Subjective Cognitive Decline (SCD)
Conditions
Keywords
Alzheimer's Disease, Dementia Prevention, Subjective Cognitive Decline, APOE-ε4 carriers, Multidomain Lifestyle Intervention, Epigallocatechin Gallate (EGCG), Brain Health, Blood Biomarkers, Long-Term Follow-up, Subjective Cognitive Decline (SCD)
Brief summary
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.
Detailed description
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.
Interventions
None listed
Sponsors
Barcelonabeta Brain Research Center, Pasqual Maragall Foundation
Hospital del Mar
Hospital del Mar Research Institute
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Any individual who has completed the PENSA study, does not meet any
Exclusion criteria
, and provides consent is eligible to participate in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Cognitive Performance (PACC-exe Composite Score) | 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) | 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) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Longitudinal changes in memory and executive function | Baseline, 12-month, 5-year | Longitudinal changes in cognitive domains (memory and executive function scores, PMCID: PMC12413734). |
| Longitudinal changes in Mediterranean diet adherence | Baseline, 12-month, 5-year | Diet will be assessed through Mediterranean Diet Adherence Screener (MEDAS-14). The MEDAS-14 is a 14-item questionnaire for the assessment of Mediterranean diet compliance. It has been developed and validated by researchers of the PREDIMED study (PMCID: PMC8710807). The maximum possible score is 14 points. This questionnaire allows the participants to be classified according to their adherence to the Mediterranean diet, being appropriate if the score is ≥10 or not appropriate if the score is \<10. |
| Longitudinal changes in physical activity | Baseline, 12-month, 5-year | Physical activity is measure through the Short Minnesota Leisure Time Activities Questionnaire (VREM). The VREM questionnaire asks for information on six activities carried out in the last month (or usual month) in order to find out the level of PA performed: walking, gardening in the garden, doing sport or dancing, climbing stairs, shopping on foot, and cleaning the house. cleaning the house (PMID: 23223762). According to the number of minutes spent on each activity and the frequency they are carried out over the course of a year, the energy expenditure is estimated for 14 days, expressed in Metabolic Equivalents (METs) per minute per 14 days (MET-min-14 days). The VREM makes it possible to distinguish between very active (more than 5,000 MET-min-14 days), active (between 3,000 and 4,999), moderately active (between 1,250 and 2,999), and sedentary (less than 1,250). |
| Longitudinal changes in quality of life | Baseline, 12-month, 5-year | Quality of life is measured through the World Health Organization Quality of Life (WHOQOL)-BREF. The WHOQOL-BREF comprises 26 items, categorized into four domains: physical health (7 items), psychological well-being (6 items), social connections (3 items), and environmental health (8 items) (PMID: 15085902). Additionally, it includes items addressing the overall quality of life and general health. Each item in the WHOQOL-BREF is assessed on a five-point ordinal scale. These scores are then linearly transformed to a 0-100 scale. The physical health domain encompasses aspects such as mobility, daily activities, functional capacity, energy, pain, and sleep. Within the psychological domain, assessments cover self-image, negative thoughts, positive attitudes, self-esteem, mentality, learning ability, memory concentration, religion, and mental status. The social relationships domain explores personal relationships, social support, and aspects of one's sex life. |
| Longitudinal changes in physical fitness - Senior Fitness Test | Baseline, 12-month, 5-year | Physical fitness will be assessed using the Senior Fitness Test (SFT), a standardized battery that evaluates overall physical fitness in older adults, including muscle strength, aerobic endurance, flexibility, agility, and dynamic balance. Higher scores in the SFT indicate better physical fitness. |
| Longitudinal changes in physical fitness - Grip Strength Test | Baseline, 12-month, 5-year | Physical Fitness will be assessed with the Grip Strength Test. For this test, the best result from 3 trials for each hand will be recorded and summed. |
| Longitudinal Changes in Plasma Alzheimer's Disease Biomarkers and Neuroimaging Measures | Baseline, 12-month, 5-year | Change and trajectory in plasma AD biomarkers and neuroimaging measures of brain structure and function. Specifically, plasma AD biomarkers include the concentration levels of phosphorylated tau (p-tau217 and p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), all expressed in pg/mL, as well as the amyloid-β 42/40 ratio. Simultaneously, neuroimaging markers derived from structural MRI include hippocampal, lateral ventricular volumes, and White Matter Hyperintensities (WMH) - all normalized to total intracranial volume (TIV)-, and a composite measure of cortical thickness in "AD-signature" regions (PMID: 21490323). |
| Economic Outcomes: Long-term Cost-Effectiveness and Cost-Utility | Baseline, 12 months, and approximately 5 years after completion of the original PENSA intervention | Incremental cost-effectiveness ratios (ICERs) expressed as cost per unit improvement in global cognitive performance (PACC-exe), and the Incremental Cost-Utility Ratio (ICUR), expressed as the cost per Quality-Adjusted Life Year (QALY) gained based on EQ-5D-5L data. |
Countries
Spain
Contacts
CONTACTNatàlia Soldevila Domènech, MPH, PhD
Outcome results
None listed