key: cord-0747918-fyz6btew authors: McEwen, Sarah C.; Merrill, David A.; Bramen, Jennifer; Porter, Verna; Panos, Stella; Kaiser, Scott; Hodes, John; Ganapathi, Aarthi; Bell, Lesley; Bookheimer, Tess; Glatt, Ryan; Rapozo, Molly; Ross, Mary Kay; Price, Nathan D.; Kelly, Daniel; Funk, Cory C.; Hood, Leroy; Roach, Jared C. title: A systems‐biology clinical trial of a personalized multimodal lifestyle intervention for early Alzheimer's disease date: 2021-07-20 journal: Alzheimers Dement (N Y) DOI: 10.1002/trc2.12191 sha: 4845e54f59eff6b295f6b88b11ed3856fe3d7e2d doc_id: 747918 cord_uid: fyz6btew INTRODUCTION: There is an urgent need to develop effective interventional treatments for people with Alzheimer's disease (AD). AD results from a complex multi‐decade interplay of multiple interacting dysfunctional biological systems that have not yet been fully elucidated. Epidemiological studies have linked several modifiable lifestyle factors with increased incidence for AD. Because monotherapies have failed to prevent or ameliorate AD, interventional studies should deploy multiple, targeted interventions that address the dysfunctional systems that give rise to AD. METHODS: This randomized controlled trial (RCT) will examine the efficacy of a 12‐month personalized, multimodal, lifestyle intervention in 60 mild cognitive impairment (MCI) and early stage AD patients (aged 50+, amyloid positivity). Both groups receive data‐driven, lifestyle recommendations designed to target multiple systemic pathways implicated in AD. One group receives these personalized recommendations without coaching. The other group receives personalized recommendations with health coaching, dietary counseling, exercise training, cognitive stimulation, and nutritional supplements. We collect clinical, proteomic, metabolomic, neuroimaging, and genetic data to fuel systems‐biology analyses. We will examine effects on cognition and hippocampal volume. The overarching goal of the study is to longitudinally track biological systems implicated in AD to reveal the dynamics between these systems during the intervention to understand differences in treatment response. RESULTS: We have developed and implemented a protocol for a personalized, multimodal intervention program for early AD patients. We began enrollment in September 2019; we have enrolled a third of our target (20 of 60) with a 95% retention and 86% compliance rate. DISCUSSION: This study presents a paradigm shift in designing multimodal, lifestyle interventions to reduce cognitive decline, and how to elucidate the biological systems being targeted. Analytical efforts to explain mechanistic or causal underpinnings of individual trajectories and the interplay between multi‐omic variables will inform the design of future hypotheses and development of effective precision medicine trials. being targeted. Analytical efforts to explain mechanistic or causal underpinnings of individual trajectories and the interplay between multi-omic variables will inform the design of future hypotheses and development of effective precision medicine trials. aerobic exercise, Alzheimer's disease, cognitive training, diet, executive function, lifestyle, memory, mild cognitive impairment, multimodal, neuroimaging, nutrition, precision medicine, systems biology, translational research Dementia is one the most important health concerns facing society today. The most common dementia-related disorder is Alzheimer's disease (AD), the leading cause of disability among individuals older than age 65. 1 Approximately 15 to 20% of people older than 65 years have mild cognitive impairment (MCI). 2 Approximately 15% of individuals with MCI convert to dementia within 1 year, 3 highlighting this prodromal period for intervention. Existing pharmaceutical and nonpharmaceutical therapies provide modest and short-term benefits at best. 4 Early detection and intervention are critical. The World Health Organization (WHO) recommends that "proactive management of modifiable risk factors can delay or slow the onset or progression of the ,disease" and stresses the importance of early intervention. 6 Epidemiological studies have linked several modifiable lifestyle factors with risk for late-life cognitive impairment and AD. 7, 8 These risk factors can be targeted with multimodal interventions to prevent cognitive decline and co-morbidities. The most significant results from trials ensue from lifestyle interventions including diet, exercise, cognitive training, and stress reduction. 