuous
replacement for deaths occurred. All participants received follow-up every two years.

EXPOSURE—Using computerized pharmacy dispensing data, cumulative anticholinergic

exposure was defined as the total standardized daily doses (TSDD) dispensed in the past 10 years.
The most recent 12 months of use was excluded to avoid use related to prodromal symptoms.
Cumulative exposure was time-varying.

MAIN OUTCOMES AND MEASURES—Incident dementia and Alzheimer’s disease using

standard diagnostic criteria. Statistical analyses used Cox proportional hazards models, adjusted
for demographic, health behaviors and health status including comorbidities.

RESULTS—The most common anticholinergic drug classes used were tricyclic antidepressants,
first generation antihistamines and bladder antimuscarinics. Over a mean follow-up of 7.3 years,
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797 participants (23%) developed dementia (637 developed Alzheimer’s). A 10-year cumulative
dose-response relationship was observed for both dementia and Alzheimer’s disease (test for
trend, p<0.001). For dementia, adjusted hazard ratios (HRs) and 95% confidence interval (CI) for
cumulative anticholinergic use was 0.92 (95% CI, 0.74-1.16) for 1-90 TSDD; 1.19 (CI, 0.94-1.51)
for 91-365 TSDD; 1.23 (CI, 0.94-1.62) for 366-1095 TSDD; and 1.54 (95% CI, 1.21-1.96) for
>1095 TSDD, compared to non-use. A similar pattern of results was noted for Alzheimer’s
disease. Results were robust to secondary, sensitivity and post-hoc analyses.

CONCLUSION AND RELEVANCE—Higher cumulative anticholinergic medication use is

associated with an increased risk for dementia. Efforts to increase awareness among health
professionals and older adults about this potential medication-related risk are important to
minimize anticholinergic use over time.
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Keywords
dementia; Alzheimer disease; pharmacoepidemiology; cohort study; anticholinergic medication
use; aged

INTRODUCTION
Medications with anticholinergic activity are widely used by older adults for diverse
conditions such as overactive bladder, seasonal allergies, and depression. Some
anticholinergic medications achieve the intended therapeutic effect by blocking the effect of
acetylcholine at the muscarinic receptor within specific organ systems (e.g gastrointestinal
antispasmodics, bladder antimuscarinics, antiparkinson agents). However, other medications
have unintended anticholinergic effects that are not the primary therapeutic activity (e.g first
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generation antihistamines, tricyclic antidepressants, and certain antipsychotics).

The prevalence of anticholinergic medication use in older adults ranges from 8-37%.1-5 This
frequent use is despite professional organizations concluding that the benefits of using these
agents in older adults may be outweighed by risks.6-8 A well-known risk with
anticholinergic medications is acute impairment in specific aspects of cognition (e.g.,
working memory, attention, psychomotor speed) which has been demonstrated in single

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dose experimental studies 9-12 and cohort studies.13 In addition, anticholinergics may be
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associated with global cognitive impairment.13 Older adults may be more sensitive to
anticholinergic effects in the central nervous system because of age-related changes in
pharmacokinetics and pharmacodynamics, reduced acetylcholine mediated transmission in
the brain, and increased permeability of the blood-brain barrier.7

The general view is that anticholinergic-induced cognitive impairment is reversible upon

medication discontinuation. However, several investigators have reported that
anticholinergic medications may be associated with increased risk for sustained cognitive
deficits such as mild cognitive impairment or dementia.1,2,14 One biologically plausible
mechanism for these findings is that cumulative use of these agents result in abnormal brain
pathology similar to that observed with Alzheimer’s Disease (AD).15 These observational
studies have four important limitations. First, current anticholinergic use was only
ascertained at study entry and periodically during follow-up by conducting a medication
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inventory. 1,14 Secondly, these studies lacked information about both the dose and duration
of anticholinergic use. Thirdly, these studies had short follow-up periods. This later point is
important as the pathophysiological changes in the brain of people with AD require several
years to occur.16 Finally, these studies did not take into account that certain anticholinergics
are used to manage insomnia and depression, two prodromal conditions that can be seen in
early but undiagnosed dementia, leading to protopathic bias.17-19 In this situation, the
association between anticholinergics and dementia would not be causal, but would arise
because anticholinergics are used to treat early symptoms (e.g. prodromal) of dementia.
Given the potentially enormous public health implications, a better understanding of the
potential risks of cumulative anticholinergic use is needed.

