The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index; 11 of the 38 sources its claims cite were checked for support.
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.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In a prospective cohort of 3,434 older adults, higher 10-year cumulative use of strong anticholinergic medications was associated with increased incident dementia and Alzheimer disease, with a dose-response trend. The highest exposure category (>1095 total standardized daily doses) had adjusted HR 1.54 for dementia and 1.63 for Alzheimer disease versus non-use.
Key findings
- Over a mean follow-up of 7.3 years, 797 participants (23%) developed dementia, of whom 637 (80%) had possible or probable Alzheimer disease.
- A 10-year cumulative dose-response relationship was observed for both dementia and Alzheimer disease (test for trend, p<0.001). Adjusted HRs for dementia versus non-use were 0.92 (95% CI, 0.74-1.16) for 1-90 TSDD; 1.19 (95% CI, 0.94-1.51) for 91-365 TSDD; 1.23 (95% CI, 0.94-1.62) for 366-1095 TSDD; and 1.54 (95% CI, 1.21-1.96) for >1095 TSDD.
- For Alzheimer disease, the highest exposure category had adjusted HR 1.63 (95% CI, 1.24-2.14) versus non-use.
- The most common anticholinergic drug classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics, together accounting for over 90% of all anticholinergic exposure. Results were robust in secondary, sensitivity, and post-hoc analyses, with no significant interactions by sex, age at entry, or APOE ε4 genotype.
Methods
- Prospective population-based cohort study using Adult Changes in Thought Study data at Group Health, Seattle, Washington. The sample included 3,434 participants aged 65 and older with no dementia at study entry, at least 10 years of health plan enrollment before entry, and at least one follow-up visit.
- Exposure was ascertained from computerized pharmacy dispensing data for medications with strong anticholinergic activity. Cumulative exposure was measured as total standardized daily doses (TSDD) over the past 10 years, excluding the most recent 12 months, and was time-varying.
- Cox proportional hazards models with age as the time scale estimated hazard ratios for incident dementia and Alzheimer disease, adjusted for demographic factors, health behaviors, health status, comorbidities, and medical indications associated with anticholinergic use.
Limitations
- The paper states that several methods exist for estimating anticholinergic burden with no single gold standard; it focused on high-potency anticholinergics, and misclassification is possible because some first-generation antihistamines are available over the counter.
- The paper notes possible unmeasured or residual confounding, that prescription fills do not guarantee medication consumption, and that generalizability is unknown and findings need replication in samples with greater numbers of minorities.
- Evident from the text: this is an observational cohort study, so causality cannot be established; the sample was 91% white, which further limits generalizability.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Claims the paper makes
11 of 38 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“This later point is important as the pathophysiological changes in the brain of people with AD require several years to occur.16”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > INTRODUCTION
What the sources say
- Supportedcites [16] Sperling RA Aisen PS Beckett LA Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease Alzheimers Dement 2011 7 3 280 292 21514248 PMC3220946 source
The Introduction states that the AD pathophysiological process begins years, if not decades, before clinical dementia. Section 2 describes a long asymptomatic period during which that process progresses, supporting the claim that these changes unfold over several years. (LLM, conf=0.88)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Our study findings are consistent with two cohort studies that have examined anticholinergic use and incident dementia risk.1,14”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [1] Jessen F Kaduszkiewicz H Daerr M Anticholinergic drug use and risk for dementia: target for dementia prevention Eur Arch Psychiatry Clin Neurosci 260 Suppl 2 S111 115 20960005 source
- Supportedcites [14] Carriere I Fourrier-Reglat A Dartigues JF Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study Arch Intern Med 2009 169 14 1317 1324 19636034 PMC2933398 source
The Associations between base-line anticholinergic drug use and 4-year incidence of dementia section reports that this population-based cohort examined anticholinergic use and incident dementia risk. It found increased risk among continuous users, so the paper supports its identification as one of the cited cohort studies; the other study is not attributed to this source alone. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [17] Amieva H Le Goff M Millet X Prodromal Alzheimer’s disease: successive emergence of the clinical symptoms Ann Neurol 2008 64 5 492 498 19067364 source
- Partly supportedcites [18] Richard E Reitz C Honig LH Late-life depression, mild cognitive impairment, and dementia JAMA Neurol 2013 70 3 374 382 23599941 PMC3694613 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [19] Stella F Radanovic M Balthazar ML Canineu PR de Souza LC Forlenza OV Neuropsychiatric symptoms in the prodromal stages of dementia Curr Opin Psychiatry 2014 27 3 230 235 24613979 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“First, current anticholinergic use was only ascertained at study entry and periodically during follow-up by conducting a medication inventory. 1,14”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [1] Jessen F Kaduszkiewicz H Daerr M Anticholinergic drug use and risk for dementia: target for dementia prevention Eur Arch Psychiatry Clin Neurosci 260 Suppl 2 S111 115 20960005 source
