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O4‐02‐06: ORAL TREATMENT WITH RD2 REDUCES Aβ OLIGOMER LOAD, ENHANCES COGNITION, DECELERATES NEURODEGENERATION, REVERSES DISEASE PHENOTYPE IN OLD‐AGED TG AD MICE, AND IS SAFE IN HUMANS
Author(s) -
Willbold Dieter,
Kutzsche Janine,
Schemmert Sarah,
Willuweit Antje
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.4751
Subject(s) - in vivo , neurodegeneration , oligomer , genetically modified mouse , phenotype , cognition , neuroscience , disease , immune system , transgene , cognitive decline , in vitro , pharmacology , chemistry , medicine , microbiology and biotechnology , biology , immunology , dementia , biochemistry , genetics , organic chemistry , gene
Background: The study of ‘gut-brain axis’ is providing a growing body of evidence identifying gut microbiota as a critical component of healthy brain function, elevating it to a clinically actionable organ. Nevertheless, very few clinical trials assess the relationship between Alzheimer’s Disease (AD) and gut microbiota. Here we report the first microbiota search for biomarkers associated with drug response in AD. ANAVEX 2-73, a selective sigma-1 receptor (SIGMAR1) agonist, was investigated in a 57week Phase 2a study with 32 mild-to-moderate AD dementia patients (NCT 02244541). The study met its primary endpoint, demonstrating a favorable safety profile, and was subsequently extended by an additional 208 weeks (NCT 02756858), during which patient’s stool collection was performed to analyze gut microbiota. Methods: Stool samples of 16 available patients were collected. After 16s metagenomics sequencing (Illumina MiSeq) a MOTHUR based, bioinformatics pipeline was used for taxonomic classification of sequences; abundances measurement of 32,875 operational taxonomic units (OTU) were mapped to 11 phylums, 81 families and 230 genera. The relationship between available microbiota biomarkers and efficacy outcome measures was investigated using a non-linear rules-based Formal Concept Analysis (FCA), as implemented in Ariana’s KEM software, generating all association rules. 8,143,928 hypotheses were explored and associations between gut microbiota abundances and cognitive outcome was identified. Results: The abundances of two microbiota families, Ruminococcaceae and Porphyromonadaceae, were associated with improved response at week 148 (p<0.01 and p<0.04 respectively). Moreover, a non-significant trend was identified linking the abundance of Verrucomicrobia phylum with cognitive improvement (Lift: 1.29, Confidence: 60%). Broadly, the abundance was found to be different for cognitive improvement compared to decline. Conclusions: This study represents an initial analysis of gut microbiota for AD patients in a clinical trial setting, testing exposure to a drug and monitoring outcome. A number of genera and families were identified as associated to response to ANAVEX 2-73 and are consistent with previous findings describing their implication in the brain-gut axis. Although our initial findings will need to be confirmed using larger cohorts from ongoing studies, this work illustrates the ability to use the KEM platform to integrate clinical, omic and microbiota data and identify potential biomarkers of response for ANAVEX 2-73. O4-02-05 CONTINUED INNOVATIONS IN STUDY START UP (SSU): ONGOING PROGRESS OF THE GAP FOUNDATION ON SITE START UP John Dwyer, Jason Bork, Gabe Goldfeder, Rona Schillinger, Doug Beauregard, Julie Nield, Elizabeth Gorman, Global Alzheimer’s Platform Foundation, Washington, DC, USA; Global Alzheimer’s Platform, Washington, DC, USA. Contact e-mail: dwyer@ globalalzplatform.org