Evaluation of the Long-Term Cognitive, Biological, and Lifestyle Effects of a Multimodal Intervention for Preventing Cognitive Decline in APOE-ε4 Carriers With Subjective Cognitive Decline
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 121
- 试验地点
- 1
- 主要终点
- Global Cognitive Performance (PACC-exe Composite Score)
研究概览
简要总结
PENSA+ is a 5-year follow-up study of participants who previously completed the PENSA clinical trial (NCT03978052), which evaluated an intensive multimodal lifestyle intervention, with or without epigallocatechin gallate (EGCG), in APOE-ε4 carriers with subjective cognitive decline, a population at increased risk of developing Alzheimer's disease.
The purpose of this study is to determine whether the cognitive, biological, and lifestyle benefits observed after the original intervention are maintained over the long term. Researchers will evaluate cognitive performance, the incidence of mild cognitive impairment, dementia risk, brain imaging, blood biomarkers, physical fitness, lifestyle behaviors, and psychosocial factors approximately five years after completion of the intervention.
The study will also investigate the biological and behavioral mechanisms associated with sustained cognitive benefit, identify participant characteristics associated with better long-term outcomes, evaluate the long-term cost-effectiveness of the intervention using healthcare utilization data, and explore whether lifestyle changes have influenced participants' study partners. No new intervention will be administered as part of this follow-up study.
详细描述
Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a long preclinical phase during which pathological changes accumulate before the onset of clinical symptoms. This extended asymptomatic period provides an opportunity to implement preventive strategies aimed at delaying or reducing cognitive decline. Multidomain lifestyle interventions targeting modifiable risk factors have emerged as one of the most promising approaches for dementia prevention, demonstrating beneficial effects on cognitive performance and overall brain health, particularly in individuals at increased risk of developing AD. However, the long-term durability of these effects, the biological mechanisms underlying sustained benefit, the characteristics of individuals most likely to respond, and the long-term economic value of these interventions remain incompletely understood.
The PENSA+ study is a long-term follow-up of the PENSA randomized clinical trial (NCT03978052), which evaluated an intensive personalized multimodal lifestyle intervention in cognitively unimpaired APOE-ε4 carriers with subjective cognitive decline. The intervention combined dietary counseling, physical exercise, cognitive training, psychoeducation, social stimulation, and vascular risk management, and was administered with either epigallocatechin gallate (EGCG)-a naturally occurring green tea polyphenol with antioxidant, anti-inflammatory, metabolic, vascular, and potential neuroprotective properties-or placebo. Participants assigned to the control group received general healthy lifestyle recommendations. The original trial demonstrated improvements in cognitive performance, lifestyle behaviors, physical fitness, cardiometabolic health, and dementia risk in the intervention groups, with cognitive and lifestyle benefits persisting beyond the active intervention period. However, whether these benefits are maintained over the longer term and the mechanisms responsible for their persistence remain unknown.
The primary objective of PENSA+ is to evaluate cognitive performance, the incidence of mild cognitive impairment, and dementia risk approximately five years after completion of the original intervention. Secondary objectives are to investigate the biological, behavioral, and psychosocial mechanisms associated with sustained cognitive benefit, identify long-term responder phenotypes, and evaluate the long-term cost-effectiveness and cost-utility of the intervention. Exploratory objectives include assessing long-term clinical outcomes and healthcare resource utilization through electronic health records for up to 10 years after the intervention and evaluating potential spillover effects on participants' study partners.
Participants who completed the original PENSA trial will undergo comprehensive follow-up evaluations, including cognitive, neurological, neuroimaging, biomarker, physical fitness, lifestyle, and psychosocial assessments. Data collected during the original trial will be integrated with the five-year follow-up data to characterize long-term cognitive trajectories, identify determinants of sustained cognitive resilience, and provide evidence on the long-term clinical and economic impact of intensive multidomain lifestyle interventions for Alzheimer's disease prevention.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- Any individual who has completed the PENSA study, does not meet any
排除标准
- •, and provides consent is eligible to participate in this study.
- •Exclusion Criteria
- •Participants will be excluded from the study if they meet any of the following conditions:
- •A prior clinical diagnosis of dementia, regardless of etiology.