- Supportedcites [14] Carriere I Fourrier-Reglat A Dartigues JF Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study Arch Intern Med 2009 169 14 1317 1324 19636034 PMC2933398 source
The Anticholinergic drug use section says a standardized interview included an inventory of prescription and over-the-counter drugs used during the preceding month. The Abstract states that anticholinergic use was evaluated at baseline and again two and four years later. Page numbers are unavailable in our copy. (LLM, conf=0.93)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > INTRODUCTION
What the sources say
- Supportedcites [7] Campbell N Boustani M Limbil T The cognitive impact of anticholinergics: a clinical review Clin Interv Aging 2009 4 225 233 19554093 PMC2697587 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 no use.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > RESULTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 increased risk for dementia as participants with continuous use or primarily recent use (eTable 5).”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > RESULTS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Participants in the next highest exposure level (366-1095 days) had a slightly 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.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > RESULTS
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > RESULTS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > RESULTS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
- Probably not a substantial claim. 18
- It may state two separate claims as one. 11
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Based on literature review we selected covariates that may confound the relationship between anticholinergic medication use and dementia.13,14”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Covariates
What the sources say
- Not checked — no full text of the sourcecites [13] Fox C Richardson K Maidment ID Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study J Am Geriatr Soc 2011 59 8 1477 1483 21707557 source
- Supportedcites [14] Carriere I Fourrier-Reglat A Dartigues JF Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study Arch Intern Med 2009 169 14 1317 1324 19636034 PMC2933398 source
The Statistical analyses section describes adjusting the dementia model for health, demographic, and lifestyle covariates. The Strengths section says this was done to limit potential confounding. The citing authors’ statement that they selected covariates based on a literature review describes their own method, not a method attributed to this source; page numbers are unavailable in our copy. (LLM, conf=0.90)
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Anticholinergic Medication Use
What the sources say
- Partly supportedcites [8] American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults J Am Geriatr Soc 2012 60 4 616 631 22376048 PMC3571677 sourceExperimental — accuracy not yet measured
The Results describe Table 9 as a list of medications rated as having strong anticholinergic properties, supporting the medication-based definition. But the ratings came from three anticholinergic scales; although the Methods describe expert-panel consensus for the Beers criteria, the paper does not say the panel itself determined those activity ratings. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [13] Fox C Richardson K Maidment ID Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study J Am Geriatr Soc 2011 59 8 1477 1483 21707557 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The Cognitive Abilities Screening Instrument (CASI) was used to screen for dementia at study entry and each biennial study visit.21”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Identification of Dementia and Alzheimer Disease
What the sources say
- Partly supportedcites [21] Teng EL Hasegawa K Homma A The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia Int Psychogeriatr 1994 6 1 45 58 8054493 sourceExperimental — accuracy not yet measured
The paper describes CASI as a dementia-screening instrument (Abstract) and reports its use in epidemiological studies (Discussion). It does not say that CASI was administered at study entry and every biennial visit; the Method section instead mentions annual return visits for one pilot-study group without establishing that screening schedule. (LLM, conf=0.86)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
What the sources say
- Supportedcites [14] Carriere I Fourrier-Reglat A Dartigues JF Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study Arch Intern Med 2009 169 14 1317 1324 19636034 PMC2933398 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [1] Jessen F Kaduszkiewicz H Daerr M Anticholinergic drug use and risk for dementia: target for dementia prevention Eur Arch Psychiatry Clin Neurosci 260 Suppl 2 S111 115 20960005 source
- Partly supportedcites [2] Ancelin ML Artero S Portet F Dupuy AM Touchon J Ritchie K Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study BMJ 2006 332 7539 455 459 16452102 PMC1382539 sourceExperimental — accuracy not yet measured
The Discussion reports that elderly anticholinergic-drug users were more likely to have mild cognitive impairment. However, the Development of dementia section reports no difference in dementia rates at eight years (16% versus 14%), so the dementia part of the claim is not supported by this paper. (LLM, conf=0.89)
- Supportedcites [14] Carriere I Fourrier-Reglat A Dartigues JF Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study Arch Intern Med 2009 169 14 1317 1324 19636034 PMC2933398 source
The Conclusion states that anticholinergic medication was associated with increased risk of cognitive dysfunction and dementia in elderly persons. The Dementia section reports higher incident dementia risk among chronic users and notes a prior finding linking anticholinergic use to mild cognitive impairment. (LLM, conf=0.92)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > RESULTS
