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Mild polypharmacy and MCI progression in older adults: the mediation effect of drug–drug interactions



Polypharmacy has been associated with worse cognitive performance, but its impact on mild cognitive impairment (MCI) progression to dementia has not been explored.


The aims of the study were to investigate the association between multidrug regimens and MCI progression, and the possible mediation of drug–drug interactions and drugs’ anticholinergic effect in such association.


This work included 342 older adults with MCI, who were involved in an Italian multicenter population-based cohort study. Information on drugs taken was derived from general practitioners’ records and data on drug–drug interactions and anticholinergic burden [evaluated through the Anticholinergic Cognitive Burden and the Anticholinergic Risk Scale (ARS)] were extracted. Multinomial logistic regressions assessed the associations between mild polypharmacy (≥ 3 drugs/day), drug–drug interactions, and anticholinergic burden with MCI changes after 1-year follow-up. Mediation analysis evaluated potential mediators of that relationship.


Approximately, 50% of participants took ≥ 3 drugs/day. During the follow-up, 4.1% of MCI patients progressed to dementia. The odds of developing dementia was sixfold higher in those who took ≥ 3drugs/day (OR = 6.04, 95% CI 1.19–30.74), eightfold higher in those with ≥ 1 drug–drug interaction/s (OR = 8.45, 95% CI 1.70–41.91), and fivefold higher in those with ARS ≥ 1 (OR = 5.10, 95% CI 1.04–24.93). Drug–drug interactions mediated 70.4% of the association between medication number and MCI progression to dementia (p = 0.07).


Our study suggests that even mild polypharmacy may increase the risk of MCI progression to dementia, probably due to the presence of drug–drug interactions, which often occur in multidrug regimens.


Older people require careful management of pharmacological treatments, with special attention to drug–drug interactions and drug-related anticholinergic effects.

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We would like to thank the Scientific Coordinators of the Dementia Registry Study Group: Dr. Carla Grasselli, Dr. Renzo Rozzini, Dr. Salvatore Bonaiuto, Dr. Domenico Cucinotta. We thank Linda Inverso Moretti for her contribution in manuscript editing.


This work was supported by a Special Program of the Ministry of Health (Special program ex art. 12, comma 2, lett B D.Lvo n. 502/92), and by the National Research Council of Italy (CNR), Research Project “Aging: molecular and technological innovations for improving the health of the elderly population (Prot. MIUR 2867 25.11.2011)

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Correspondence to Caterina Trevisan.

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The study was approved by the ethics committees of the local health units of the participating centers and complies with the ethical standards of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Trevisan, C., Limongi, F., Siviero, P. et al. Mild polypharmacy and MCI progression in older adults: the mediation effect of drug–drug interactions. Aging Clin Exp Res 33, 49–56 (2021).

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  • Polypharmacy
  • Drug interactions
  • Anticholinergic cognitive burden
  • Mild cognitive impairment
  • Dementia