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

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 efective 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 defned polyphenol that acts by multimodal specifc mechanisms. Our group previously showed that genistein supplementation is efective to treat the double transgenic (APP/PS1) AD animal model. Methods: In this double-blind, placebo-controlled, bicentric clinical trial, we evaluated the efect of daily oral supplementation with 120 mg of genistein for 12 months on 24 prodromal Alzheimer’s disease patients. The amyloidbeta deposition was analyzed using 18F-futemetamol 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 signifcant 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 signifcant 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.This work was supported by the following grants: CB16/10/00435 (CIBERFES) from Instituto de Salud Carlos III, (PID2019-110906RB-I00/ AEI/10.13039/501100011033) and RED2018-102576-T from the Spanish Ministry of Innovation and Science, PROMETEO/2019/097 from “Consellería de Innovación, Universidades, Ciencia y Sociedad Digital de la Generalitat Valen ciana” and EU Funded H2020- DIABFRAIL-LATAM (Ref: 825546), European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL) and of the ERA-NET Cofund ERA-HDHL (GA N° 696295 of the EU Horizon 2020 Research and Innovation Programme) and Fundación Ramón Areces y Fundación Soria Melguizo. to J.V. and Grant PID2020-113839RB-I00 funded by MCIN/ AEI/10.13039/501100011033, PCIN-2017-117 of the Ministry of Economy and Competitiveness, and the EU Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (JPI HDHL INTIMIC-085) to CB. We also acknowledge funding from the Spanish Ministry of Science, Innovation, and Universities (RTI2018099200-B-I00), the Generalitat of Catalonia, Agency for management of University and Research Grants (2017SGR696) and the Department of Health (SLT002/16/00250) to RP. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-fnanced with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). M.J. is a “Serra Hunter” Fellow