Minocycline fails to slow progression of mild Alzheimer's disease

  • Howard R & al.
  • JAMA Neurol
  • 18 Nov 2019

  • International Clinical Digest
Access to the full content of this site is available only to registered healthcare professionals. Access to the full content of this site is available only to registered healthcare professionals.


  • 2 years of treatment with minocycline, an anti-inflammatory tetracycline that crosses the blood-brain barrier, was not efficacious for slowing cognitive and functional decline in patients with mild Alzheimer's disease.

Why this matters

  • Lack of disease-modifying treatments for Alzheimer's disease.

Key results

  • Rate of completion: 28.8% in the 400-mg minocycline group, 61.9% in the 200-mg minocycline group, 63.7% in the placebo group (P<.001>
  • Minocycline-treated patients were significantly more likely to stop because of gastrointestinal symptoms, dermatologic adverse effects, dizziness.
  • Compared with the placebo group, the combined minocycline group had similar 24-month worsening in:
    • Standardised Mini-Mental State Examination (sMMSE) score (treatment effect, 0.07; P=.90).
    • Bristol Activities of Daily Living Scale (BADLS) score (treatment effect, –0.53; P=.57).
  • Trend toward smaller decrease in sMMSE score with 400 mg vs 200 mg minocycline (P=.08).
  • Results similar across subgroups and after adjusting for missing data.

Study design

  • English and Scottish randomised controlled trial among 554 patients (mean age, 74.3 years) with mild Alzheimer’s disease (sMMSE score ≥24; MADE trial).
  • Randomization: 400 mg/day minocycline, 200 mg/day minocycline, or placebo, for 24 months.
  • Main outcomes: changes in sMMSE, BADLS scores.
  • Funding: National Institute of Health Research; UK Medical Research Council; MODEPHARMA Limited (manufactured minocycline, placebo).


  • Non-use of biomarkers to confirm diagnosis.
  • Problematic adherence with differential drop-out.

Expert comment

  • In an editorial, Lon S. Schneider, MD, writes, "In light of dozens of therapeutic failures, lack of efficacy evidence for any drug or drug class other than cholinesterase inhibitors, prior negative minocycline trials for other neurological disorders, and absent of a clear, validated drug target for Alzheimer disease, minocycline’s lack of effectiveness was not surprising."