The objective of this study was to examine the association between 10-year cumulative
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anticholinergic use and risk of dementia. We hypothesized that greater cumulative use of
anticholinergics would be associated with increased risk.

METHODS
Design, Study Setting, and Participants
This population-based prospective cohort study was conducted within Group Health (GH),
an integrated health-care delivery system in the northwest US. Participants were from the
Adult Changes in Thought (ACT) study and details about study procedures have been
detailed elsewhere.20 Briefly, study participants aged 65 years and older were randomly
sampled from Seattle-area GH members. Participants with dementia were excluded. The
original cohort of 2,581 participants was enrolled between 1994 and 1996. An additional
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811 participants were enrolled between 2000 and 2003. In 2004 the study began continuous
enrollment to replace those who die or drop out. Participants were assessed at study entry
and returned biennially to evaluate cognitive function and collect demographic
characteristics, medical history, health behaviors and health status. The current study sample
was limited to participants with at least 10 years of GH health plan enrollment prior to study
entry to permit sufficient and equal ascertainment of cumulative anticholinergic exposure.
The study sample was further limited to those with at least one follow-up study visit, as this
is necessary to detect incident dementia. Of the 4,724 participants enrolled in ACT, 3,434

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were eligible for the current study (2 withdrew consent to use GH data for research, 674 had
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less than 10 years of GH enrollment and 614 had no follow-up visits). Data through Sept
2012 were included in these analyses. The research protocol for this study was reviewed and
approved by the GH and University of Washington’s institutional review boards.

Identification of Dementia and Alzheimer Disease

The Cognitive Abilities Screening Instrument (CASI) was used to screen for dementia at
study entry and each biennial study visit.21 CASI scores range from 0 to 100 with higher
scores indicating better cognitive performance. Participants with CASI scores of 85 or less
(sensitivity 96.5%; specificity 92%)22 underwent a standardized dementia diagnostic
evaluation, including a physical and neurological examination by a study neurologist,
geriatrician or internist, and a battery of neuropsychological testing. The results of these
evaluations and laboratory testing, along with clinical data from participants’ medical
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records, were then reviewed in a multidisciplinary consensus conference. The diagnoses of

dementia and AD were made using research based criteria.23,24 The date of dementia
diagnosis was assigned as the midpoint between the ACT study visit where the diagnosis
was made and the preceding visit. Participants with new onset dementia underwent at least
one annual follow-up examination to confirm the dementia diagnosis.

Anticholinergic Medication Use

Medication use was ascertained from GH computerized pharmacy dispensing data that
included drug name, strength, route of administration, date dispensed, and amount dispensed
for each drug. Anticholinergic use was defined as those medications deemed to have strong
anticholinergic activity as per consensus by an expert panel of health care professionals.8,13
Since we were drawing on medication data from as early as 1984 (e.g. extending back 10
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years prior to study entry), it was necessary to enhance this contemporary list with
medications no longer on the market. Therefore, two clinician/investigators (SLG, JTH)
reviewed previously published standard pharmacology/pharmacotherapy reference books to
identify additional anticholinergic medications.25,26 eTable 1 lists the strong anticholinergic
medications according to medication class (e.g., first generation antihistamines, tertiary
tricyclic antidepressants, bladder antimuscarinics).

