Larger, More Controlled Studies Needed to Confirm Genistein’s Potential to Curve Alzheimer Cognition

A meta-analysis presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31, in Toronto, Canada, highlighted the therapeutic potential of genistein, a soy-derived isoflavone, to improve cognitive function and reduce amyoid-ß (Aß) deposition in prodromal Alzheimer disease (AD). The analysis included only 3 studies, reinforcing the need for larger studies with standardized protocols to validate genistein’s treatment potential.

Led by Kevin Gustavo dos Santos Silva, an undergraduate student at the University of São Paulo, in Brazil, the review searched through Medline and Lilacs databases, identifying trials that evaluated genistein in patients diagnosed with prodromal AD according to standardized criteria. The 3 studies included a 2015 trial by Carey Gleason et al, the GENIAL trial published in 2022, and a 2020 retrospective pilot study of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline.

Each trial differed slightly, but highlighted the potential of genistein as a potential target for AD treatment. Previous research has shown that genistein has multitarget actions relevant to AD, including weak estrogen-receptor-ß agonism, broad tyrosine-kinase inhibition, antioxidant/anti-inflammatory effects, and autophagy/mTOR pathway modulation. In addition, it crosses the blood-brain barrier (limitedly) and is typically given as the aglycone to improve bioavailability.

The 2015 trial included 65 men and women over the age of 60 who were treated with 100 mg/day soy isoflavones, or matching placebo capsules for 6 months. About half (47.7%) of the cohort were positive for apolipoprotein e4. All told, the study found no significant differences in treatment effects for cognition between the treatment groups or genders. Despite this, exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency, suggesting the need to reexamine the role of isoflavone mechanism.2

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The second study, the GENIAL trial, was a double-blind, placebo-controlled, bicentric clinical trial that tested daily oral supplementation with 120 mg of genistein for 12 months on 24 patients with prodromal AD. At the conclusion of the treatment period, investigators reported a significant improvement among genistein-treated patients in 2 of the tests used: dichotomized direct Complutense Verbal Learning Test (TAVEC; P = .031) and dichotomized delayed Centil REY copy (P = .002).³

Patients in the study also reported improvements in other neurocognitive tests such as Mini-Mental State Exam, Memory Alteration Test, Clock Drawing Test, and Barcelona Test-Revised. In addition, the Aß deposition analysis revealed that those on genistein did not increase their uptake in the anterior cingulate gyrus after treatment (P = .878), while placebo-treated patients showed increases (P = .036).

The final study included in the AAIC poster looked at PhytoSERM, a selective estrogen receptor beta modulator of 3 phytoestrogens: genistein, daidzein, and S-equol. The retrospective analysis, published in 2020, included 46 participants who were randomly assigned to placebo (n = 16) or 2 doses of PhytoSERM (50 mg/day: n = 18; 100 mg/day: = n = 12). While the study was not powered for efficacy analysis, results showed that 50 mg daily of PhytoSERM preserved cognitive function in certain aspects of verbal learning and executive function. Notably, the study suggested that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response.⁴

Overall, genistein has been seen as a biologically plausible, low-cost, multitarget candidate with suggestive but inconclusive early human signals. Many in the field, including Gustavo dos Santos Silva et al point out that there needs to be more adequately powered, longer randomized controlled trials with harmonized cognitive and biomarker end points.

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REFERENCES
1. Gustavo dos Santos Silva K, Souza VF, Alves GLF, Oliveira CR. Genistein as a Therapeutic Agent in the Prodromal Phase of Alzheimer's Disease:Systematic Review. Presented at: AAIC 2025; July 27-31; Toronto, Canada. ABSTRACT 103969
2. Gleason CE, Fischer BL, Dowling NM, et al. Cognitive Effects of Soy Isoflavones in Patients with Alzheimer's Disease. J Alzheimers Dis. 2015;47(4):1009-19. doi:10.3233/JAD-142958
3. Viña J, Escudero J, Baquero M, et al. Genistein effect on cognition in prodromal Alzheimer's disease patients. The GENIAL clinical trial. Alzheimers Res Ther. 2022;14(1):164. doi:10.1186/s13195-022-01097-2.
4. Wang Y, Hernandez G, Mack WJ, Schneider LS, Yin F, Brinton RD. Retrospective Analysis of PhytoSERM for Management of Menopause-Associated Vasomotor Symptoms and Cognitive Decline: A Pilot Study on Pharmacogenomic Effects of Mitochondrial Haplogroup and APOE Genotype on Therapeutic Efficacy. Menopause. 2020;27(1):57-65. doi:10.1097/GME.0000000000001418