Years of stacked anticholinergic drugs, including some antidepressants and antipsychotics, were linked to dementia
In 58,769 people with dementia and 225,574 controls, the highest cumulative anticholinergic exposure carried an adjusted odds ratio of 1.49. Anticholinergic antidepressants at top exposure: 1.29; antipsychotics: 1.70.
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: Observational; reverse causation (prodromal dementia leading to prescriptions) is the standard objection, partly addressed by the longer exposure windows. The 10.3% attributable fraction assumes causation. Not all antidepressants or antipsychotics are anticholinergic; SSRIs other than paroxetine mostly are not.
Some interactions are not between two named drugs but between a property several of them share. Anticholinergic burden is the clearest example in psychiatry: tricyclic antidepressants, some antipsychotics, bladder drugs and older antihistamines all block the same receptor, and the effects add.
Significant findings
Coupland and colleagues (JAMA Internal Medicine, 2019) ran a nested case-control study in English general practice records: "58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time." Exposure was the cumulative prescribed dose of 56 strongly anticholinergic drugs in the 1 to 11 years before diagnosis.
"The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date."
By class, at the highest exposure: "anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57)". "Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%."
Worth asking
A case-control study cannot rule out that early, undiagnosed dementia leads to these prescriptions rather than the reverse, though the authors tested windows starting 3 and 5 years before diagnosis and the association held. What the study supports is a question, not a decision: how many of your medications are strongly anticholinergic, and is the total something anyone has added up? A pharmacist can score it. The clozapine label in this wave carries the short-term version of the same warning, anticholinergic toxicity when such drugs are combined.
Source
Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study — Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J (2019)
Top-tier peer-reviewed journal
Read the source: https://doi.org/10.1001/jamainternmed.2019.0677
DOI: 10.1001/jamainternmed.2019.0677
How this was scored
- Study design
- Case-control study
- Funding
- Funding not disclosed
- Published in
- Top-tier peer-reviewed journal
- Sample size
- 284,343
- Preregistered
- not recorded
- Conflicts disclosed
- Yes
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published September 21, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 57 out of 100 on our published rubric. One caveat travels with that badge: Observational; reverse causation (prodromal dementia leading to prescriptions) is the standard objection, partly addressed by the longer exposure windows. The 10.3% attributable fraction assumes causation. Not all antidepressants or antipsychotics are anticholinergic; SSRIs other than paroxetine mostly are not. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study — Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J (2019). Published in: Top-tier peer-reviewed journal. DOI: 10.1001/jamainternmed.2019.0677. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Case-control study. Funding: Funding not disclosed. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.