Strength:plain· not yet calibratedn = 797Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our secondary analyses revealed no significant interactions with sex, age at entry, or APOE ε4 genotype and our exposure measure (P> 0.05).”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > RESULTS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“As in any observational study, unmeasured or residual confounding could introduce bias in our estimates.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Proportional hazards assumption was assessed by testing the interactions between the exposures of interest and age at follow-up (the time scale of the analysis).”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Statistical Analyses
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Identification of Dementia and Alzheimer Disease
What the sources say
- Not checked yetcites [22] Graves AB Teng EL Larson EB White LR Education in cross-cultural dementia screening: Applications of a new instrument Neuroepidemiology 1992 11 8
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“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”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [15] Perry EK Kilford L Lees AJ Burn DJ Perry RH Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs Ann Neurol 2003 54 2 235 238 12891676 source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 antidepressants, such as first generation antihistamines and bladder antimuscarinics.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“However, GH members often purchase OTC medications at health plan pharmacies, and these purchases are recorded in the computerized pharmacy database, improving data capture.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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 protopathic bias.30”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Anticholinergic Medication Use
What the sources say
- Not checked — no full text of the sourcecites [30] Tamim H Monfared AA LeLorier J Application of lag-time into exposure definitions to control for protopathic bias Pharmacoepidemiol Drug Saf 2007 16 3 250 258 17245804 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The study sample was further limited to those with at least one follow-up study visit, as this is necessary to detect incident dementia.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Design, Study Setting, and Participants
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Misclassification of exposure is possible because several first-generation antihistamines are available as over the counter (OTC) medications.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The diagnoses of dementia and AD were made using research based criteria.23,24”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Identification of Dementia and Alzheimer Disease
What the sources say
- Not matchedcites [23] Diagnostic and Statistical Manual of Mental Disorders 4 Washington, DC American Psychiatric Association 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [24] McKhann G Drachman D Folstein M Katzman R Price D Stadlan EM Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease Neurology 1984 34 7 939 944 6610841 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > METHODS > Statistical Analyses
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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 dose experimental studies 9-12 and cohort studies.13”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [9] Ray PG Meador KJ Loring DW Zamrini EW Yang XH Buccafusco JJ Central anticholinergic hypersensitivity in aging J Geriatr Psychiatry Neurol 1992 5 2 72 77 1317178 source
- Not checked — no full text of the sourcecites [10] Molchan SE Martinez RA Hill JL Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model Brain Res Brain Res Rev 1992 17 3 215 226 1467811 source
- Not checked — no full text of the sourcecites [11] Flicker C Ferris SH Serby M Hypersensitivity to scopolamine in the elderly Psychopharmacology (Berl) 1992 107 2-3 437 441 1615141 source
- Not checked — no full text of the sourcecites [12] Flicker C Serby M Ferris SH Scopolamine effects on memory, language, visuospatial praxis and psychomotor speed Psychopharmacology (Berl) 1990 100 2 243 250 2305013 source
- Not checked — no full text of the sourcecites [13] Fox C Richardson K Maidment ID Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study J Am Geriatr Soc 2011 59 8 1477 1483 21707557 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Our exposure measure relied on prescription fills and does not guarantee that the medication was consumed.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, the generalizability is unknown and our findings will need replication in other samples with greater numbers of minorities.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
- Rests on an assumption: The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We were able to look separately at anticholinergic use by drug class, comparing effects of antidepressant medications to other classes.”
§ Cumulative Use of Strong Anticholinergic Medications and Incident Dementia > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
Prescription dispensing data accurately reflect actual anticholinergic medication consumption.
“Our exposure measure relied on prescription fills and does not guarantee that the medication was consumed.”
The paper relies on this without support.
The 10-year cumulative exposure window is sufficient to capture the relevant etiologic period for dementia.
“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 paper relies on this without support.
The date of dementia diagnosis midpoint accurately estimates dementia onset.
“The date of dementia diagnosis was assigned as the midpoint between the ACT study visit where the diagnosis was made and the preceding visit.”
The paper relies on this without support.
Complete case analysis excluding individuals with missing covariates does not introduce bias.
