title: Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: School of Pharmacy, University of Washington, Seattle.
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Gray
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Anderson
authors.affiliation: Group Health Research Institute, Seattle, Washington3Department of Epidemiology, University of Washington, Seattle.
authors.forename: Sascha
authors.initials: S
authors.lastname: Dublin
authors.affiliation: Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Hanlon
authors.affiliation: Group Health Research Institute, Seattle, Washington5Department of Biostatistics, University of Washington, Seattle6currently with the Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hubbard
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Rod
authors.initials: R
authors.lastname: Walker
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Onchee
authors.initials: O
authors.lastname: Yu
authors.affiliation: Division of General Internal Medicine, University of Washington, Seattle.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Group Health Research Institute, Seattle, Washington7Division of General Internal Medicine, University of Washington, Seattle.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000209:etiology; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000009:adverse effects; D018680:Cholinergic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects*; D015331:Cohort Studies; D003704:Dementia / Q000139:chemically induced / Q000453:epidemiology*; D005260:Female; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies
chemical_list: D000929:Antidepressive Agents, Tricyclic; D018680:Cholinergic Antagonists; D006634:Histamine H1 Antagonists; D018727:Muscarinic Antagonists