5, 9, 10 Results from multimodal lifestyle prevention trials in asymptomatic older adults show mild but significant effects on cognitive functioning. [11] [12] [13] [14] The largest trials to date have been FINGER, 12 MAPT, 15 The PREVENTION pilot study is a prospective, 12-month, two-arm, RCT (ClinicalTrials.gov NCT04082611) in older adults with early stage AD. Participants are assigned randomly to a personalized, multimodal lifestyle intervention with or without health coaching. The primary objectives of PREVENTION are: (1) conduct a pilot feasibility and efficacy study and (2) gather dense data from patients to explore the trajectory of their cognitive health using a systems-biology approach. To achieve the latter objective, we will analyze longitudinal multi-omic data. These data include metabolomics, proteomics, genetics, microbiome, behavior metrics, and cognition metrics from each participant assembled as personalized, dense, dynamic data (PD3) 22 clouds. This dense phenotyping approach allows us to create comprehensive data sets on individuals to draw inferences, as opposed to necessitating clinical trials with larger sample sizes (N = 1000 +), which is prohibitive in most cases due to unrealistic recruitment targets of this well-characterized population and the excessive cost, staffing, and time limitations related to running those trials. The Participants in both treatment arms will receive personalized, evidence-based, multimodal lifestyle recommendations for improving their brain health from a study physician. Recommendations, includ- A personalized program is given to each participant to educate them about and prioritize lifestyle changes. Personalization is informed from their medical history, assessments, clinical blood labs, physical activity levels, body mass index, and apolipoprotein gene (APOE) status (Table 1) . They also receive personalized intervention TA B L E 1 Six systemic pathways to optimize brain health: clinical and discovery laboratory biomarkers Albumin/globulin (A/G) ratio; cortisol, serum; matrix metalloproteinase-9 (MMP9), serum; interleukin-6 (IL-6), serum; high-sensitivity C-reactive protein (hs-CRP), serum; tumor necrosis factor alpha (TNFα), serum. Four-point cortisol (saliva-at home; assay: ZRT Laboratory, Beaverton, OR). Neurofilament light chain (NfL) protein (serum; Quanterix, Billerica, MA). White blood cells (WBCs); red blood cells (RBCs); hemoglobin, hematocrit; mean corpuscular volume (MCV); mean corpuscular hemoglobin (MCH); mean corpuscular hemoglobin concentration (MCHC); red cell volume distribution width-CV (RDW-CV); platelet count; mean platelet volume (MPV); automated absolute neutrophils; absolute neutrophils; absolute lymphocytes; absolute monocytes; absolute eosinophils; absolute basophils; absolute immature granulocytes; %nRBC; absolute nRBC. Lipid panel: total cholesterol, triglycerides, high-density lipoprotein (HDL), cholesterol, low-density lipoprotein (LDL), lipid ratios; LipoFit lipoprotein by NMR: LDL particle number (LDL-p), small LDL-p, large very-low-density-lipoprotein (VLDL-p), HDL-p (total), large HDL-p; LDL size, VLDL size, HDL size, total cholesterol, triglycerides, HDL cholesterol, LDL, calculated, EER LipoProfile; omega-3 and -6 fatty acids: eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA); omega-3 (EPA+DHA) index; omega-6/omega-3 ratio; arachidonic acid; EPA/arachidonic acid ratio; lipoprotein (a); oxidized LDL cholesterol; small dense LDL cholesterol. Apolipoprotein E (APOE) genotype; methylenetetrahydrofolate reductase (MTHFR) genotype. Proteomics (discovery) Cardiovascular II; cardiovascular III; inflammation, neurology; and neuro-exploratory panels collectively assay 1161 unique proteins (plasma; Olink, Uppsala, Sweden). Sodium (Na); potassium (K); chloride (Cl); carbon dioxide (CO 2 ); anion gap; glucose; blood urea nitrogen (BUN); creatinine; calcium; albumin; bilirubin total (calculated); total protein; aspartate aminotransferase (AST) (SGOT); alanine aminotransferase (ALT) (SGPT); alkaline phosphatase (ALP); globulin; A/G ratio; BUN/creatinine ratio. Fasting glucose; hemoglobin A1c (HbA1c); insulin, serum; HOMA-IR. Global Metabolic Profile that surveys ≈1000 metabolites (including amino acids, carbohydrates, lipids, nucleotides, microbiota metabolites, cofactors, and vitamins (plasma; Metabolon, Morrisville, NC). Magnesium, RBC; magnesium, serum; vitamin