A multimodal lifestyle intervention complemented with epigallocatechin gallate to prevent cognitive decline in APOE- ɛ4 carriers with Subjective Cognitive Decline: a randomized, double-blinded clinical trial

Background: The potential of dietary compounds to enhance the effects of multimodal lifestyle interventions (MLIs) on cognition in individuals at high risk of cognitive impairment remains unclear.

Objectives: To assess whether the addition of a green tea extract enriched with epigallocatechin-3-gallate (EGCG) enhances the effects of an MLI.

Design: Double-blind, randomized, two-arm, and placebo-controlled trial. Exploratory comparisons were made with a non-randomized group (NRG) receiving healthy lifestyle recommendations.

Setting: Population-based study conducted in Barcelona, Spain PARTICIPANTS: APOE-ɛ4 carriers aged 60-80 with subjective cognitive decline INTERVENTION: A 12-month intensive MLI including dietary counseling, guided physical activity, and cognitive stimulation, combined with EGCG (5-6 mg/kg) or placebo, followed by a 3-month washout.

Measurements: Primary endpoint was change in the modified Preclinical Alzheimer Cognitive Composite (PACC-exe) score.

Results: 129 participants (65.1% 84 women, aged 66.7±5.5 years) were enrolled (52 MLI+EGCG, 52 MLI+placebo and 25 NRG), with126 (97.7%) included in the modified intention-to-treat analysis. After 12 months, no statistically significant difference was observed between MLI+EGCG and MLI+placebo in the PACC-exe (adjusted mean difference [AMD]: 0.12; 95%CI: -0.01, 0.24; p=0.061). However, participants in the MLI+EGCG group were 2.6 times more likely to show a reliable cognitive improvement. In exploratory analyses following a 3-month washout, the MLI+EGCG group showed significant cognitive benefits compared to the MLI+placebo (AMD: 0.19; 95%CI: 0.06, 0.32; p=0.005). Exploratory comparisons with the NRG also suggested greater gains in cognition and dementia risk reduction in both MLI groups, particularly with EGCG.

Conclusions: While the primary outcome was not met, this proof-of-concept trial suggests that combining MLIs with EGCG warrants further investigation in larger, confirmatory studies.