A multimodal intervention for Alzheimer’s disease results in multifaceted systemic effects reflected in blood and ameliorates functional and cognitive outcomes

Introduction Comprehensive treatment of Alzheimer’s disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. The Coaching for Cognition in Alzheimer’s (COCOA) trial was a prospective randomized controlled trial (RCT) to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage Alzheimer’s disease (AD). AD results from the interplay of multiple interacting dysfunctional biological systems. Specific causes of AD differ between individuals. Personalized, multimodal therapies are needed to best prevent and treat AD. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic and microbiome data at multiple timepoints across two years for each participant. These data enable systems-biology analyses. We report analyses of the first COCOA data freeze. This analysis includes an evaluation of the effect of the intervention on outcome measures. It also includes systems analyses to identify molecular mediators that convey the effect of personalized multimodal lifestyle interventions on amelioration of cognitive trajectory. Methods A total of 55 participants with early-stage AD from Southern California were randomized into two parallel arms. Arm 1 (control; N=24) received standard of care. Arm 2 (intervention; N=31) also received telephonic personalized coaching for multiple lifestyle interventions including diet, exercise, and cognitive training. COCOA’s overarching aim was to gather dense molecular data from an AD cohort to improve understanding of pathophysiology and advance treatment. For the RCT, COCOA’s objective was to test the hypothesis that the Memory Performance Index (MPI) trajectory would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test (FAST) was assessed for a secondary outcome. Assessments were blinded. The nature of the intervention precluded participant blinding. Results The intervention arm ameliorated 2.6 ± 0.8 MPI points (p = 0.0007; N = 48) compared to the control arm over the two-year intervention. Top-ranked candidate mediators included: albumin, propionylcarnitine, sphingomyelin, hexadecanedioate, acetylkynurenine, tiglylcarnitine, IL18R1, palmitoyl-sphingosine-phosphoethanolamine, acetyltryptophan, and IL17D. These individual molecules implicated inflammatory and nitrogen/tryptophan metabolism pathways. No important adverse events or side effects were observed. Conclusions Clinical trials should include frequent assessment of dense data to maximize knowledge gained. Such knowledge is useful not only in testing a primary hypothesis, but also in advancing basic biological and pathophysiological knowledge, understanding mechanisms explaining trial results, generating synergistic knowledge tangential to preconceived hypotheses, and refining interventions for clinical translation. Data from every trial should allow an intervention to be refined and then tested in future trials, driving iterative improvement. Multimodal lifestyle interventions are effective for ameliorating cognitive decline and may have an effect size larger than pharmacological interventions. Effects may be molecularly idiosyncratic; personalization of interventions is important. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic. ### Competing Interest Statement Dr. Shankle is an employee of EMBIC Corporation. Dr. Hara owns stock in EMBIC Corporation. There are no other conflicts of interest for any of the authors. ### Clinical Trial NCT03424200 ### Clinical Protocols ### Funding Statement This work was supported by the Alzheimer's Translational Pillar of Providence St. Joseph Health, by the National Science Foundation (NSF) Research Experiences for Undergraduates site "Research Opportunities in Systems Biology", by the Saint John's Health Center Foundation, by the Pacific Neuroscience Institute Foundation (including the Cary and Will Singleton family), and by National Institutes of Health (NIH) grants R01AG062514, U01AG046139, RF1AG057443, & U01AG061359. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of the Western Institutional Review Board gave ethical approval for this work (WIRB protocol #20172152). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is available in Supplemental Table 1. * AD : Alzheimer’s disease ADRD : Alzheimer’s disease and related disorders (or nearly equivalently: Alzheimer’s disease and related dementias) COCOA : Coaching for Cognition in Alzheimer’s Trial FAST : Functional Assessment Staging Test MCI : mild cognitive impairment MCIS : MCI Screen RCT : randomized controlled trial MID : minimal important difference (aka, MCID, minimal clinically important difference) MoCA : Montreal Cognitive Assessment MPI : Memory Performance Index