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Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB. 
“Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study”. 
JAMA Intern Med. 2015 Mar 03;175(3):401-7.

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 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 PARTICIPANTS

3,434 participants aged 65 and older with no dementia at study entry. Initial 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, 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.

Key Words: dementia, Alzheimer disease, pharmacoepidemiology, cohort study, anticholinergic medication use, aged
Comments and Responses to this Article
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Nov 1, 2017 22:05
LimitationsofFindings #

This is another in a series of interesting papers developing evidence that anticholinergic drugs might be causally related to late-age dementia and/or Alzheimer's.

This paper includes the claim that antihistamines such as CPM and diphenhydramine also appear to be associated with severe mental declines.


They do not break out the substances by group or by substance and instead are using a large list of drugs.

They are using prescription data, not reported usage data, so we aren't sure whether people used the drugs or if they took more from other sources.

The Confidence Interval for the Hazard Ratio (Risk Odds Ratio) overlaps 1 for all the main groupings, meaning that the risk of using these drugs might actually result in *reduced* risk of dementia.

Dose-Response problematic: It is notable that the low-exposure grouping had a lower odds risk ("Hazard Ratio") than the no-exposure group.

Toxic response to high dose or to cumulative exposure? One thing the authors can't address because of their dataset is whether possible mental decline are related to low dose chronic exposure or from a smaller number of high dose toxic events.

I've asked the first author whether they have any information about whether any individual drugs in their list accounted for unusually high or low proportions of the risk of negative outcomes.
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