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

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).

Conditions

• Alzheimer Disease
• Cognitive Decline

Interventions

DIETARY_SUPPLEMENT

EGCG

FontUp capsules (100 mg of EGCG each) 12 months, three to five capsules per day (participant's weight ≤ 50kg: 3 capsules/day; weight \>50kg: 5 capsules/day.

DIETARY_SUPPLEMENT

Placebo EGCG

Placebo FontUp (same appearance as active). 12 months, three to five capsules per day (participant's weight ≤ 50kg: 3 capsules/day; weight \>50kg: 5 capsules/day.

OTHER

Healthy lifestyle recommendations

Personalized advice on diet, physical activity, cognitive training, and social stimulation activities.

OTHER

Multimodal lifestyle intervention

* Dietary intervention: personalized dietary recommendations based on MedDiet, 9 individual counseling sessions. * Physical activity intervention: Guided gymnasium (aerobic, strength, and balance activities). Minimum one class/week the first 6months, and two classes/week from month 7 to 12). Achieve a physically active lifestyle (10,000 steps/day; individuals living with disability 8,500 steps/day). Achieve moderate physical exercise in older adults (150 to 210 minutes/week or 90 to 150 minutes depending on medical history. * Cognitive training: NeuronUP, 3/week, 30 min sessions * Psychoeducation: ten 90-minute sessions * Social stimulation activities: ten to twelve 90-to-120-minute sessions.

Sponsors & Collaborators

• Hospital del Mar Research Institute

  collaborator UNKNOWN

• Barcelonabeta Brain Research Center, Pasqual Maragall Foundation

  collaborator OTHER

• Parc de Salut Mar

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

TRIPLE

Model

CROSSOVER

Eligibility

Min Age

60 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2019-10-30

Primary Completion

2023-03-29

Completion

2023-06-28

Countries

• Spain

Study Locations