Accepted for/Published in: JMIR Research Protocols
Date Submitted: Apr 13, 2026
Date Accepted: Sep 28, 2026
Protocol Effects of Supplementation with Genistein on the Progression of Cognitive Decline in Patients with Mild Cognitive Impairment due to Alzheimer’s disease: Protocol for a Randomized Controlled Trial
ABSTRACT
Background:
Mild cognitive impairment (MCI) is considered a prodromal stage of dementia, and delaying the transition of MCI to Alzheimer’s disease is a focus of increasing research. Anti-amyloid therapies in subjects with MCI have provided inconsistent results, and there is a need to explore further therapeutic alternatives. Genistein, a naturally occurring phytoestrogenic isoflavone, is characterized by pharmacological multimodality and exerts simultaneous effects on multiple pathogenetic pathways of MCI and Alzheimer’s disease. We previously showed that genistein reverses cognitive decline in the APP/PS1 model of Alzheimer’s disease. It also lowers the amyloid β levels in the brain. (1)
Objective:
The aim of this paper is to describe in detail the protocol we intend to use in a clinical trial to determine the effects of oral genistein supplementation on the progression of cognitive decline in patients with MCI to Alzheimer’s disease, compared with placebo.
Methods:
Participants will be patients ≥ 50 years diagnosed with MCI according to criteria of the National Institute on Aging and the Alzheimer’s Association, who will be randomized 1:1 to 200 mg/day of genistein or maltodextrin-based placebo. The follow treatment duration will be 18 months. A battery of neuropsychological tests will be administered at baseline, mid-study, and at the final visit, including the Integrated Alzheimer’s Disease Rating Scale (iADRS) (primary outcome), Clinical Dementia Rating-Sum of Boxes scale, Alzheimer’s Disease Cooperative Study-Activities of Daily Living for Mild Cognitive Impairment (MCI) (ADCS-ADL-MCI) scale, Disability Assessment for Dementia scale, Geriatric Depression Scale-15, Mini-Mental State Examination (MMSE), Complutense Verbal Learning test, Rey-Osterrieth Complex Figure test, Clock Drawing, Digit Span (forward, backward), Trail Making test (parts A and B), and the Frontal Assessment Battery and verbal fluency test. We will also determine amyloid beta load using positron emission tomography with flutemetamol, as well as serum biomarkers of Alzheimer’s disease.
Results:
Recruitment of study centers will be started after approval by the Clinical Research Ethics Committee (CEIm) of the participating centers, with predicted completion of this phase by the end of 2026. The patients’ enrollment period is expected to last approximately 9 months from the first study visit. The follow-up period will extend for 18 months, with an estimated total study duration of 30 months.
Conclusions:
If oral supplementation with genistein can improve different domains of cognitive function and reduce amyloid burden as determined by neuroimaging in patients with MCI due to Alzheimer’s disease, it has the potential to open an innovative and clinically valuable approach in the therapy of MCI. Clinical Trial: NCT07385937
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