- •Current institutionalization (e.g., residence in nursing homes, long-term care facilities, or similar institutions).
- •Impaired decision-making capacity, defined as the inability to provide informed consent independently due to cognitive, legal, or medical reasons (e.g., loss of autonomy or requirement of a legal representative).
- •Current participation in another interventional clinical trial, or participation in an interventional clinical trial within the previous 3 months prior to baseline; unless deemed by the investigator not to interfere with PENSA+ procedures or outcomes.
结局指标
主要结局
Global Cognitive Performance (PACC-exe Composite Score)
时间窗: Baseline, 12 months, and approximately 5 years after completion of the original PENSA intervention
Global cognitive performance assessed using the Preclinical Alzheimer Cognitive Composite for executive function, a composite score derived from six neuropsychological tests: Montreal Cognitive Assessment (score 0-30, higher scores indicate better cognition), Free and Cued Selective Reminding Test (score 0-48, higher scores indicate better episodic memory), Logical Memory Delayed Recall from the Wechsler Memory Scale (score 0-48, higher scores indicate better delayed verbal memory), WAIS-IV Coding (higher scores indicate better processing speed), Stroop Color-Word Test Interference score (higher scores indicate better inhibitory control and executive function), and Five Digit Test (higher scores indicate better executive functioning and cognitive flexibility). Individual test scores are converted to standardized z-scores based on the baseline mean and standard deviation of the study cohort, and the PACC-exe score is calculated as the arithmetic mean of these z-scores.
Incidence of Mild Cognitive Impairment (MCI)
时间窗: Approximately 5 years after completion of the original PENSA intervention
Incidence of Mild Cognitive Impairment determined according to clinical diagnostic criteria based on neuropsychological evaluation and clinical assessment performed at the 5-year follow-up visit. Diagnosis will require: (1) evidence of objective cognitive impairment on standardized neuropsychological assessment; (2) reported cognitive decline from previous functioning by the participant, an informant, or documented longitudinal assessment; (3) preserved independence in activities of daily living (impaired performance will be defined as below the 10th percentile, scaled score \<7, or ≥1.3 SD below age- and education-adjusted normative means); and (4) absence of dementia. Domain-specific impairment will be defined as low performance in ≥3 of 5 memory measures, ≥3 of 5 executive function measures, or ≥2 of 2 language measures. Final diagnosis will be established by a neurologist based on the integrated evaluation of neuropsychological, clinical, functional, and behavioral information.
Dementia Risk (LIBRA Index)
时间窗: Baseline, 12 months, and approximately 5 years after completion of the original PENSA intervention
Dementia risk assessed using the Lifestyle for Brain Health (LIBRA) Index, a weighted composite score of modifiable risk and protective factors for dementia. Lower scores indicate lower estimated dementia risk. The dementia risk assessed with the LIBRA Index is a weighted composite score of 12 modifiable risk and protective factors for dementia. These modifiable risks are the following: 1. Coronary heart disease 2. Chronic kidney disease 3. Hypertension 4. Hypercholesterolemia 5. Diabetes 6. Depression 7. High cognitive activity 8. Obesity 9. Low/moderate alcohol use 10. Physical inactivity 11. Smoking 12. Healthy diet
次要结局
- Longitudinal changes in memory and executive function(Baseline, 12-month, 5-year)
- Longitudinal changes in Mediterranean diet adherence(Baseline, 12-month, 5-year)
- Longitudinal changes in physical activity(Baseline, 12-month, 5-year)
- Longitudinal changes in quality of life(Baseline, 12-month, 5-year)
- Longitudinal changes in physical fitness - Senior Fitness Test(Baseline, 12-month, 5-year)
- Longitudinal changes in physical fitness - Grip Strength Test(Baseline, 12-month, 5-year)
- Longitudinal Changes in Plasma Alzheimer's Disease Biomarkers and Neuroimaging Measures(Baseline, 12-month, 5-year)
- Economic Outcomes: Long-term Cost-Effectiveness and Cost-Utility(Baseline, 12 months, and approximately 5 years after completion of the original PENSA intervention)