Update on Prevention Trials in Alzheimer's Disease

An evolving consensus about the need to treat AD in the presymptomatic phase has emerged following the disappointing results of several trials that enrolled subjects with mild to moderate disease, as well as accumulating research demonstrating that AD pathologic process begins decades before the appearance of symptoms. Several lessons can be learned from past prevention trials. The targeted populations were too diverse, the interventions probably not strong enough, and the time of exposure was most likely too short. We have learned from these trials that future prevention trials must be targeted, use strong interventions with known biological activity, and must be sustained with a long-term intervention. In this paper, we focus on three prevention trial approaches: A. Targeted therapy: Preventing AD by targeting a specific population with a specific intervention. Such preventive approaches and trials must be based on biomarkers and imaging to select a study population in accordance with the mechanism of the specific intervention; B. Multi-domain interventions targeting a larger, more diverse population over a longer time period with long-term exposure to non-specific, multi-domain intervention. The rationale for this approach stems from studies showing that several environmental factors are associated with the risk of developing dementia. These factors may include educational level, vascular and metabolic risk factors, physical activity, cognitive stimulation, and nutritional status. It may also be possible to identify healthy adults at high risk of AD and likely to benefit from intervention based on subjective memory complaint, ApoEε4 carriage, family history of AD, or the presence of frailty; and use multidomain interventions to compensate for low specificity; C. What will be probably the future of clinical practice: A preventive approach, integrated into primary care settings that begins with longitudinal monitoring of memory function in a general population to identify decliners, followed by a specific intervention based on biomarkers and imaging discussed case by case. Finally, preventing AD will require new and improved infrastructure.