This study evaluates the efficacy and mechanism of internet-based cognitive training in patients with amnestic mild cognitive impairment (aMCI). Half of participants will receive multi-domain adaptive internet-based training program, while the other half will receive a fixed, primary difficulty level task.

Background: Alzheimer's disease (AD) is the most common dementia and the major cause for senile dementia. With the increase of life expectancy, AD has become a global problem. However, to date, drug therapies only have modest benefits for patients with AD. Recently, researchers have begun to focus on early intervention of AD at its preclinical stages. Individuals with amnestic mild cognitive impairment (aMCI), often the prodromal stage of AD, report mild short-term memory difficulties but preserved independence in activities of daily living. The aMCI stage is important to slow or even prevent the development of AD. Some previous studies have suggested cognitive training is a potential non-pharmacological intervention for aMCI, however, the results were inconsistent. Thus, investigators will conduct this multi-center randomized controlled trial to explore whether and how cognitive training improves cognitive function in patients with aMCI.

Objectives: The first aim of this multi-center single-blinded, randomized controlled trial is to assess whether internet-based cognitive training improves cognitive abilities in patients with aMCI. Furthermore, the second objective is to evaluate the effect of cognitive training on neural plasticity, including brain activation and white matter integrity, which are assessed by functional and structural MRI.

Patients and Methods: The study will include 260 patients diagnosed with aMCI from eight centers around China. The patients will be randomized to either a cognitive training group or an active-control group. The intervention is 12-week internet-based cognitive training performed for 40 minutes per day, 4 days a week. Within each task, high accuracy (80%) is required to upgrade to the next difficulty level. The active- control group will receive five processing speed and attention tasks, whose duration also total to 40 min each training day. However, these tasks are set to a fixed, primary difficulty level across the study.

Neuropsychological assessments and structural and functional magnetic resonance imaging (MRI) will be performed at the baseline, end of intervention, and 6 months after randomization to measure long-term resilience of the effect.

Relevance: Early intervention of aMCI has the potential to delay or even prevent the development of dementia. Some previous studies have suggested cognitive training is a potential non-pharmacological intervention for aMCI, however, the results were inconsistent. Thus, the proposed study is to determine the efficacy of cognitive training in patients with aMCI. Secondly, using functional and structural MRI, this study is to reveal the potential mechanisms underlying cognitive training.

Inclusion Criteria:

1. Literate Han Chinese, 50-85 years of age with a caregiver that accompanies the subject consistently at least 4 days a week;
2. Complaint and/or informant report of a cognitive impairment lasting for at least 3 months;
3. Clinical diagnosis of MCI according to the MCI core clinical criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines;
4. A prominent manifestation of memory deficit with or without other cognitive domain impairments;
5. Mini-Mental State Examination (MMSE) score ≥24, and Clinical dementia rating (CDR) = 0.5, and
6. Normal or slightly impaired activities of daily living as defined by a total score of ≤ 1.5 on the three functional CDR domains (home and hobbies, community affairs, and personal care).

Exclusion Criteria:

1. Severe aphasia, physical disabilities, or any other disease that may preclude completion of neuropsychological testing;
2. A medical history of stroke with focal neurological features including hemiparesis, sensory loss, visual field deficits, and evidence of responsible lesions on MRI;
3. Significant white matter lesions (Fazekas score = 3-6);
4. Disorders other than aMCI that may affect cognition;
5. Depression or other psychiatric disorders;
6. Clinically significant gastrointestinal, renal, hepatic, respiratory, infectious, endocrine, or cardiovascular diseases, cancer, alcoholism, drug addiction;
7. Use of medications that may affect cognitive functioning, including tranquilizers, anti-anxiolytics, hypnotics, nootropics, and cholinomimetic agents;
8. Inability to undergo a brain MRI; and
9. Other conditions that in the investigator's opinion might not be suitable for the study.