Minocycline at 2 Different Dosages vs Placebo for Patients With Mild Alzheimer Disease

Abstract

; for the Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group 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 Ն24) 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...

Minocycline-induced microbiome alterations predict cafeteria diet-induced spatial recognition memory impairments in rats

“…In terms of the translatability of these finding, minocycline is currently under investigation as adjunctive therapy for Alzheimer's disease 68 , schizophrenia 69 and multiple sclerosis 70 with mixed results. While some studies report superiority over placebo, for instance in a metanalysis of adjunctive minocycline for schizophrenia 71 , others report little or no therapeutic benefit as well as issues of tolerability of a higher 400 mg dose 68 . Future work determining whether minocycline provides the same cognitive benefits to people with obesity as observed in these rodent studies, as well as investigations into long-term cognitive rescue, are warranted.…”

Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases

“…However, findings about minocycline's effects in animal models of AD and TBI have been mixed, ranging from beneficial to harmful (Garwood et al , ; Ferretti et al , ; Yang et al , ; Scott et al , ). Minocycline also did not delay the progression of cognitive impairment in people with mild AD over a 2‐year period (Howard et al , ). These results suggest that more specific targets of microglia or astrocytes are required to alleviate cognitive impairment without also triggering side effects.…”

Potential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer’s Disease

“…In humans, unfortunately, a recent randomized clinical trial reported that 24 months of minocycline treatment did not delay the progression of cognitive or functional impairment in patients with mild AD [106]. The authors speculated that the absence of clinical benefits in this trial could be ascribed to (i) the potentially lesser pathological significance of neuroinflammation in mild AD, (ii) potentially insufficient doses of minocycline to afford efficacy (of note, this agent would not result in apparent benefits even if higher doses were used, because of its tolerability), and (iii) potential clinical benefits that would be too small for detection [106]. In addition to minocycline, there is an emerging list of factors with therapeutic potential, including taxifolin [4,57], ω-3 polyunsaturated fatty acids [107,108], oxytocin [109,110], and exercise [111,112]; therefore, concurrent treatment might be beneficial, as suggested recently [113].…”

“…Minocycline exerts inhibitory effects on microglial activation, thereby leading to neuroprotection and suppression of cognitive impairment in a mouse model of CAA [101,104] and AD [102,103,105]. In humans, unfortunately, a recent randomized clinical trial reported that 24 months of minocycline treatment did not delay the progression of cognitive or functional impairment in patients with mild AD [106]. The authors speculated that the absence of clinical benefits in this trial could be ascribed to (i) the potentially lesser pathological significance of neuroinflammation in mild AD, (ii) potentially insufficient doses of minocycline to afford efficacy (of note, this agent would not result in apparent benefits even if higher doses were used, because of its tolerability), and (iii) potential clinical benefits that would be too small for detection [106].…”