Assessment of medication-related risks for mortality prediction in Alzheimer's disease

In Alzheimer's disease, exposure to medications with anticholinergic or cognitive adverse effects may contribute to excess mortality, but direct comparisons between measures of this drug-related risk remain scarce.

We retrospectively included from a memory clinic 440 patients aged ≥65 years with Alzheimer's disease confirmed by cerebrospinal fluid biomarkers (A + T+). Medication exposure was characterized in relation to polypharmacy and potentially inappropriate medications related to cognition (PIMCog, according to the Beers criteria), both treated as binary variables, and participants' anticholinergic burden (none, low-moderate or high) as rated by three scales (the ACB, ADS, and ARS). Mortality was ascertained until December 2024. Models were adjusted for demographic, clinical, and biomarker variables.

The mean age was 74.1 ± 5.8 years, and 58.2% were women. Polypharmacy was present in 42.5% and PIMCog in 32.3%. High anticholinergic burden was found in 21.0% of patients using ACB, 8.6% using ADS, and 6.8% using ARS. During a mean follow-up of 7.3 years, 225 patients (51.1%) died. In adjusted models, mortality was associated with the number of drugs [hazard ratio (HR) 1.06, 95% confidence interval (CI) 1.01-1.11], continuous PIMCog (HR 1.21, 95% CI 1.02-1.45), high ACB (HR 1.45, 95% CI 1.01-2.11), and high ADS (HR 2.00, 95% CI 1.23-3.26), but not ARS. Antidepressants were the most frequent drugs recorded on each scale, representing 38.9% (ACB), 41.2% (ADS), and 56.1% (ARS), as well as PIMCog (33.8%). Substantial overlap was observed, with 98 patients identified by all four scales.

ACB and ADS scores and PIMCog were more strongly associated with mortality than polypharmacy. These findings highlight the combined effect of clinical factors and support systematic medication review targeting anticholinergic drugs in cognitively vulnerable patients.