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

Study Overview
=================
Brief Summary
-----------------
Alzheimer's disease (AD) neuropathology is characterized by deposits of insoluble amyloid β-peptide (Aβ) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. Current knowledge, has allowed a shift in the definition of AD from a syndromal to a biological construct, based on biomarkers that are proxies of pathology. However, little is known about mechanisms underlying the disease progression at its early stages. The loss of dendritic spines, the primary locus of excitatory synaptic transmission in the mammalian central nervous may be linked to cognitive and memory impairment in AD: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD). In humans, alterations in functional connectivity (FC) have been observed in early AD stages, subjective cognitive decline (SCD) and mild cognitive impairment (MCI). A hyper-synchronized anterior network and a posterior network characterized by a decrease in FC are the spatial features. These disruptions also seen in AD indicate that FC alterations appear very early in the course of the disease . Experimental research strongly suggests that in order to increase our cerebral reserves, we have to follow a lifestyle that takes into account many factors. Clinical studies provided evidence that individuals with more cerebral reserves are those who have a high level of education, who maintain regular physical activity and who eat in a healthy way. The environmental enrichment (EE) animal models confirmed that the experience plays a key role in increasing brain plasticity phenomena .There is a growing understanding that a valid therapeutic emerging approach in AD is prevention. A large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that primary prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. The therapeutic approach proposed in the present project aims at improving synaptic plasticity and functional connectivity in early stages of AD, and specifically in SCD in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. In this context the proposed clinical trial design will evaluate the efficacy of EGCG in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. Early phase I studies in Down syndrome young adults showed that while subjects were under EGCG, improvements in cognition were observed but these vanished when treatment was discontinued. Phase II studies combining EGCG with cognitive training showed improvements in cognitive performance and adaptive functionality but interestingly sustained effects after treatment discontinuation. Observations made in humans are in agreement with preclinical studies showing that EGCG combined with environmental enrichment resulted in an improvement of age-related cognitive decline. These observations are in favor of the option of combining EGCG with a personalized multimodal intervention. The personalized multimodal intervention will take into account medical comorbidities (i.e. metabolic syndrome, T2DM), diet (including nutritional status), physical exercise, and will incorporate cognitive training and a behavioral intervention to aid subject's adherence and empowerment to the intervention proposed. This will be in-line with other clinical studies in AD showing the superiority of multimodal interventions vs. a single life style intervention (i.e. single nutrient, physical activity). Hypothesis: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD).

Detailed Description
-----------------
Study Design: Randomized, double-blind, personalized clinical trial with 200 subjects with subjective cognitive decline (SCD) of both genders, with 4 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): To evaluate several underlying mechanisms that could explain the efficacy of the intervention in preventing the progression of cognitive decline: (i) changes in gut microbiota composition and in the metabolome derived by the action of microorganisms, (ii) changes in AD biomarkers (iii) changes in biomarkers of oxidation/inflammation Target Population: Subjects (approximately 200) diagnosed of Subjective Cognitive Decline (SCD), carriers of the Apolopoprotein E4 allele, fulfilling at least 3 additional SCD plus score (at least 5 criteria) recruited either from Hospital del Mar and its primary care provider or from Barcelona Beta Brain Research Centre. Preselection criteria i.Adults aged 60-80 years with a BMI ≥18.5 and <32 kg/m2. ii.Subjective Cognitive Decline Questionnaire (SCD-Q) items 1 and 3 positive. (BBRC) iii.Subjects willing to participate and to perform all study procedures, including Apolipoprotein E4 genotyping iv.Subject has one informant partner who, in the investigator's judgment has frequent and sufficient contact with the subject as to be able to provide accurate information about subject's cognitive and functional abilities. Study Arm(s): 1. Arm I: EGCG and a multimodal intervention (n=50) 2. Arm II: Placebo EGCG and a multimodal intervention (n=50) 3. Arm III: EGCG and healthy lifestyle recommendations (n=50) 4. Arm IV: Placebo EGCG and healthy lifestyle recommendations (n=50) Duration of Patient Participation: The total duration of the patient participation is expected to be 16 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 520 mg/day will be administered to subjects for 12 months or matched placebo Multimodal intervention (12 months): 1) Cognitive stimulation, guided group activities once per month; 2) Cognitive training, twice per week 30-45min sessions; 3) Psychoeducational support groups, 10 sessions, 4) personalized diet 8 sessions, 5) personalized physical activity. End point The preclinical Alzheimer cognitive composite ADCS-PACC-Plus-exe

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

Conditions
-----------------
Alzheimer Disease, Nutritional Intervention, Cognitive Function

Intervention / Treatment
-----------------
* Dietary Supplement: EGCG
* Dietary Supplement: Placebo EGCG
* Other: Personalized intervention
* Other: Lifestyle recommendations


