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Background: Interventions based on the modification of several lifestyle factors have provided promising results to maintain cognitive function in late/middle‐aged individuals at higher risk of developing Alzheimer's disease (AD). Framed under the WW‐FINGERS network, the PENSA clinical trial is focused on the prevention of cognitive decline in individuals with subjective cognitive decline who are also APOEε4 carriers. It consists of a 12‐month multimodal lifestyle intervention supplemented with EGCG, a natural flavonoid from green tea. In this study, we looked for the brain structure correlates of cognitive performance for PENSA participants at baseline. Methods: One hundred thirty‐one (N = 131) participants of the PENSA study at baseline [Table 1] with valid T1w, T2w and FLAIR MRI scans were included. They underwent a neuropsychological assessment battery consisting of the modified Alzheimer Disease Cooperative Study ‐ Preclinical Alzheimer Cognitive Composite (ADCS‐PACC‐Plus‐exe) that includes MMSE, Free and Cued Selective Reminding Test (FCSRT), Delayed Recall Logical Memory (DRLM), Five Digits Test, Digit Symbol Substitution Test, and Stroop. Additional cognitive measurements were obtained from semantic verbal fluency (SVF), Boston Naming Test, digit span subtest, visual puzzle subtest (VPT) and the Montreal Cognitive Assessment. FLAIR images were used to segment white matter hyperintensities and perform a lesion filling procedure in T1w and T2w images. These two later modalities were then entered into a multimodal segmentation in the SPM12 voxel‐based morphometry pipeline. Associations between test scores and grey matter volumes (GMv) were sought (p<0.001) including age, sex, education, and total intracranial volume as confounders. Results: A positive association was found (p uncorr <0.001; k>200) between GMv and ADCS‐PACC‐Plus‐exe composite [Figure 1] in the bilateral hippocampus, amygdala, entorhinal and parahippocampal gyri. Additionally, positive correlations (p uncorr <0.001; k>200) were found between GMv and FCSRT, DRLM, VPT and SVF tests albeit in less consistent regional patterns. No associations were found between GMv and the remaining tests. Conclusion: In a sample at high risk of developing AD, the ADCS‐PACC‐Plus‐exe composite is associated with GMv in brain areas known to be affected in AD. These results suggest that the ADCS‐PACC‐Plus‐exe composite might be sensitive to detect subtle cognitive changes in cognitively unimpaired at‐risk individuals. [ABSTRACT FROM AUTHOR]

Background: Not all individuals may respond to a cognitive decline preventive intervention. However, the low frequency of cognitive assessments during short‐lasting interventions hampers the study of the heterogeneity of treatment effects (HTE). We have recently developed and validated an innovative method for remote monthly monitoring of executive functions, which leverages the performance indicators from cognitive training games (CTG) (Figure 1). Here, we aimed to examine the HTE to a multimodal intervention using this CTG measure and to identify which baseline glycaemic, lipidic, and inflammatory factors are associated with the cognitive response profiles. Methods: We included N = 98 individuals (65.3% females; 67.2 ±4.6 years) APOE‐ɛ4 carriers with Subjective Cognitive Decline who had completed eight months of the PENSA Study multimodal intervention on January 2023. We analysed P = 62 baseline exposures that included: anthropometric factors, biochemical parameters, endocannabinoids, and plasma metabolites of the tryptophan and glutamine metabolism. First, we examined the HTE with the CTG measure as the outcome (6 repeated measures/subject) using growth mixture models. Second, we assessed the partial correlations between exposures using graphical LASSO with stability selection. Finally, we identified the most contributing predictors to the cognitive response profiles using stability selection‐based LASSO multinomial regression, fit on 500 random 80% subsamples of the data using the R package 'sharp'. Results: We identified and labelled three different cognitive response trajectories: 'average respondents' (75.6%), 'super respondents' (16.3%), and 'non‐respondents' (8.2%) (Figure 2A). The network of exposures showed higher intra‐family than inter‐family correlations (Figure 2B). Finally, four out of 62 exposures were identified as stable predictors of the cognitive response profiles (Figure 2C). Compared to 'average respondents' the 'super‐respondents' and 'non‐respondents' presented higher carnitine and serotonin concentrations. However, fasting plasma glucose and total cholesterol were lower in 'super‐respondents' (OR = 0.63 and OR = 0.69) and higher in 'non‐respondents' (OR = 6.07 and OR = 2.40). Conclusions: This study shows that not all individuals at high risk of Alzheimer's disease respond to an intensive lifestyle‐based multimodal intervention, and that baseline cholesterol and glycaemic homeostasis could determine the success of preventive interventions for cognitive decline. Further cholesterol‐ and glycaemic‐related metabolites should be analysed to better understand the underlying mechanisms of these findings. [ABSTRACT FROM AUTHOR]