E, serum; vitamin B12, serum; vitamin B6, serum; homocysteine, serum; vitamin B1 (thiamine), whole blood; vitamin C (ascorbic acid), serum; copper, serum; zinc, serum; glutathione, total; selenium, serum. Antidiuretic hormone (ADH), plasma; compliment C4a level by radioimmunoassay (RIA); human leukocyte antigen (HLA)-DR/DQ genotype; leptin, serum; alpha melanocyte stimulating hormone (MSH), plasma; osmolality, plasma; transforming growth factor beta (TGFB1), serum; vascular endothelial growth factor (VEGF), plasma; vasoactive intestinal protein (VIP), plasma. Heavy metals (clinical) Arsenic, whole blood; mercury, whole blood; lead, whole blood; cadmium, whole blood. Total testosterone, serum; free testosterone, serum; estradiol, serum; DHEA-sulfate, serum; progesterone, serum; pregnenolone, serum; thyroid stimulating hormone (TSH); serum; free T3, serum; free T4, serum; reverse T3, serum. Standard of care plus data-driven, multimodal, and lifestyle clinical recommendations (Appendix B) will be given to participants in the CR arm. These participants will be incentivized to remain in the trial through the same schedule of clinical labs and study physician visits as the MMIC arm. The study physician will support the lifestyle and nutritional supplement recommendations by discussing compliance and providing adjustments as needed. At the end of the trial, participants in the CR arm will have the option to receive health coaching, group exercise, and nutrition counseling for 3 months. The MMIC arm will also engage with supportive coaching and be pro- The will also complete an authorization of use and disclosure of protected health information and authorization of medical record release. We monitor each patient for 12 months. We will perform comprehensive, predominately remote assessments and biomarker collection at baseline, and at 3, 6, and at 12 month timepoints to evaluate differences in cognitive trajectory and impact on biomarkers between the two arms ( Figure 1 ). Participants in the CR group may be monitored for up to 18 months if they elect to receive intervention services. An MRI scan is conducted on a GE 3T at baseline and at 12 months to examine changes in our primary outcome measure of hippocampal volume. MRI data are processed using the Neuroreader 42 neuroimaging software to extract normalized region brain volumes. Neuoreader is an FDA-cleared brain volumetric software package that has validated that hippocampal volume remains the best single volumetric predictor of conversion from MCI to AD. 43 Additional exploratory outcome scans for future analyses include: 15-direction DTI, resting-state functional MRI, and 3D ASL. We will measure and analyze ease of recruitment and the retention rate. We expect to have low attrition (≤30%) for both arms and a high adherence to the multimodal lifestyle recommendation-coached intervention, with a target of ≥70% adherence to be an effective intervention. 39 In response to the COVID-19 pandemic we developed a predominately remote trial delivery. Remote delivery should lead to increased protocol adherence. Adherence will be calculated as the ratio of completed to assigned sessions. We have systematically considered retention and behavioral engagement strategies. [44] [45] [46] To determine adherence to coached intervention we track the attendance to: health coaching calls, FitBrain group exercise sessions, dietary counseling calls, usage of computerized cognitive training, and consumption of supplements (as determined by the study physician). Compliance reports from CRA interviews will generate subjective compliance scores to each of the seven primary intervention components: exercise, diet, cognitive stimulation, social interaction, supplements, sleep, and stress management. The ability to assess individual adherence to study sessions and compliance to the primary interventions will allow investigation of the relative contribution of each to overall effect. Activity and sleep data will be aggregated using a custom FitBit data aggregation platform. These will be objective measures of compliance, will assist with health coaching, and will help determine if patients increase their physical activity (METS/minutes) and sleep habits (FitBit Sleep Score). The study physician also generates a measure of subjective compliance from the patient, corroborated by their care partner, using the Clinician Rating Scale every 3 months. 