IMPORTANCE: There are no disease-modifying treatments for Alzheimer disease 
(AD), the most common cause of dementia. Minocycline is anti-inflammatory, 
protects against the toxic effects of β-amyloid in vitro and in animal models of 
AD, and is a credible repurposed treatment candidate.
OBJECTIVE: To determine whether 24 months of minocycline treatment can modify 
cognitive and functional decline in patients with mild AD.
DESIGN, SETTING, AND PARTICIPANTS: Participants were recruited into a 
double-blind randomized clinical trial from May 23, 2014, to April 14, 2016, 
with 24 months of treatment and follow-up. This multicenter study in England and 
Scotland involved 32 National Health Service memory clinics within secondary 
specialist services for people with dementia. From 886 screened patients, 554 
patients with a diagnosis of mild AD (Standardised Mini-Mental State Examination 
[sMMSE] score ≥24) were randomized.
INTERVENTIONS: Participants were randomly allocated 1:1:1 in a semifactorial 
design to receive minocycline (400 mg/d or 200 mg/d) or placebo for 24 months.
MAIN OUTCOMES AND MEASURES: Primary outcome measures were decrease in sMMSE 
score and Bristol Activities of Daily Living Scale (BADLS), analyzed by 
intention-to-treat repeated-measures regression.
RESULTS: Of 544 eligible participants (241 women and 303 men), the mean (SD) age 
was 74.3 (8.2) years, and the mean (SD) sMMSE score was 26.4 (1.9). Fewer 
participants completed 400-mg minocycline hydrochloride treatment (28.8% [53 of 
184]) than 200-mg minocycline treatment (61.9% [112 of 181]) or placebo (63.7% 
[114 of 179]; P < .001), mainly because of gastrointestinal symptoms (42 in the 
400-mg group, 15 in the 200-mg group, and 10 in the placebo group; P < .001), 
dermatologic adverse effects (10 in the 400-mg group, 5 in the 200-mg group, and 
1 in the placebo group; P = .02), and dizziness (14 in the 400-mg group, 3 in 
the 200-mg group, and 1 in the placebo group; P = .01). Assessment rates were 
lower in the 400-mg group: 68.4% (119 of 174 expected) for sMMSE at 24 months 
compared with 81.8% (144 of 176) for the 200-mg group and 83.8% (140 of 167) for 
the placebo group. Decrease in sMMSE scores over 24 months in the combined 
minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). 
The combined minocycline group had mean sMMSE scores 0.1 points higher than the 
placebo group (95% CI, -1.1 to 1.2; P = .90). The decrease in mean sMMSE scores 
was less in the 400-mg group than in the 200-mg group (3.3 vs 4.7 points; 
treatment effect = 1.2; 95% CI, -0.1 to 2.5; P = .08). Worsening of BADLS scores 
over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 
200-mg group, and 6.2 in the placebo groups (treatment effect for minocycline vs 
placebo = -0.53; 95% CI, -2.4 to 1.3; P = .57; treatment effect for 400 mg vs 
200 mg of minocycline = -0.31; 95% CI, -0.2 to 1.8; P = .77). Results were 
similar in different patient subgroups and in sensitivity analyses adjusting for 
missing data.
CONCLUSIONS AND RELEVANCE: Minocycline did not delay the progress of cognitive 
or functional impairment in people with mild AD during a 2-year period. This 
study also found that 400 mg of minocycline is poorly tolerated in this 
population.
TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN16105064.