Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study
Open accessAbstract
IMPORTANCE: Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia. OBJECTIVE: To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia. DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses. EXPOSURES: Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) 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 updated as participants were followed up over time. MAIN OUTCOMES AND MEASURES: Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities. RESULTS: The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses. CONCLUSIONS AND RELEVANCE: Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.
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Tricyclic antidepressants such as desipramine have anticholinergic side-effects that may exacerbate urinary retention, cognitive changes, and fatigue.
“For example, tricyclic antidepressants such as desipramine have anticholinergic side-effects that may exacerbate urinary retention, cognitive changes, and fatigue (Politte et al., 2008; Campbell et al., 2009; Gray et al., 2015”
From Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis (2016) · cites this paper as Gray et al., 2015
The Introduction (page not provided) identifies tricyclic antidepressants as having unintended anticholinergic effects and describes cognitive impairment as a risk of anticholinergic medications. Our copy does not establish the claim for desipramine specifically or address urinary retention or fatigue. (LLM, conf=0.88)
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No Association Between Proton Pump Inhibitor Use and Risk of Alzheimer’s Disease
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Fine Particulate Matter and Dementia Incidence in the Adult Changes in Thought Study
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The cognitive effect of anticholinergics for patients with overactive bladder
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Allergy, Histamine and Antihistamines
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- Authors
- Gray, S. L., Anderson, M. L., Dublin, S., Hanlon, J. T., Hubbard, R., Walker, R., Yu, O., Crane, P. K., & Larson, E. B.
- Affiliations
- University of Washington (US)
- Kaiser Permanente Washington Health Research Institute (US)
- University of Pittsburgh (US)
- ORCID
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2015-03-01
- Volume
- 175
- Issue
- 3
- Pages
- 401
- ISSN
- 2168-6106 (ISSN-L)
- PMC
- PMC4358759
- OpenAlex
- W2168499550
- Cited by
- 1,111
- References
- 52
- Citations by year
- 2026: 81 · 2025: 102 · 2024: 100 · 2023: 83 · 2022: 98 · 2021: 89 · 2020: 151 · 2019: 113 · 2018: 84 · 2017: 79 · 2016: 79 · 2015: 51
- FWCI
- 48.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ag037451-05, 5k07ag033174-05)
- National Institute on Aging (R01-AG037451, R01AG027017, U01AG00678, U01AG006781, K07‐AG033174, AG021885, R03AG042930, Z01AG000678, P30AG024827, T32AG021885)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- anticholinergic agents, cumulative drug exposure, dementia risk, Alzheimer's disease, tricyclic antidepressants, antihistamines, antimuscarinic agents, dose-response relationship, older adults, drug safety, Adult Changes in Thought study, pharmacy dispensing data, comorbidities, polypharmacy
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Antidepressive Agents, Tricyclic, Dementia, Female, Histamine H1 Antagonists, Humans, Male, Prospective Studies, Cohort Studies, Cholinergic Antagonists, Muscarinic Antagonists
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