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Pre-symptomatic Intervention Is Rare in Neurodegenerative Disease Clinical Trials

Key findings

  • This study reviewed data on disease stages and therapeutic hypotheses studied in clinical trials of four neurodegenerative diseases between 2000 and 2020
  • 3,238 trials were included that tested an intervention hypothesized to confer therapeutic benefit in Alzheimer's disease, Parkinson's disease, frontotemporal dementia/amyotrophic lateral sclerosis, or Huntington's disease
  • Trials in pre-symptomatic patients represented just 2.7% of all trials; moreover, they were more likely to investigate a behavioral intervention than a drug or device
  • Trials of already-approved drugs, for their approved indications, comprised 18% of all patient-years of enrollment in drug trials
  • Of 577 drug trials testing novel therapeutic hypotheses, 74% lacked any direct human genetic association implicating the target in the disease; more than half lacked an identifiable molecular target

The prevalence of adult-onset neurodegenerative disease continues to rise globally, with no proven preventive measures available.

Massachusetts General Hospital researchers used two decades of clinical trials registry data to characterize trials across significant neurodegenerative disease indications, identifying correlations and temporal trends—a key finding: trials are overwhelmingly still aimed at the treatment of patients who are already symptomatic.

Sonia M. Vallabh, PhD, and Eric Vallabh Minikel, PhD, associated scientists at the McCance Center for Brain Health and Department of Neurology at Massachusetts General Hospital and in the Broad Institute of MIT and Harvard, and Meredith A. Mortberg, a research associate in the Vallabh/Minikel Lab, report the results in Scientific Reports.


The research team searched for trials started between 2000 and March 31, 2020, in Alzheimer's disease, Parkinson's disease, frontotemporal dementia/amyotrophic lateral sclerosis (ALS), or Huntington's disease. The search yielded 4,542 "hits."

After manually annotating the registration data for those trials, the researchers included 3,238 trials that tested an intervention hypothesized to confer therapeutic benefit. Gene–disease links established through March 2020 were identified through manual searches of Online Mendelian Inheritance in Man and Open Targets Genetics.

Disease Stage

Pre-symptomatic interventions were rare:

  • 89% of trials required that patients have symptoms meriting a diagnosis of the neurodegenerative disease in question
  • 7.8% enrolled patients with mild cognitive impairment or an analogous level of other functional impairment
  • The 2.7% of trials that included pre-symptomatic patients were less likely than other trials to be industry-sponsored and less likely to test a drug or device; they were much more likely to test a behavioral intervention

Overall, trials shifted over time toward enrolling less-impaired patient populations and screening more patients out with proliferating inclusion and exclusion criteria.

Therapeutic Hypotheses

748 unique molecular entities (including unique combinations) were tested across 1,864 drug trials. Trials of already-approved drugs for their approved indications comprised 18% of patient-years of enrollment.

Post-approval trials—conducted, for example, to expand the label, gain regulatory approval in other countries, understand drug effects on additional endpoints, or test new formulations or administration routes—outnumbered trials preceding initial approval by a factor of >4.

577 trials (31%) tested novel therapeutic hypotheses:

  • 429 (74%) of those trials lacked any direct human genetic association with the molecular target
  • Of those, for 307 trials, it was impossible to identify the target
  • The 26% of trials that tested genetically supported hypotheses represented only half as many patient-years as novel hypotheses without genetic support, and no genetically supported agent was investigated as intensively as gingko biloba
  • 68% of the genetically supported trials and 84% of their patient-years were devoted to a single target: beta-amyloid protein in Alzheimer's disease


These findings suggest missed opportunities. For some targets investigated, pre-symptomatic populations might represent the best opportunity for efficacy, or in some cases, the only one. Yet an overwhelming majority of trials are conducted in symptomatic patients.

Genome-wide association studies of disease progression rates may help identify targets likely to yield efficacy in symptomatic patients. In parallel, greater investment in well-powered, well-controlled trials at earlier disease stages is needed to realize the potential of targets involved in disease initiation.

of clinical trials in major neurodegenerative diseases between 2000 and 2020 addressed prevention

of drug trials in major neurodegenerative diseases between 2000 and 2020 that tested novel therapeutic hypotheses were genetically unsupported

Learn more about the Henry and Allison McCance Center for Brain Health

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