Multidomain Therapy for Alzheimer’s Disease: A Scoping Review

Background Alzheimer’s disease (AD) leading to cognitive decline and dementia results from the interplay of multiple interacting dysfunctional biological systems. These systems can be categorized by domain , such as inflammation, cardiovascular health, proteostasis, or metabolism. Specific causes of AD differ between individuals, but each individual is likely to have causes stemming from multiple domains. Personalized multidomain therapy has been proposed as a standard of care for AD. Objectives We sought to enumerate and describe prospective randomized controlled trials (RCTs) for multidomain interventions for AD, and to extract their inclusion criteria, trial design parameters (length, number of participants), and outcome measures. We sought to clarify gaps and opportunities in research and clinical translation. Eligibility criteria We include all cohort studies and RCTs for multidomain (also known as multimodal, multicomponent, multidimensional, or multisystem) therapy of any stage of AD. Results There have been 22 studies (completed or reported as ongoing) of multidomain interventions for AD, including 18 RCTs. Of the 14 completed RCTs, 11 demonstrate benefit from their intervention in at least one arm. Conclusions Although these RCTs differ widely in their parameters, the majority support the use of multidomain therapy, and show effect sizes greater than reported for unimodal therapies, including pharmaceuticals. Multidomain therapy should be the standard of care for AD. Multidomain interventions (also known as treatments) should be employed widely, early, and first-line. Treatment or prevention is likely to be most effective at early, presymptomatic stages, but is worthwhile at all stages of disease. In order to influence multiple domains, multiple modes of therapy are likely necessary in all patients. Some individual modes, such as particular lifestyle interventions, may target multiple domains. Nevertheless, most patients will benefit from multiple modes of intervention (multimodal intervention) that together target multiple domains. Standard-of-care guidelines should explicitly include multidomain interventions. Future clinical trials must be designed to iteratively improve multidomain therapies. Payors should embrace reimbursement for effective multidomain intervention, including personalized coaching.