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: * Meet all selection criteria and none exclusion criteria. Fulfill SCD criteria (113) including cognitive performance within normal values* (adjusted for age and education). At least SCD-Q items 1 and 3 positives. Age between 60 and 80 with a BMI ≥18.5 and <32 kg/m2. Carrying the ApoE4 allele.*. Fulfilling 2 additional SCD plus features from the ones listed below: memory-centered*, onset of symptoms within the last 5 years*,, corroborated by an informant*, concern about cognitive decline* and perception of lower performance compared with same age group* (criteria marked with* are among those proposed features for SCD-plus syndrome which may point to participants with a greater risk of AD pathology). Participants willing to participate and to perform all study procedures. *: Normal scoring on psychometric evaluation. Exclusion Criteria: Inability or unwillingness to give written informed consent or communicate with the study staff or illiteracy. Clinically significant unstable psychiatric disorder that may affect cognition (e.g. major depression disorder, schizophrenia, bipolar or psychotic disorder according to diagnostic and statistical manual of mental disorders fifth edition ) Neurological conditions that may affect cognition or may imply an early stage of neurodegenerative disease other than AD (i.e. cranioencephalic trauma with permanent neurologic effects, epilepsy, multiple sclerosis, previous stroke, extrapyramidal signs at physical exploration, history of brain tumor...). History or evidence of any medical condition or use of medication that in the opinion of the investigator could affect subjects' safety or interfere with the study assessments (e.g. use of neuroleptic drugs, corticosteroids or immunosuppressive therapies that may affect inflammatory parameters). Any contraindication to perform Lumbar Puncture procedure (e.g. platelet count <100.000/ml, lumbar spine deformity, anticoagulant treatment). Any contraindication to perform brain MRI procedure (e.g. pacemaker, MRI-incompatible aneurysm clips). Current intake of vitamin supplements, catechins or products containing EGCG (i.e. , Mega Green Tea capsules Life Extension or Font-UP Grand Fontaine Laboratories) for at least 3 months previous to the screening visit.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Arm I: EGCG and a multimodal intervention (n=50) Arm II: Placebo EGCG and a multimodal intervention (n=50) Arm III: EGCG and healthy lifestyle recommendations (n=50) Arm IV: Placebo EGCG and healthy lifestyle recommendations (n=50)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>EGCG + multimodal intervention (n=50) Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day) + personalized intervention | Dietary Supplement: EGCG<br>* Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up). Participants that weight <50kg intake one oral dose in the morning for breakfast (266 mg/EGCG, 49 of Font-up<br>Other: Personalized intervention<br>* A personalized intervention include a physical activity plan,dietary intervention, mental health promotion interventions,<br>|
| Active Comparator: 2<br>Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day) non personalized intervention | Dietary Supplement: EGCG<br>* Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up). Participants that weight <50kg intake one oral dose in the morning for breakfast (266 mg/EGCG, 49 of Font-up<br>Other: Lifestyle recommendations<br>* The recommendations are to balance caloric intake and physical activity to achieve and maintain a healthy body weight; consume a diet rich in vegetables and fruits;<br>|
| Placebo Comparator: 3<br>Placebo Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day) + personalized intervention | Dietary Supplement: Placebo EGCG<br>* Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up)<br>Other: Personalized intervention<br>* A personalized intervention include a physical activity plan,dietary intervention, mental health promotion interventions,<br>|
| Sham Comparator: 4<br>Placebo Font-Up 49 to 98 gr Font-up (260-520mg EGCG)/day (If participant weight is ≤ 50kg will take 1 sachet each day, if participant weight is >50kg will take 2 sachets each day) non personalized intervention | Dietary Supplement: Placebo EGCG<br>* Participants that weight >50kg intake one oral dose in the morning for breakfast and a second dose in the afternoon in (266 + 266 mg/EGCG, 49 + 49 g of Font-up)<br>Other: Lifestyle recommendations<br>* The recommendations are to balance caloric intake and physical activity to achieve and maintain a healthy body weight; consume a diet rich in vegetables and fruits;<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preclinical Alzheimer Cognitive Composite- Plus-exe like score (ADCS-PACC-like) | Changes in Alzheimer's cognitive compound score plus a PACC-like score (ADCS-PACC). that includes The Total Recall score from the Free and Cued Selective Reminding Test (FCSRT) (which range from 0-48 words),The Delayed Recall score on the Logical Memory IIa subtest from the Wechsler Memory Scale (which range from 0-25 story units), The Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale-Revised (which range from 0-93 symbols), The MMSE total score (which range from 0-30 points).Each of the component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite. Thus, change off 0.5 ADCS-PACC units will be significative | Screening, 6, 12 and 15 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Functional neuronal connectivity (assessed by a functional magnetic resonance imaging) | Changes in Maps of change in connectivity of the Default mode network Changes in Maps of change in connectivity of the Limbic network Changes in Maps of change in connectivity of the Salience network | Screening and 12 months. | 
| Changes in structural connectivity networks known to be affected in Alzheimer Disease | Changes in Connectivity changes of the parahippocampus/fornix Changes in Connectivity changes of the cingulum/cingulate fiber bundle Changes in connectivity changes of the caudate heads | Screening and 12 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EGCG Epigallocatechin gallate,, Dietary supplement, personalized medicine,, Subjective Cognitive Complaints (SCD), Apolipoprotein E4