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Published on: March 11, 2021
Low-dose ladostigil for mild cognitive impairment: A phase 2 placebo-controlled clinical trial
Lon S Schneider1, Yona Geffen2, Jonathan Rabinowitz2
1From the Keck School of Medicine of the University of Southern California (L.S.S.), Los Angeles; Avraham Pharmaceuticals, Ltd (Y.G.), Yavne; Bar Ilan University (J.R.), Ramat Gan, Israel; University of California (R.G.T.), San Diego; Department of Neurology (R.S., S.R.), Medical University, Graz, Austria; and Hebrew University (M.W.), Jerusalem, Israel. lschneid@usc.edu.
Objective:
Ladostigil reduces oxidative stress and microglial activation in aging rats. We assessed its safety and potential efficacy in a 3-year, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild cognitive impairment (MCI) and medial temporal lobe atrophy.
Methods:
Patients 55 to 85 years of age with MCI, Clinical Dementia Rating (CDR) score of 0.5, Mini-Mental State Examination (MMSE) score >24, Wechsler Memory Scale-Revised Verbal Paired Associates I score ≤18, and Medial Temporal Lobe Atrophy Scale score >1 were stratified by APOE ε4 genotype and randomly assigned (1:1) to ladostigil 10 mg/d or placebo. Primary outcomes were safety and onset of Alzheimer disease dementia. Secondary endpoints were Neuropsychological Test Battery (NTB) composite, Disability Assessment in Dementia (DAD), and Geriatric Depression Scale (GDS) scores. Exploratory outcomes were NTB component, CDR, and MMSE scores. Biomarkers included MRI-derived whole-brain, hippocampus, and entorhinal cortex volumes.
Results:
Two hundred ten patients from 15 sites in Austria, Germany, and Israel were randomly allocated to placebo (107 patients) or ladostigil (103 patients). After 36 months, 21 of 103 patients on placebo and 14 of 99 patients receiving ladostigil progressed to Alzheimer disease (log-rank test p = 0.162). There were no significant effects on the NTB composite, DAD, or GDS score. Whole-brain and hippocampus volumes decreased more in the placebo than in the ladostigil group (whole brain, p = 0.025, Cohen d = 0.43; hippocampus, p = 0.043, d = 0.43). Serious adverse events were reported by 28 of 107 patients treated with placebo and 26 of 103 with ladostigil.
Conclusion:
Ladostigil was safe and well tolerated but did not delay progression to dementia. Its association with reduced brain and hippocampus volume loss suggests a potential effect on atrophy.
Clinicaltrialsgov Identifier:
NCT01429623.
Classification Of Evidence:
This study provides Class II evidence that for patients with MCI and medial temporal lobe atrophy, ladostigil did not significantly decrease the risk of the development of Alzheimer disease.
Insights
Ladostigil, tested in a clinical trial for mild cognitive impairment (MCI), was found to be safe but did not prevent progression to Alzheimer disease dementia. However, it may reduce brain and hippocampus volume loss in these patients.
Area of Science:
- Neuroscience
- Pharmacology
- Gerontology
Background:
- Ladostigil has shown potential in reducing oxidative stress and microglial activation in aging rats.
- Mild cognitive impairment (MCI) and medial temporal lobe atrophy are significant risk factors for Alzheimer disease.
- Assessing novel therapeutic agents for MCI is crucial for neurodegenerative disease prevention.
Purpose of the Study:
- To evaluate the safety and efficacy of ladostigil in patients with MCI and medial temporal lobe atrophy.
- To determine if ladostigil delays the progression to Alzheimer disease dementia.
- To investigate ladostigil's effect on cognitive decline and brain atrophy markers.
Main Methods:
- A 3-year, randomized, double-blind, placebo-controlled phase 2 trial was conducted.
- Patients with MCI (CDR 0.5, MMSE >24) were stratified by APOE ε4 genotype and received ladostigil (10 mg/d) or placebo.
- Primary outcomes included safety and onset of Alzheimer disease dementia; secondary outcomes assessed cognitive and functional measures, with MRI for brain volumes.
Main Results:
- 210 patients were randomized; 103 received ladostigil and 107 received placebo.
- Ladostigil was safe and well-tolerated, with similar rates of serious adverse events compared to placebo.
- No significant delay in progression to Alzheimer disease dementia was observed (log-rank test p=0.162); however, ladostigil was associated with reduced whole-brain and hippocampus volume loss.
Conclusions:
- Ladostigil is a safe and well-tolerated treatment for patients with MCI and medial temporal lobe atrophy.
- The drug did not significantly delay the onset of Alzheimer disease dementia in this trial.
- Observed reductions in brain and hippocampus atrophy suggest a potential neuroprotective effect warranting further investigation.
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