To effectively combat dementia onset and progression, lifestyle-based interventions targeting multiple risk factors and disease mechanisms through a multidomain approach - tailored and implemented early in the disease process - have emerged as promising. Electronic databases and relevant websites (clinicaltrials.gov, euclinicaltrials.eu, PubMed and EMBASE) were systematically searched for randomized controlled trials (RCTs) testing the combination of multidomain lifestyle and pharmacological interventions. Studies were included if 1) lifestyle intervention was multimodal (≥2 domains); 2) it was combined with drugs, supplements, or medical food; 3) the study population was within the Alzheimer’s disease (AD) and related dementias continuum, including cognitively normal individuals at-risk for dementia, people with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or prodromal AD; 4) outcomes included cognitive or dementia-related measure(s), and 5) intervention lasted at least 6 months. Twelve combination RCTs were identified, incorporating 2 to 7 lifestyle domains (physical exercise, cognitive training, dietary guidance, social activities, sleep hygiene, cardiovascular/metabolic risk management, psychoeducation or stress management), combined with pharmacological components (e.g., Omega-3, Tramiprosate, vitamin D, BBH-1001, epigallocatechin gallate, Souvenaid, and metformin). Seven RCTs targeted participants with prodromal AD, MCI or early dementia, five focused on at risk individuals or SCD. Additionally, 2 studies adopted a precision medicine approach by enriching populations with APOE-ε4 carriers. Findings suggest that well-designed interventions - tailored to the right individuals, implemented at the optimal time - may effectively improve cognition. However, further refinement of the RCT methodology is warranted, for better alignment with the multifaceted nature of dementia prevention and management.