To create our exposure measures, we first calculated the total medication dose for each
prescription fill by multiplying the tablet strength by the number of tablets dispensed. This
product was then converted to a standardized daily dose (SDD) by dividing by the minimum
effective dose per day recommended for use in older adults according to a well-respected
geriatric pharmacy reference (eTable 1).27 For each participant, we summed the SDD for all
anticholinergic pharmacy fills during the exposure period to create a cumulative total
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standardized daily dose (TSDD) (see example calculation in eFigure 1). This previously
published method allows for standardized conversion of doses of different anticholinergic
medications into a single exposure measure so that we are able to capture overall
anticholinergic burden.28,29

The primary measure of anticholinergic use was 10-year cumulative exposure (eFigure 2).
Prescription fills in the most recent 1 year period were excluded because of concern about

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protopathic bias.30 Our exposure was time-varying; we assessed 10-year cumulative

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exposure at study entry and updated the exposure as participants were followed forward in
time. We categorized cumulative exposure as no use, 1-90 days, 91-365 days, 366-1095
days, or >1095 days (i.e. >3 years), with cut-points based on clinical interpretability and the
exposure distribution observed in our sample. As an example, a person would reach the
heaviest level of exposure if they took any of the following medications daily for more than
3 years: oxybutynin 5 mg, chlorpheniramine 4 mg, olanzapine 2.5 mg, meclizine 25 mg or
doxepin 10 mg.

Covariates
Based on literature review we selected covariates that may confound the relationship
between anticholinergic medication use and dementia.13,14 Information about covariates
came from standardized questionnaires that were administered by research staff at each
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study visit or GH electronic health databases. Demographic factors included age, sex, and
years of education (at least some college vs not). Body mass index (BMI) was calculated
from measured weight and height (i.e., underweight = <18.5, normal weight = 18.5–24.9,
overweight = 25–29.9, obese = BMI of 30 or greater).31 Participants were asked about
current smoking status and whether they engaged in regular exercise (self-report of
performing one of several listed activities for at least 15 minutes, at least three times per
week).32 For health status, we created dichotomous variables for self-rated health status
(fair/poor vs better) and specific comorbidities including medication-treated hypertension
and diabetes (computerized pharmacy data), history of stroke (i.e., self-report or
International Classification of Diseases, version 9 codes 430.X, 431.X, 432.X, 434.X, 436.X
and 438.X), and coronary heart disease (i.e., self-reported history of heart attack, angina,
angioplasty, or coronary artery bypass surgery). APOE status was categorized as the
presence or absence of any ε4 alleles.33,34
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We also adjusted for medical indications associated with anticholinergic use to account for
bias due to confounding by indication such as self-reported history of Parkinson’s disease,
high depressive symptoms (i.e., score of 10 or higher on the short version of the Center for
Epidemiologic Studies Depression [CES-D] scale)35 and current benzodiazepine use
(computerized pharmacy data) as a proxy for sleep or anxiety disorders.

Statistical Analyses
We used multivariable Cox proportional hazards models with participant’s age as the time
scale36 to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association
between anticholinergic medication use and incident dementia or possible/probable AD.
Participants were censored at the earlier of their last ACT visit, disenrollment from the
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health plan GH or death if they did not have a dementia diagnosis. In addition, for the AD
analysis, individuals were censored at the time of the dementia diagnosis that was not
attributed to possible or probable AD. Separate models were fit for each outcome. Coronary
heart disease, stroke, history of depressive symptoms, and current benzodiazepine use were
entered as time-varying measures. Values at study entry were used for all other covariates.
We conducted a complete case analysis, excluding individuals with missing covariates.

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Proportional hazards assumption was assessed by testing the interactions between the
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exposures of interest and age at follow-up (the time scale of the analysis).