Background: The CAIDE (Cardiovascular Risk Factors –CVRF‐, Aging, and Incidence of Dementia) Dementia Risk Score is a validated tool to predict late‐life dementia risk based on midlife CVRF. Sex differences in metabolic pathways related to cognitive decline have been described. The aim of this study was to explore associations between measures of insulin resistance, biomarkers of endothelial activation and peripheral inflammation and an increased CAIDE risk score (CAIDE‐rs) in individuals at higher risk of Alzheimer's disease (AD). Sex differences in these associations were explored. Method: A total of 129 participants of the PENSA study were recruited. Participants were categorized into high (≥ 9 points) or low CAIDE‐rs groups (HR and LR respectively). Homeostatic model assessment was calculated (HOMA IR = fasting insulin (μIU/ml) × fasting glucose (mmol/ml)/22.5). The following biomarkers were analyzed: soluble intercellular adhesion molecule‐1 (ICAM‐1, ng/ml), vascular cell activation molecule‐1 (VCAM‐1, ng/ml), C‐reactive protein (CRP, mg/dl) and fibrinogen (mg/dl), using ELISA and Clauss method assays. Result: Participants were 67.2 ±4.8 years, 65.1% were women and 32.6% were classified into the HR group. The HR group was older (68.5 vs. 66.5 years, P = 0.026) and presented higher levels of CRP (median of 0.08 vs. 0.06 mg/dL; P = 0.037) and HOMA‐IR (2.1 vs. 1.6; P = <.001). No differences were found for ICAM‐1, VCAM‐1 or fibrinogen. Comparisons between sex groups showed higher fibrinogen median values in women both among the HR group and in the global sample (HR 372 vs. 327mg/dl; P = 0.011; GS 350.5 vs. 340.5mg/dl; P = 0.032). Higher HOMA‐IR and VCAM‐1 median values in men were found in the global sample (2.13 vs. 1.65; P = 0.006 and 495.8 vs. 434.5 ng/ml; P = 0.028). The HR female group showed higher HOMA‐IR and fibrinogen median values than the LR female group (2.06 vs. 1.58; p = <.001 and 372 vs. 343 mg/dl; P = 0.029 respectively). HR male group showed higher CRP values compared to LR male group (0.03 vs. 0.12 mg/dl; p = 0.026). Conclusion: Associations of metabolic alterations and an increased CAIDE‐rs were found in individuals at higher risk of AD. Moreover, sex differences in metabolic alterations were also found. These results highlight the necessity of personalizing preventive interventions for AD taking into account sex‐related profiles. [ABSTRACT FROM AUTHOR]

Introduction: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer’s disease prevention trials. Methods: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention+EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color andWord Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium. Discussion: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions. [ABSTRACT FROM AUTHOR]

