Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention

Study Design: Randomized, double‐blind, personalized clinical trial with 150 subjects with subjective cognitive decline (SCD) of both genders, with 3 arms of treatment Duration of the Study: The total duration of the study is expected to be 24 months (subject recruitment, baseline period, treatment period, follow‐up, data analysis, and study report). Primary Objective(s): To evaluate the efficacy of a multimodal intervention (dietary, physical activity, and cognition) combined with epigallocatechin gallate (EGCG) in slowing down cognitive decline. Secondary Objective(s): 1 To evaluate the safety of the interventions 2 To evaluate several underlying mechanisms that could explain the efficacy of the intervention in preventing the progression of cognitive decline: (i) Changes in brain connectivity, (ii) changes in AD biomarkers, (iii) changes in biomarkers of oxidation/inflammation, (iv) changes in gut microbiota composition and the metabolome derived by the action of microorganisms, v) changes in biological aging predictors. Target Population: Subjects diagnosed with Subjective Cognitive Decline (SCD) criteria including cognitive performance within normal values (Normal scoring on psychometric evaluation, adjusted for age and education), carriers of the Apolipoprotein E4 allele, recruited either from either the Parc de Salut Mar and its primary care providers, from Barcelona Beta Brain Research Centre or through a web‐based system. Preselection criteria i.Adults aged 60‐80 years with a BMI ≥18.5 and <32 kg/m2. ii. Ad‐hoc Subjective Cognitive Decline Questionnaire (SCD‐Q) item "do you perceive memory or cognitive difficulties?" positive. iii. Subjects willing to participate and perform all study procedures, including Apolipoprotein E4 genotyping iv. The subject has one informant partner who, in the investigator's judgment has frequent and sufficient contact with the subject to provide accurate information about the subject's cognitive and functional abilities. Study Arm(s): 1. Arm I: EGCG and multimodal intervention (n=50) 2. Arm II: Placebo EGCG and multimodal intervention (n=50) 3. Arm III: Healthy lifestyle recommendations (n=50) Duration of Patient Participation: The total duration of patient participation is expected to be 17 months. Run‐in period (1 month): Basal assessment of cognitive performance (cognitive battery), diet and physical activity, daily living activities (self‐reported tests), and mood (self‐reported tests at basal assessment and EMA's). Interventions will last 12 months. Follow‐up after intervention discontinuation: at least 3 months Treatment: EGCG (Font‐UP, laboratories Grand Fontaine), a daily dose of approximately 5‐6 mg/kg up to 500 mg/day will be administered to subjects for 12 months or a matched placebo Multimodal intervention (12 months): 1) Social stimulation, ten 90‐120 minutes guided group activities; 2) Cognitive training, trice per week, 30‐minute sessions; 3) Psychoeducational support groups, 10 sessions, 4) personalized diet 8 sessions, 5) personalized physical activity. End point: modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS‐PACC), including additional tests of executive functions: the PACC‐exe.