Secondary and Sensitivity Analyses—In secondary analyses, interaction terms were

used to estimate separate hazard ratios for anticholinergic exposure categories according to
several subgroups (sex, age at entry, and APOE genotype). We also performed several pre-
specified sensitivity analyses designed to explore the possibility that an association between
anticholinergic use and dementia could be attributed to anticholinergics used to treat early
symptoms of dementia. First, we separated anticholinergic medications into two sub-types,
antidepressants versus all other anticholinergic medication classes, and entered both sub-
types into a single model. We hypothesized that if an association was strictly due to
treatment of prodromal symptoms, a significant association with dementia would be found
for antidepressants, but not for other anticholinergic medication classes. Next, we included
the CES-D score category at each visit in the model rather than a history of depressive
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symptoms. Recent depression, rather than history of depression may be more strongly
related to cognitive outcomes.37 Finally, we extended the lag-time to two years and
excluded the prescriptions during this period from the calculation of cumulative use. The
longer lag-time decreases the likelihood that we included medications prescribed for
prodromal symptoms. Post-hoc, we conducted an exploratory analysis to better understand
our finding of increased dementia risk among those with the heaviest anticholinergic use by
further defining heavy use sub-categories (primarily recent users, primarily past users or
continuous users; eFigure 2).

All analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC).

RESULTS
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Table 1 provides participant characteristics overall and by 10-year cumulative exposure at

study entry. The median age of participants at study entry was 74, 91% were white, 60%
were female, and the majority had some college education. Overall, 78% had at least one fill
for an anticholinergic medication in the 10 years prior to study entry (Table 1). Participants
with anticholinergic use prior to study entry were more likely to be female, have fair or poor
self-rated health, have higher depressive symptoms, and have comorbidities (e.g.
hypertension, stroke, coronary heart disease, Parkinson’s disease) than non-users. The most
common anticholinergic drug classes used were antidepressants, antihistamines and bladder
antimuscarinics (Table 2), which together accounted for over 90% of all anticholinergic
exposure. The most common individual agents from these three drug classes were doxepin,
chlorpheniramine and oxybutynin.
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Over a mean (SD) follow-up of 7.3 (4.8) years, 797 (23%) participants developed dementia,
of whom 637 (80%) were considered to have possible or probable AD. Table 3 shows
unadjusted and adjusted risk estimates for dementia and AD associated with cumulative
anticholinergic use. A 10-year cumulative dose-response relationship was observed for both
dementia and Alzheimer’s disease (test for trend, p<0.001). In particular, participants in the
highest exposure category (>1095 days) had a statistically significant increased risk for
dementia (adjusted HR 1.54, 1.21-1.96) or AD (HR 1.63; 1.24-2.14) compared to those with

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no use. Participants in the next highest exposure level (366-1095 days) had a slightly
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elevated risk for dementia (HR 1.23; 0.94-1.62) and AD (HR 1.30; CI 0.96-1.76) compared
with no use.

Our secondary analyses revealed no significant interactions with sex, age at entry, or APOE
ε4 genotype and our exposure measure (P> 0.05). Moreover, our pre-specified sensitivity
analyses supported the robustness of the main findings. Participants in the highest exposure
category were at similarly elevated risk for dementia and AD compared to non-users (eTable
2), regardless of anticholinergic sub-type (antidepressant vs. other anticholinergic classes).
Risk estimates also did not change appreciably when adjusting for recent rather than history
of depressive symptoms (eTable 3), or extending the lag-time to 2 years (eTable 4). In our
post-hoc analysis, we found that among those participants with the heaviest use (>1095
TSDD), that the timing of heavy use within the 10-year exposure window was not
important; participants with cumulative exposure accrued primarily by past use had a similar
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increased risk for dementia as participants with continuous use or primarily recent use
(eTable 5).

DISCUSSION
In this population-based, longitudinal study of persons age 65 years and older, we found that
higher cumulative use of anticholinergic medications is associated with an increased risk for
of all-cause dementia and Alzheimer’s disease. Our findings were robust in secondary and
sensitivity analyses, including those performed to take into account the potential use of
anticholinergics (e.g., antidepressants) for prodromal symptoms of dementia. It is worth
noting that the increased risk for dementia was consistent across anticholinergic subclasses,
with increased risk found for people with high use of anticholinergic medications other than
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antidepressants, such as first generation antihistamines and bladder antimuscarinics. Thus

our findings do not appear to be explained by protopathic bias due to treatment of
depression, a condition commonly seen in patients with early undiagnosed dementia.

