Genistein effect on cognition in prodromal Alzheimer's disease patients. The GENIAL clinical trial

Abstract

Background: Delaying the transition from minimal cognitive impairment to Alzheimer's dementia is a major concern in Alzheimer's disease (AD) therapeutics. Pathological signs of AD occur years before the onset of clinical dementia. Thus, long-term therapeutic approaches, with safe, minimally invasive, and yet effective substances are recommended. There is a need to develop new drugs to delay Alzheimer's dementia. We have taken a nutritional supplement approach with genistein, a chemically defined polyphenol that acts by multimodal specific mechanisms. Our group previously showed that genistein supplementation is effective to treat the double transgenic (APP/PS1) AD animal model.

Methods: In this double-blind, placebo-controlled, bicentric clinical trial, we evaluated the effect of daily oral supplementation with 120 mg of genistein for 12 months on 24 prodromal Alzheimer's disease patients. The amyloid-beta deposition was analyzed using 18F-flutemetamol uptake. We used a battery of validated neurocognitive tests: Mini-Mental State Exam (MMSE), Memory Alteration Test (M@T), Clock Drawing Test, Complutense Verbal Learning Test (TAVEC), Barcelona Test-Revised (TBR), and Rey Complex Figure Test.

Results: We report that genistein treatment results in a significant improvement in two of the tests used (dichotomized direct TAVEC, p = 0.031; dichotomized delayed Centil REY copy p = 0.002 and a tendency to improve in all the rest of them. The amyloid-beta deposition analysis showed that genistein-treated patients did not increase their uptake in the anterior cingulate gyrus after treatment (p = 0.878), while placebo-treated did increase it (p = 0.036). We did not observe significant changes in other brain areas studied.

Conclusions: This study shows that genistein may have a role in therapeutics to delay the onset of Alzheimer's dementia in patients with prodromal Alzheimer's disease. These encouraging results indicate that this should be followed up by a new study with more patients to further validate the conclusion that arises from this study.

Trial registration: NCT01982578, registered on November 13, 2013.

Keywords: Amyloid-beta cingulate gyrus; Cognitive impairment; Phytoestrogens; Soy isoflavones.

Conflict of interest statement

This was supported exclusively by public funds in Spain and was performed in two public hospitals in Valencia. No private industry support must be disclosed. Genistein-containing pills were bought from commercially available sources that were distributed in the chemist shop system in Spain. Moreover, no non-financial conflicts of interest exist for any of the authors.

© 2022. The Author(s).

Figures

Fig. 1

Enrollment, randomization, allocation, follow-up, and clinical completion

Fig. 2

Plasma genistein concentration at baseline and after 12 months of genistein treatment. Boxes show adjusted means while confidence intervals are represented with error bars of n = 12–13 individuals

Fig. 3

Genistein effects on cognitive tests. Interaction plot between treatment and time for dichotomized Centil REY Delayed copy test

Fig. 4

Punctuations evolution at 6 and 12 months of genistein or placebo treatment. Results of interaction plot between treatment and time points (baseline and 6–12 months after treatment) using a linear mixed model for Mini-Mental State Exam (MMSE, MEC) (A), Memory Alteration Test (M@T) (B), Clock-Drawing Test (C), Complutense Verbal Learning Test (direct TAVEC) (D), Complutense Verbal Learning Test (delayed TAVEC) (E), Barcelona Test-Revised (TBR) (F), Barcelona Test-Revised (TBR) phonological (G), Rey Complex Figure Test (direct copy) (H), and Rey Complex Figure Test (Centil copy) (I). Red lines correspond to genistein-treated patients and black lines to placebo-treated patients. Tukey adjusted the p-value for comparison between treatments at 12 months (details of the meaning of each test are in the method section)