47 Subjective compliance is rated on a scale from 1 to 7 (7 the highest compliance). We are seeking to determine the efficacy of the personalized multimodal lifestyle intervention in early stage AD patients to reduce (or reverse) cognitive decline and elucidate individual differences in disease progression. We believe that the coached intervention will promote greater compliance with the recommendations, producing greater improvements in cognitive functioning and brain volumetrics compared participants those in the CR arm. We will employ a linear mixed model to characterize the change over time of our primary neuropsychological outcome measure (RAVLT learning score) and neural biomarker outcome (hippocampal volume) and our secondary outcome measures (composite cognitive score and BUN). We will also conduct exploratory analyses on the neuroimaging data sets (DTI, resting state functional MRI, and ASL) to assess effects of compliance on brain structure and function. Systems-biology personal, dense, dynamic data analysis We will conduct analyses of molecular and physiological subsystems that drive and respond to healthy and disease states to create understanding of health and disease trajectories in each individual. We will perform time-dependency, dose-response, and other knowledgegenerating analyses. Thousands of inter-omic correlations will be computed using personal, dense, dynamic data clouds to identify associations that could be followed up with perturbation experiments. We will partition the correlations into data communities, which place biomarkers in context within biological networks. We will also apply multiple machine-learning techniques for classification. These analyses are facilitated by contextual and validation data in our aggregated database of all prior studies from the Institute for Systems Biology (ISB) and coupled with larger databases such as ADNI and AMP-AD. This enables demonstration of consistency of newly acquired data with past knowledge and data. The ISB-led Pioneer 100 Wellness Project study demonstrated our longitudinal, multi-omic data analytical approach. 22 Analysis of data from individuals on a trajectory of early stage AD will permit exploration between measured variables and models of causation that can further advance the knowledge of and research into the pathologies that contribute to brain degeneration. Random assignment to intervention arms increases the diversity of interventions to Although no disease-modifying pharmacological therapies exist for early stage AD, preventative lifestyle modification strategies and interventions have been posited to be the most promising means to slow AD-related cognitive decline. 48 Furthermore, the COVID-19 pandemic has exacerbated barriers that prevent individuals from fully engaging in healthy lifestyle behaviors to ameliorate and remediate cognitive decline. To promote sustainable behavioral changes through lifestyle modification, it is critical that preventative interventions are personalized, allowing for individual variability, personal preferences, and variations in access. 5 Health coaching can encourage, inspire, and empower patients to reach their maximum potential. 49 The PREVENTION trial is designed to evaluate the efficacy of a personalized, predominantly remote-based, multimodal intervention for the treatment of early stage cognitive decline due to AD neuropathology. In this trial we are also systematically identifying biomarkers across all physiological systems for the earliest possible detection of the AD transition in individuals as well as biomarkers for assessing and improving the AD in response to multimodal systems therapeutic approaches. The PREVENTION trial design should enable not just paradigm shifts in the conduct of clinical trials, but also innovations in therapy, including a focus on multimodal therapies that are delivered through coaching interventions. We expect completion of the PREVENTION trial within the next 2 years. From this trial we seek to develop an evidence-based framework for a clinical implementation model of reducing cognitive decline. Our multi-omic, systems-biology analytical efforts to explain mechanistic or causal underpinnings of individual trajectories, seeks to inform the design of future hypotheses and to improve and better personalize the intervention in patients in the early stage of AD. World Health Organization. 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