Our study findings are consistent with two cohort studies that have examined anticholinergic
use and incident dementia risk.1,14 In a large population based cohort study of individuals
age 65 years and older living in France, chronic anticholinergic use was associated with an
increased risk for dementia (adjusted HR 1.65) and AD (adjusted HR 1.94) over 4 years of
follow-up.14 Based on the exposure definition used in this study, it is difficult to determine
the temporal relationship between chronic exposure and outcome, and protopathic bias
cannot be ruled out. Another study conducted in Germany among primary care patients 75
years and older found that any anticholinergic use during the 54 month study period was
associated with an increased risk for dementia (adjusted HR 2.0) compared to non-use.1 Our
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results are not directly comparable to the German study because they also used a different
exposure definition.

Our study has a number of strengths when compared to these previous studies. Specifically,
using computerized pharmacy data to ascertain exposure in this cohort of older adults with
long-term enrollment in their health plan, we were able to characterize medication use 10-
years before study entry and throughout follow-up, to capture detailed cumulative

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anticholinergic exposure. As described previously, other studies had limited ability to

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capture long-term cumulative exposure because of the method of exposure

ascertainment.1,14 In addition, we were able to examine whether risk varies according to
extent of cumulative exposure and exclude use that may have been for prodromal symptoms.
We were able to look separately at anticholinergic use by drug class, comparing effects of
antidepressant medications to other classes. Additional strengths include the large
community based sample, the average of over 7 years of follow-up, and the use of standard
definitions for dementia and AD ascertainment.

We found that among the heaviest users, people who had past heavy use had a similar
dementia risk as those with recent or continued heavy use. This suggests that the risk for
dementia with anticholinergic use may persist despite discontinuation. Carriere et al. also
reported an elevated dementia risk in people who had discontinued their anticholinergics,
but the findings were not significant, likely because of lack of power.14 Further study is
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needed to better understand whether dementia risk is attenuated after anticholinergic

discontinuation as this has important clinical implications.

The mechanism by which anticholinergic medications might contribute to dementia risk has
not been elucidated; however, a few lines of evidence suggest that it is biologically
plausible. In a small autopsy study of patients with Parkinson’s disease, participants that
were receiving anticholinergic drugs for two years or longer had increased levels of AD
neuropathology compared with those using for shorter durations.15 Moreover, in animal
models, reduced cholinergic transmission via atropine or cortical cholinergic denervation
increased amyloid beta concentrations.38-40

A few potential limitations should be noted. Several methods exist for estimating
anticholinergic burden, with no single gold standard.41 We focused on high potency
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anticholinergics based on pharmacology and our list is in alignment with what is endorsed
by the American Geriatrics Society.8,41 Misclassification of exposure is possible because
several first-generation antihistamines are available as over the counter (OTC) medications.
However, GH members often purchase OTC medications at health plan pharmacies, and
these purchases are recorded in the computerized pharmacy database, improving data
capture. As in any observational study, unmeasured or residual confounding could introduce
bias in our estimates. We did however control for a number of factors not typically found in
studies restricted to administrative data (e.g., self-rated health, depressive symptoms). Our
exposure measure relied on prescription fills and does not guarantee that the medication was
consumed. Finally, the generalizability is unknown and our findings will need replication in
other samples with greater numbers of minorities.
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In conclusion, an increased risk for dementia was seen in people with higher use of
anticholinergic medications. Our findings suggest that a person taking an anticholinergic
medication such as oxybutynin 5 mg daily or doxepin 10 mg daily for more than 3 years
would have a greater risk for dementia. Prescribers should be aware of this potential
association when considering anticholinergic medications for their older patients and should
consider alternatives when possible. For conditions where therapeutic alternatives may not
be available, prescribers should use the lowest effective dose and discontinue therapy if