Background: Multicomponent interventions including diet, physical activity and cognitive training have shown great potential to prevent cognitive decline in individuals at risk of developing the clinical stages of Alzheimer's disease (AD). The PENSA study is a clinical trial focused on the prevention of cognitive decline in individuals with subjective cognitive decline (SCD) who are also APOE ε4 carriers. It is based on a 12‐month multimodal intervention (nutritional, physical and cognitive) combined with epigallocatechin‐3‐gallate (EGCG), a natural flavanol and known synaptic plasticity booster. In this study, we sought for neuroimaging correlates of cognitive performance of the PENSA participants at baseline. Method: Twenty‐five (N=25) SCD participants of the PENSA Study at baseline (Table 1) with valid T1w and T2w MRI scans were included. They also underwent a neuropsychological assessment battery consisting of the modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS‐PACC‐like) and additional cognitive performance scores obtained from (i) semantic verbal fluency, (ii) Boston Naming Test, (iii) digit span subtest, (iv) visual puzzle subtest and (v) the Montreal Cognitive Assessment. In addition, measurements of mental health, functionality, quality of sleep and quality of life perception have been assessed. T1w and T2w MRI scans were used to perform a multimodal segmentation of grey matter volumes (GMv) entered in the SPM12 voxel‐based morphometry (VBM) pipeline. Associations between test scores and GMv were sought (p<0.001) including age, sex, education and total intracranial volume as confounders. Result: A negative correlation was found between the Free and Cued Selective Reminding Test (FCSRT) performance and GMv in the left anterior cingulate gyrus, left medial temporal lobe, right and middle temporal gyrus and left medial orbital gyrus (Figure 1). The rest of comparisons did not survive the statistical significance threshold. Conclusion: Preliminary results show the expected pattern of negative associations between GMv and episodic memory performance, therefore suggesting that the PENSA study is recruiting the intended population of SCD individuals at risk of developing clinical stages of AD who could benefit from multimodal preventive interventions. [ABSTRACT FROM AUTHOR]

Background: 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 benefits. The PENSA Study is a clinical trial aiming at preventing cognitive decline in APOE‐ɛ4 carriers with subjective cognitive decline (SCD). The proposed clinical trial design will evaluate the efficacy of epigallocatechin‐3‐gallate (EGCG) in the context of a personalized medicine approach including a multimodal intervention looking at improving person‐centered outcomes in this population. Method: We have established a randomized, double‐blind, multimodal personalized clinical trial with 200 participants (60‐80 years; APOE‐ε4 allele carriers; fulfilling SCD criteria with 2 additional SCD plus supportive features) with 4 arms of 50 participants each (Fig 1). Recruitment is primarily achieved through web‐based forms capturing information about participants' subjective cognitive status. Those participants a priori eligible will be tested for APOE status, and carriers of the APOE‐ε4 allele will be invited to the study. The intervention lasts for 12 months and the multimodal lifestyle approach will include physical activity, dietary, and mental health promotion interventions. Result: The trial's primary efficacy outcome is a modified ADCS‐PACC score. The secondary efficacy outcome will be evaluated by Functional neuronal connectivity (fcMRI) and structural connectivity (MRI). Exploratory outcomes include Microbiota composition, Dietary patterns (metabolomics), additional cognitive performance scores and plasma AD biomarkers assessment. Conclusion: The multimodal intervention approach of PENSA is expected to slow down cognitive decline and improve brain connectivity in a population of APOE‐e4 participants with SCD. The study also intends to evaluate several underlying mechanisms that could explain the efficacy of the intervention in slowing down cognitive decline such changes in brain connectivity, gut microbiota composition, AD biomarkers and biological ageing predictors. Further, this trial will give us information regarding participants' retention and compliance, and therefore feasibility of this kind of high‐demanding engagement prevention studies. [ABSTRACT FROM AUTHOR]

Background: In recent years, there has been a growing concern about the hierarchical relationship between researchers and patients. A change of paradigm has been promoted by recent initiatives supporting an active citizenship involvement in research. The combination of patients' views together with the expertise of clinicians and researchers may lead to a change on how research actions are identified, designed, conducted and disseminated. Following this approach, we introduced a co‐creation action in the intervention design process of the project Prevention of cognitive decline in APOE‐ɛ4 carriers with SCD after epigallocatechin‐gallate and a multimodal intervention (PENSA study). We aimed to assess participants' opinion about the multimodal intervention and its viability, and to identify aspects of improvement. Methods: We performed a qualitative descriptive study in a focus group composed by 10 participants (5 women and 5 men) between 60 and 80 years. Two researchers and a qualitative methodology specialist planned the content of a 2‐hour group session, that was guided by the specialist and audio recorded. Subsequently, an analysis of the thematic content was performed to extract the participants' global comprehension of the phenomenon. Results: The qualitative analysis revealed that participants positively rated the intervention and found it as a useful tool to implement a healthy lifestyle. Facilitators and barriers for the implementation of the multimodal intervention were identified. The former related to the great support received by the health professionals and the opportunity of acquiring reliable knowledge about Alzheimer's disease and its management. The later were mostly related with time availability and a general worry about the return and dissemination of the study results. Moreover, alternatives and changes were proposed to improve the intervention, such as the possibility of adapting the proposed activities to participants' preferences. The research team has implemented a number of actions to adequate the multimodal intervention to the participants needs. Conclusions: Our study shows that co‐creation actions considering patients experience represents a rich source of information for designing effective health interventions. The co‐creation process represents an exercise of public commitment in responsible research and innovation. [ABSTRACT FROM AUTHOR]

