Effect of age on clinical trial outcome in participants with probable alzheimer's disease

Steven D. Targum, Lisa Fosdick, Kristen E. Drake, Paul B. Rosenberg, Anna D. Burke, David A. Wolk, Kelly D. Foote, Wael F. Asaad, Marwan Sabbagh, Gwenn S. Smith, Andres M. Lozano, Constantine G. Lyketsos

Research output: Contribution to journalArticlepeer-review


Background: Age may affect treatment outcome in trials of mild probable Alzheimer's disease (AD). Objective: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. Methods: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation ('on') or sham DBS-f ('off') for 12 months. Results: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the 'on' and 'off' groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer's Disease Assessment Scale; ADAS-cog-13 (p=0.028). Six of the 12 enrolled participants<65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7%of the 30 participants≥65 years old regardless of treatment assignment (p=0.005). While not significant, post-hoc analyses favored DBS-f 'off' versus 'on' over 12 months in the<65 age group but favored DBS-f 'on' versus 'off' in the≥65 age group on all clinical metrics. On the integrated Alzheimer's Disease rating scale (iADRS), the effect size contrasting DBS-f 'on' versus 'off' changed from +0.2 (favoring 'off') in the<65 group to -0.52 (favoring 'on') in the≥65 age group. Conclusion: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials.

Original languageEnglish (US)
Pages (from-to)1243-1257
Number of pages15
JournalJournal of Alzheimer's Disease
Issue number3
StatePublished - 2021


  • Age
  • Alzheimer's disease
  • clinical trials
  • deep brain stimulation
  • subject selection

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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