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ineffective. These findings also have public health implications for education of older adults
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about potential safety risks since some anticholinergic medications are available as OTC
products. Given the devastating consequences of dementia, informing older adults about this
potential modifiable risk would allow them to choose alternative products and collaborate
with their health professionals to minimize overall anticholinergic use. Further studies are
needed to confirm these findings and to understand the underlying mechanisms.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
We would like to thank Drs. Susan McCurry, Wayne McCormick and James Bowen, who participated in
multidisciplinary consensus committee meetings that determined study participants’ dementia status.
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Funding: This work was supported by National Institute on Aging NIH Grants U01AG00678 (Dr Larson), R01AG
027017, R01AG037451, P30AG024827, T32 AG021885, K07AG033174 (Dr. Hanlon), and by R03AG042930 (Dr.
Dublin) and by the Branta Foundation (Dr. Dublin).

Role of the Sponsors: The sponsors did not play a role in design and conduct of the study; collection, management,
analysis, and interpretation of the data; or in preparation, review, or approval of the manuscript; or the decision to
submit the manuscript for publication.

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Table 1

Characteristics of Participants at Study Entry, Overall and by Prior 10-Year Cumulative Anticholinergic Medication Usea

All Subjects Cumulative anticholinergic medication use in 10 years before study entry (TSDD)
Gray et al.

None 1-90 91-365 366-1095 >1095

N=3434 N=745 N=1083 N=701 N=347 N=558
Age in years, median (IQR) 74.4 (70, 80) 73.0 (69, 78) 74.7 (71, 80) 74.5 (70, 80) 75.1 (70, 80) 74.7 (70, 80)
Male 1387 (40.4) 384 (51.5) 474 (43.8) 271 (38.7) 116 (33.4) 142 (25.5)
White 3134 (91.4) 686 (92.1) 982 (90.8) 640 (91.7) 309 (89.1) 517 (92.8)
College education 2279 (66.4) 544 (73.0) 686 (63.3) 458 (65.4) 228 (65.7) 363 (65.1)
Obese 853 (25.4) 160 (21.9) 254 (23.8) 177 (25.8) 91 (26.8) 171 (32.0)
Current smoker 173 (5.1) 35 (4.7) 60 (5.6) 22 (3.2) 19 (5.5) 37 (6.6)

Regular exerciseb 2453 (71.6) 563 (75.9) 801 (74.1) 498 (71.1) 235 (67.7) 356 (64.0)

Fair or poor self-reported health 532 (15.5) 65 (8.8) 136 (12.6) 127 (18.1) 66 (19.0) 138 (24.8)

Treated hypertensionc 1662 (48.4) 292 (39.2) 501 (46.3) 367 (52.4) 177 (51.0) 325 (58.2)

Treated diabetesd 272 (7.9) 47 (6.3) 77 (7.1) 63 (9.0) 33 (9.5) 52 (9.3)

History of stroke 221 (6.4) 34 (4.6) 42 (3.9) 51 (7.3) 31 (8.9) 63 (11.3)

Coronary heart disease 633 (18.4) 94 (12.6) 205 (18.9) 135 (19.3) 87 (25.1) 112 (20.1)
Parkinson’s disease 24 (0.7) 5 (0.7) 5 (0.5) 7 (1.0) 1 (0.3) 6 (1.1)

High depressive symptomse 336 (10.0) 29 (4.0) 80 (7.5) 79 (11.4) 58 (16.8) 90 (16.5)

Current benzodiazepine usef 96 (2.8) 1 (0.1) 20 (1.9) 19 (2.7) 16 (4.6) 40 (7.2)

APOE ε4 genotype 768 (25.7) 163 (24.6) 234 (24.7) 159 (26.0) 89 (29.6) 123 (26.2)

