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Randomized Controlled Trial
. 2022 Nov 4;14(1):164.
doi: 10.1186/s13195-022-01097-2.

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

José Viña  1 , Joaquín Escudero  2 , Miquel Baquero  3 , Mónica Cebrián  1 , Juan Antonio Carbonell-Asíns  4 , José Enrique Muñoz  5 , Encarnación Satorres  6 , Juan Carlos Meléndez  6 , José Ferrer-Rebolleda  7 , Mª Del Puig Cózar-Santiago  7 , Jose Manuel Santabárbara-Gómez  7 , Mariona Jové  8 , Reinald Pamplona  8 , Francisco José Tarazona-Santabalbina  9 , Consuelo Borrás  10
Affiliations
Randomized Controlled Trial

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

José Viña et al. Alzheimers Res Ther. .

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.

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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.

Figures

Fig. 1
Fig. 1
Enrollment, randomization, allocation, follow-up, and clinical completion
Fig. 2
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
Fig. 3
Genistein effects on cognitive tests. Interaction plot between treatment and time for dichotomized Centil REY Delayed copy test
Fig. 4
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)
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