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Introduction Rivastigmine is the only approved transdermal therapy for Alzheimer’s disease (AD). Reduced drug concentration variability compared to oral formulations may improve tolerability and optimize treatment effectiveness. Objectives The EXEPT study evaluated patient compliance, caregiver treatment preference and clinical outcomes in patients with mild to moderate AD initiating oral monotherapy (OM) or transdermal monotherapy (TM) with approved AD drugs. Methods EXEPT was a Portuguese observational multicentre trial that prospectively evaluated two cohorts of patients over 6 months (± 3 months): OM and TM, to which patients were assigned according to clinical criteria. Endpoints included patient compliance (evaluated by caregivers on a 0-10 scale), caregiver treatment preference and change in Mental State Examination (MMSE) and Neuropsychiatric Inventory domains scores. Results Eighteen investigators recruited 190 patients (63.5% female, mean age 75.99 [± 7.67]), of which 69.5% were initiated on TM. Patient compliance at study end was significantly higher in the TM group (9.4 versus 8.6 points, p<0.001); 95.3% of caregivers in TM cohort preferred this formulation. MMSE increased by a median of 2.0 points in both cohorts (p<0.001 versus baseline) but no difference was observed between groups (p=0.790). A higher proportion of patients on TM showed reduced agitation/aggression (30.9% versus 15.4%, p=0.035); after controlling for baseline MMSE and use of antipsychotics this difference remained significant (OR=2.795; p=0.030). Conclusions Transdermal rivastigmine was associated with higher compliance and caregiver preference and reduced agitation/aggression compared to OM. These findings may impact treatment decisions in AD patients with agitation and aggression and high caregiver burden. [ABSTRACT FROM AUTHOR]