TSDD Total Standardized Daily Dose; IQR, interquartile range

JAMA Intern Med. Author manuscript; available in PMC 2015 March 13.
a
Values are numbers (percentages) unless otherwise stated. Column percentages are based on non-missing data. Missing data is <1% for each covariate except for body mass index (2.2% overall),
depressive symptoms (1.6% overall)
b
≥15min of activity at least three times a week
c
Two or more fills in computerized pharmacy data for antihypertensive medications in the year prior to ACT enrollment
d
One fill in computerized pharmacy data for an oral hypoglycemic medication or insulin in the year prior to ACT enrollment
e
Modified version of the Center for Epidemiologic Studies Depression (CES-D) score of 10 or greater
f
Two or more fills in computerized pharmacy data for a benzodiazepine in 6 months prior to ACT enrollment
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Table 2

Any and Cumulative Anticholinergic Use During Study Period

Author Manuscript

All participants (N=3434) TSDD a

Medication Class Nb % Total TSDD filled % of all TSDD

Antihistamines 2,224 64.8 1,158,404 17.2

Gastrointestinal antispasmodics 1,566 45.6 365,141 5.4
Antivertigo/antiemetics 1,433 41.7 154,488 2.3
Antidepressants 1,352 39.4 4,241,590 63.1
Bladder antimuscarinics 668 19.5 702,825 10.5
Skeletal muscle relaxants 175 5.1 20,274 0.3
Antipsychotics 38 1.1 45,888 0.7
Antiarrhythmic 22 0.6 31,249 0.5
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Antiparkinson agents 12 0.3 1,615 0.0

Total 6,721,473 100.0

TSDD Total Standardized Daily Dose

a
A participant’s study period included 10 years prior to study entry through the time they were diagnosed with dementia or censored. We summed
TSDD for all participants for their entire study period.
b
Number of participants with at least 1 fill for a medication in the category at any time during the follow-up period. Participants may have fills in
multiple drug categories so the percentages do not sum to 100%.
Author Manuscript
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Table 3

Association of Incident Dementia and Alzheimer’s Disease with 10-year Cumulative Anticholinergic Medication Usea

Unadjustedc,d Adjustedd,e
Gray et al.

TSDDb Follow-up time (person-years) Number of Events HR 95% CI HR 95% CI

Dementia
0 5618 136 1.00 Reference 1.00 Reference
1-90 7704 203 0.96 0.77-1.20 0.92 0.74-1.16
91-365 5051 172 1.31 1.04-1.65 1.19 0.94-1.51
366-1095 2626 102 1.39 1.07-1.82 1.23 0.94-1.62
>1095 4022 184 1.77 1.40-2.23 1.54 1.21-1.96

Alzheimer’s Disease
0 5618 112 1.00 Reference 1.00 Reference
1-90 7704 168 0.96 0.75-1.24 0.95 0.74-1.23
91-365 5051 128 1.21 0.93-1.58 1.15 0.88-1.51
366-1095 2626 83 1.38 1.03-1.85 1.30 0.96-1.76
>1095 4022 146 1.73 1.34-2.24 1.63 1.24-2.14

TSDD Total Standardized Daily Dose; HR Hazard Ratio; CI Confidence Interval; ACT Adult Changes in Thought
a
Observations with missing adjustment variables are excluded from the model (n=115; 3.3%).
b
TSDD example; the minimum effective daily dose for oxybutynin is 5 mg daily (=1 TSDD); a person would fall into the following TSDD category if they were using 5 mg daily for 45 days (TSDD 1-90);
5 mg daily for 180 days (TSDD 91-365); 5 mg daily for 720 days (TSDD 366-1095); 5 mg daily for 4 years (TSDD>1095)
c
Age adjustment via the time-axis.

JAMA Intern Med. Author manuscript; available in PMC 2015 March 13.
d
Test for trend P value <0.001 for an association between exposure categories and each outcome
e
Adjusted for ACT cohort, age (via the time-axis), age at ACT study entry, sex, education, body mass index, current smoking, regular exercise, self-rated health, hypertension, diabetes, stroke, coronary
heart disease, Parkinson’s disease, history of depressive symptoms, and current benzodiazepine use.
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