IMHO, I think the jury can be brought in that Parkinson's is not one disease, but that there are many subsets.
" ... can we justify further large and expensive trials of single putative, disease‐modifying therapies in our current state of ignorance? Considering the many potential explanations for past failures (Table 1), it is very difficult to justify continuing to utilize existing disease‐modifying treatment paradigms in the absence of major advances in a number of areas particularly biomarkers, especially those that successfully subtype patients into categories that predict response to specific mechanistic interventions."
"In this article, we review the concept of “disease modification,” the reasons for past failures, the approaches that are currently being explored or that will be explored in patients in the near future, and how the field should proceed over the short‐ and medium‐term future."
"Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca2+ (isradipine), iron (deferiprone), and extracellular α‐synuclein (passive immunization), and upcoming trials of interventions affecting c‐Abl, glucagon‐like peptide‐1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past."
The answer as to “Which therapeutic developments are more likely to modify progression in PD?” may depend, at a basic level, on the understanding of what PD means from the standpoint of therapeutic development. We would argue that our emphasis should not be about the tools of warfare (the design of clinical trials, the sensitivity of the endpoints, the therapeutic interventions) but about the reconfiguration of warfare itself. The who/what we are fighting (based on disease model of pathogenicity) is as important as how we fight. The face of our “enemy” has undergone relatively few changes ever since we evaluated whether vitamin E and selegiline could have neuroprotective effects using a 2 × 2 factorial design. During the subsequent 3 decades, we have tested ever more interesting potential treatments but have used the same enemy, “early, drug naïve PD,” with features only cosmetically more attractive than those originally described over 200 years ago. Our overall tools have been refined, but the who/what targets with those tools have not. We have excused ourselves for therapeutic failures with a variety of cogent reasons (Table 1), but have only tangentially included in the list our definition of the target as a problem.