Background: Current evidence suggests that multimodal interventions with diet, physical activity and cognitive training could prevent cognitive decline in individuals at preclinical stages of Alzheimer's disease. However, maintaining subject compliance is a critical challenge for the success of studies that involve intensive behavioral changes. The PENSA Study is a clinical trial that aims to prevent cognitive decline in 200 older adults (60‐80 years) APOE‐ɛ4 carriers with subjective cognitive decline. A personalized multimodal intervention will combine with a dietary supplement enriched with epigallocatechin gallate (7mg/kg) during 12 months. To continuously monitor the adherence to the intervention and to motivate participants in engaging in healthy promoting behaviors, a digital health platform provided by Medtep has been incorporated in the PENSA Study. Methods: The Medtep App collects daily information on participant's diet, mood and social activities using ecological momentary assessments, and registers the attendance to gymnasium, cognitive stimulation and psychoeducational sessions. It also integrates measures of physical activity, heart rate, sleep quality and cognitive performance collected from an activity tracker and a cognitive training telematic platform. Researchers can control the progression of each participant and automatically personalize the intervention according to their characteristics and progression. Results: During the two weeks prior to the intervention starting date, the information collected is used to establish a reliable lifestyle pre‐treatment measure and to provide each participant with a personalized plan on diet and physical activity. Throughout the intervention, participants receive personalized goals and recommendations, as well as a monthly report with feedback on their behaviors. To this end, several indexes or scores have been created based on participants' adherence and progression on Mediterranean diet, physical activity, cognition, sleep and social health. Conclusions: The use of Medtep in the PENSA study is expected to improve participants' adherence and motivation to the intervention as they might be more aware of what they are expected to do, their strengths and weaknesses, and their progression throughout the study. Furthermore, it will be useful for researchers to track intervention compliance, to make improvements in the intervention throughout the study and to better understand longitudinal changes in behaviors and their impact on cognition. [ABSTRACT FROM AUTHOR]

The effect of immunosuppressant treatments on the incidence of coronavirus disease (COVID-19) remains largely unknown. We studied the association between the pre-exposure to disease-modifying antirheumatic drugs (DMARDs) that decrease immunological responses and the incidence of COVID-19 to explore the possible effects of these treatments in early manifestations of the disease. For this purpose, we performed a cross-sectional study including 2,494 patients with immunomediated inflammatory diseases (IMIDs) recruited at the outpatient Rheumatology, Dermatology and Gastroenterology services of Hospital del Mar. The primary outcome was the clinical diagnosis of COVID-19 performed by a physician at the hospital or at the primary care center, from the March 1–29, 2020. Multivariable Poisson regression models were fitted to estimate COVID-19 relative risk (RR) adjusted by comorbidities. We revealed that biological (RR = 0.46, CI 95% = 0.31–0.67) and synthetic (RR = 0.62, CI 95% = 0.43–0.91) DMARDs used in IMIDs diminished the incidence of COVID-19. Striking sex differences were revealed with anti-TNFα compounds (RR = 0.50, CI 95% = 0.33–0.75) with higher effects in women (RR = 0.33, CI 95% = 0.17–0.647). Treatment with low glucocorticoid doses also revealed sex differences decreasing the incidence of COVID-19 predominantly in women (RR = 0.72, CI 95% = 0.42–1.22). Our results report a decreased incidence of COVID-19 in patients receiving specific DMARDs with different immunodepressor mechanisms with striking sex differences. These results underline the interest of repurposing specific DMARDs for the possibility of minimizing the severity of disease progression in the early stages of COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials., Methods: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium., Discussion: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions., Competing Interests: The authors declare no conflicts of interest or other relevant disclosures., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)