Mediation of modifiable risk factors in two multidomain dementia prevention trials

INTRODUCTION: We explored which dementia risk factors in two multidomain prevention trials mediate beneficial, neutral, or counteracting effects on dementia incidence. METHODS: We pooled data from the multidomain MAPT (Multidomain Alzheimer Preventive Trial; n = 1679, up to 5-year follow-up) and preDIVA trials (Prevention of Dementia by Intensive Vascular Care; n = 3526, up to 12-year follow-up) in adults aged 70+. We used multiple mediation analysis to quantify the role of 2-year changes in body mass index, systolic blood pressure, total cholesterol, and physical activity in the intervention effects on dementia incidence. Mixed linear and Cox proportional hazard models were used to explore pathways. RESULTS: We observed no mediation of individual risk factors in the effect of the interventions on dementia incidence. The interventions slightly lowered only blood pressure, but this did not translate into an effect on dementia incidence. DISCUSSION: In older populations, multidomain interventions may not sufficiently affect dementia risk factors to lower dementia incidence, particularly in settings where cardiovascular risk factor management is well implemented. Highlights: There is no mediating role of risk factor change in the effects of multidomain interventions on dementia incidence in two large dementia prevention randomized controlled trials. The lack of effect of the interventions on risk factors explains the absence of impact on dementia. Counteracting mediators do not explain the lack of effect of the interventions on dementia. A small effect of the interventions on blood pressure did not translate into a lower dementia incidence.