“We conducted a complete case analysis, excluding individuals with missing covariates.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Over the past decade, prolonged exposure to anticholinergic drugs has been linked to long term cognitive decline or dementia incidence among community living cohorts and nursing home residents.12 13 14 15 16 17”
From Anticholinergic drugs and risk of dementia: case-control study (2018) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, Gray et al. revealed that the cumulative use of tricyclic antidepressants, was related to a higher hazard ratio for dementia, and this finding was consistent with our results [52].”
From Risk analysis of use of different classes of antidepressants on subsequent dementia: A nationwide cohort study in Taiwan (2017) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Earlier studies [5-8] reporting a potential causal-relationship between antidepressant drugs and the risk of being diagnosed with dementia controlled for none or only part of depression-related disorders.”
From Understanding the Association Between Antidepressants and the Risk of Being Diagnosed with Dementia in Older People: A Self-Controlled Case Series Study (2020) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, our results do not support earlier conclusions [5-8] that a causal association between antidepressant treatment and the development of dementia may exist (i.e. antidepressant drugs may increase the risk of dementia).”
From Understanding the Association Between Antidepressants and the Risk of Being Diagnosed with Dementia in Older People: A Self-Controlled Case Series Study (2020) · cites this paper as [6]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A cohort study11 that reduced protopathic bias by excluding prescriptions in the final year of follow-up found that higher cumulative anticholinergic drug use was associated with a significantly increased risk of dementia but had limited power for analysis of separate types of anticholinergic drug.”
From Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study (2019) · cites this paper as [11]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Many studies have linked anticholinergic drug use with concurrent or short term cognitive effects, but few have examined associations of long term anticholinergic exposure;8 the latter tend to report positive associations.12 14 15”
From Anticholinergic drugs and risk of dementia: case-control study (2018) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Anticholinergic antidepressants were linked to dementia incidence, consistent with our results, however, the authors did not test specific classes of the remaining anticholinergics.”
From Anticholinergic drugs and risk of dementia: case-control study (2018) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Our findings are consistent with these studies, particularly a US cohort study of 3434 participants monitored over an average of seven years.12”
From Anticholinergic drugs and risk of dementia: case-control study (2018) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Anticholinergic drugs block acetylcholine, a neurotransmitter essential for cognitive function, and have been associated with an increased risk of dementia in older adults [15, 31, 32].”
From Long-Term Antidepressant Use and Dementia Risk: A Propensity Score-Matched Study of Swiss Older Adults, with an Anticholinergic-Specific Analysis (2026) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“Anticholinergic drugs block acetylcholine, a neurotransmitter essential for cognitive function, and have been associated with an increased risk of dementia in older adults [15, 31, 32].”
From Long-Term Antidepressant Use and Dementia Risk: A Propensity Score-Matched Study of Swiss Older Adults, with an Anticholinergic-Specific Analysis (2026) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“This association between anticholinergic antidepressants and dementia aligns with previous longitudinal cohort studies indicating that anticholinergic medications negatively affect cognitive performance [15, 31, 32, 43, 44].”
From Long-Term Antidepressant Use and Dementia Risk: A Propensity Score-Matched Study of Swiss Older Adults, with an Anticholinergic-Specific Analysis (2026) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“Long-term observational data are needed, but cohort studies to date have produced contrasting results. While various studies observed increased risk of dementia in antidepressant users, 4,8-14 several others did not. 15-19”
From Antidepressant use in relation to dementia risk, cognitive decline, and brain atrophy (2024) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“In contrast, other studies did link antidepressant use to increased dementia risk. 4,8-14”
From Antidepressant use in relation to dementia risk, cognitive decline, and brain atrophy (2024) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“We used the approach of Gray et al,11 which included drugs identified as having strong anticholinergic properties by the American Geriatrics Society 2012 Beers Criteria Update Expert Panel.14”
From Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study (2019) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Sensitivity analyses using multiply imputed data (eTable 13 in the Supplement) or restricted to anticholinergic drugs included in the study by Gray et al11 (eTable 14 in the Supplement) did not change study findings.”
From Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study (2019) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Our findings are consistent with other studies, including a US cohort study of 3434 participants,11 which reported a hazard ratio of 1.54 (95% CI, 1.21-1.96) for the highest exposure category (>1095 TSDDs), similar to our AOR of 1.49 (95% CI, 1.44-1.54).”
From Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study (2019) · cites this paper as [11]
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Metadata
- 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
- Semantic Scholar
- 2db7224d3159016b72138c63da0ce5201e88452f
- 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 (medical) › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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