Background

EGCG is a polyphenolic flavonoid extracted from green tea leaves and widely considered to be the key bioactive ingredient of green tea. It has been reported to have beneficial effects ranging from antitumor and anti-inflammatory to neuroprotective. EGCG has been reported to affect multiple biological pathways, such as gene expression, growth-factor-mediated signaling, mitogen-activated-protein kinase-dependent pathways, antioxidant pathways, and ubiquitin/proteasome degradation. Specifically in neurodegeneration research, EGCG has been proposed to inhibit the formation of toxic oligomers by steering misfolded Aβ, α-synuclein, and mutant huntingtin away from folding pathways that lead to amyloidogenic β-sheet structures, either by binding the protein directly or possibly by acting on a protein chaperone (May 2008 news). EGCG has also been proposed to increase α-secretase cleavage of the amyloid precursor protein, and to improve the cognitive, synaptic, inflammatory, and metabolic phenotypes of multiple different strains of APP/PS1 transgenic mouse model (Obregon et al., 2006; Bao et al., 2020; Ettcheto et al., 2020).

EGCG's effects are consistently reported in vitro. In vivo, however, EGCG is unstable. Its bioavailability in target tissues has been questioned, and efforts to develop synthetic analogs with stronger pharmacological drug properties are underway (Mereles and Hunstein, 2011; Landis-Piwowar et al., 2013).

Findings

More than 60 trials on various EGCG extracts and formulations have been conducted or are ongoing, the majority on various types of cancer. 

In Alzheimer's disease, one Phase 2/3 study conducted at Charite University in Berlin compared 18 months of treatment with EGCG to placebo in one group of patients who also took donepezil and another group who did not. The trial enrolled 21 early stage patients and measured change on the ADAS-cog battery as the primary outcome. The trial started in October 2009 and was completed in February 2015. No results have been published. 

In 2012, a Phase 2 trial began at the Parc de Salut Mar Hospital in Barcelona. It assessed the effect of 12 months of treatment with EGCG on various cognitive outcomes and plasma Aβ biomarkers in 84 people with Down's syndrome, age 14 to 29, to assess whether EGCG slows the development of AD-like symptoms and biomarkers in Down's. Secondary outcomes include further cognitive and brain imaging tests, among others. Participants who received ECGC and cognitive training did significantly better on tests of memory, executive function, and attention than those who did cognitive training only. Amyloid biomarkers were not reported due to technical problems with measurement (de la Torre et al., 2012; de la Torre et al., 2016).

In January 2014, a Phase 3 trial ramped up at Ludwig Maximilians Universität and Technische Universität, both in Munich, to evaluate EGCG in multiple-system atrophy. MSA is a rapidly progressing Parkinsonian disease that responds poorly to dopaminergic therapy and for which there is no effective therapy. In this trial, 92 patients with clinically possible or probable MSA took high-dose EGCG (1.2 g per day, equivalent to 50 cups of green tea) for one year and were compared with patients on placebo on the Unified MSA Rating Scale (UMSARS-ME) and other clinical and neuroimaging outcomes (Levin et al., 2016). According to results presented at the April 2020 AAT-AD/PD conference, the treatment had no effect on the primary readout, and led to liver damage in some participants.

In October 2019, investigators in Barcelona, Spain, began a trial to test the ability of a one-year multimodal intervention including ECGC to prevent cognitive decline in ApoE4 carriers with subjective cognitive impairment. The study will enroll 200 participants in four arms, who will receive ECGC or placebo along with a program of social activities, cognitive training, and personalized diet and exercise, or ECGC or placebo with lifestyle recommendations only. The maximum ECGC dose will be 520 mg per day. The primary outcome is a Preclinical Alzheimer’s Cognitive Composite-like battery. Secondary outcomes are brain connectivity measured by functional MRI; exploratory endpoints include changes in microbiota, plasma, saliva and urine metabolomics, additional cognitive markers, and AD-related biomarkers of Aβ and tau. Treatment is scheduled to run through December 2020.

EGCG has also been evaluated in multiple sclerosis, Huntington's disease, and Fragile X, as well as in many non-neurological conditions. For all clinical trials of EGCG, see clinicaltrials.gov.