Towards early disease modification of Parkinson's disease: a review of lessons learned in the Alzheimer field

Parkinson's disease (PD) research is beginning to focus on early disease modification and prevention. The therapeutic pipeline includes a growing range of pharmacological interventions that could theoretically intervene with the underlying disease process. It is hoped that applying such interventions in a very early stage of the disease pathology, before the onset of motor symptoms or during its early stages, may prevent or delay further disease progression. To identify people in this early disease stage, criteria for 'prodromal PD' have been proposed-describing people with one or more specific features that jointly constitute a variably increased risk of developing clinically manifest PD. Here, we aim to draw lessons from the field of Alzheimer's research, which has followed a similar strategy over the last decade, including the expansion of the disease label to 'prodromal' stages. Importantly, none of the large and costly randomized-controlled trials aiming to slow down or prevent Alzheimer's dementia by targeting the alleged disease pathology, i.e., amyloid-β aggregation, resulted in detectable clinical effects. Lack of sufficiently robust phase 2 trial results before moving to phase 3 studies, suboptimal participant selection, insensitive outcomes, a too narrow target focus, and trial design flaws contributed to this disappointing outcome. We discuss the various similarities between these Alzheimer's and PD approaches, and review the design of prevention or early disease modification trials for both diseases including the potential for immunotherapy. Finally, we offer considerations to optimize the design of such trials in PD, benefiting from the lessons learned in Alzheimer's prevention research