Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial

Abstract

Importance: Effective therapeutics for Alzheimer's disease and mild cognitive impairment are needed. Objective: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment, in which potential contributors to cognitive decline are identified and targeted therapeutically, is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. Rationale: Previous clinical trials for Alzheimer's disease have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, that may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective therapeutic strategy. Hypothesis: Alzheimer's disease is a multi-factorial network dysfunction that results from a chronic or repeated insufficiency of support for a neuroplasticity network; thus factors that increase demand — such as infections or toxin exposure — or reduce support — such as reduced energetics or trophic support — may contribute to the neurodegenerative process. Rectifying this hypothesized network dysfunction represents a rational approach to the treatment of the cognitive decline associated with Alzheimer's disease and mild cognitive impairment. Design: Twenty-five patients with Alzheimer's disease or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure (metals, organic toxicants, and biotoxins), genetic predisposition to cognitive decline, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol that addressed each patient's identified potentially contributory factors, and cognition was assessed at t = 0, 3, 6, and 9 months. Trial registration and IRB approval: The clinical trial was registered at clinicaltrials.gov (NCT03883633), 1 and approved by the Advarra IRB. Support for the trial: The trial was supported by a grant from the Four Winds Foundation via Evanthea, LLC, and we are grateful to Diana Merriam and Gayle Brown for their interest, discussions, and support. Main Outcome Measures: Trained external raters evaluated the study subjects with the Montreal Cognitive Assessment (MoCA), CNS Vital Signs (a computerized cognitive assessment battery), AQ-21 (a subjective scale completed by the significant other or study partner), and AQ-C change scale (a subjective scale of cognitive improvement or decline, completed by the significant other or study partner). Follow-up brain MRI with volumetrics was carried out at the completion of the trial. Results: All outcome measures revealed improvement: statistically highly significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and AQ-C were documented. No serious adverse events were recorded. Conclusions and Relevance: Based on the cognitive improvements observed in this study of patients with Alzheimer's disease or mild cognitive impairment, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

ReCODE: A Personalized, Targeted, Multi-Factorial Therapeutic Program for Reversal of Cognitive Decline

“…Although the current study documented significant cognitive benefits in those with MoCA scores ≥ 10, neither the magnitude of the improvements nor the fraction of patients who improved matched the results obtained in the recent proof-of-concept trial that employed the same approach [14]. This held true even when the evaluation in the current study was restricted to those with MoCA scores ≥ 19 (which matched the cognitive scores in the trial).…”

“…These overall findings indicate that participants in the ReCODE program experienced improved metabolic parameters and cognition. Although not shown here, a subset of other risk factors that improved by similar strategies included several hormones, vitamin B12, homocysteine, and serum zinc, supporting the notion that the ReCODE strategy to effectively mitigate metabolic risk factors may result in arresting cognitive decline or improving cognitive performance [13,14].…”

“…Out of the 151 subjects, 76 (50%) improved their scores, 41 (27%) showed a decline in scoring, and 34 (23%) were unchanged. For comparison, in the proofof-concept trial using this same approach, 76% of the patients showed an improvement in MoCA scores at the end of the 9-month trial [14]. The current results, together with the metabolic evaluations, demonstrate improvement that is highly significant statistically.…”

“…Thus, a therapeutic strategy to identify and attenuate all the risk factors specific to each affected individual may have a significant impact on disease progression, as has been shown recently [10][11][12][13][14]. Here we present pilot data that a comprehensive and personalized therapeutic program designed to mitigate AD risk factors can improve several risk factor scores and stabilize cognitive function, warranting prospective, longitudinal cohort studies, and controlled clinical trials.…”

“…The ReCODE program includes information on the metabolic factors that drive the symptoms of cognitive decline and provides detailed, personalized recommendations to address these factors, such as nutrition, exercise (physical and mental), sleep, stress management, detoxification, supplements, and hormones. The ReCODE program evolved from other similar programs that used precision medicine approaches to identify and target the drivers of Alzheimer's or pre-Alzheimer's [13][14][15]. Following the completion of labs, medical questionnaires, and cognitive testing, a softwarebased algorithm generates a personalized report that addresses the identified putative contributors to cognitive decline, such as specific pathogens, toxins, or hormonal alterations.…”