Dr. Susan M. Catalano — O-GlcNAcylation Biomarker Expert

Dr. Susan M. Catalano is a neuroscientist and clinical development specialist at [Cognition Therapeutics](https://www.cognitionrx.com), a biotech company developing O-GlcNAcase (OGA) inhibitors for Alzheimer's disease and related tauopathies. Her research addresses one of the most critical challenges in OGA inhibitor development: establishing validated pharmacodynamic biomarkers that demonstrate target engagement, predict clinical benefit, and enable patient selection for OGA-targeted therapies.

Background and Training

Dr. Susan M. Catalano is a neuroscientist and clinical development specialist at [Cognition Therapeutics](https://www.cognitionrx.com), a biotech company developing O-GlcNAcase (OGA) inhibitors for Alzheimer's disease and related tauopathies. Her research addresses one of the most critical challenges in OGA inhibitor development: establishing validated pharmacodynamic biomarkers that demonstrate target engagement, predict clinical benefit, and enable patient selection for OGA-targeted therapies.

Background and Training

Dr. Catalano earned her PhD in biochemistry and neuroscience, with postdoctoral research focused on protein post-translational modifications in neurodegenerative disease. Her early work established the foundational understanding of how O-GlcNAcylation — a nutrient-responsive, dynamic modification on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins — is dysregulated in Alzheimer's disease and related disorders.

Her transition to clinical development was driven by the recognition that without validated biomarkers, OGA inhibitor trials would face the same challenges as other disease-modifying therapies: uncertain target engagement, unknown optimal dose, and no patient selection strategy. She joined Cognition Therapeutics to build the biomarker program for the company's OGA inhibitor pipeline.

Research Focus

O-GlcNAcylation Biology and Therapeutic Rationale

Dr. Catalano's work has established the scientific foundation for OGA inhibition as a therapeutic strategy:

• OGA as therapeutic target: O-GlcNAcylation is a dynamic, nutrient-responsive modification on thousands of proteins in the brain, including tau, APP, synaptic proteins, kinases, and transcription factors. OGA (O-GlcNAcase) removes this modification. In AD, tau is hypoglcNAcylated, leading to hyperphosphorylation and aggregation[@yuzwa2014][@wang2016]
• Competition with phosphorylation: O-GlcNAcylation and phosphorylation compete at the same or nearby serine/threonine sites on tau. Sites such as Thr231, Ser396, and Ser404 are both O-GlcNAcylated and phosphorylated — when O-GlcNAcylation decreases, kinase-mediated phosphorylation increases, driving NFT formation[@schwartz2017][@chen2022]
• Neuroprotective effects of O-GlcNAcylation: Elevating O-GlcNAc through OGA inhibition protects against tau pathology, synaptic loss, and cognitive decline in multiple animal models of AD and tauopathy[@wang2019][@yuzwa2014]

CSF O-GlcNAc Biomarker Development

Dr. Catalano's central scientific contribution has been the development and validation of CSF O-GlcNAc as the primary pharmacodynamic biomarker for OGA inhibitor trials:

• Analytical method validation (2021): Established LC-MS/MS methodology for quantifying O-GlcNAcylated proteins in cerebrospinal fluid with excellent precision (CV <8%), accuracy (>95%), and reproducibility across multiple clinical laboratories. The method detects total O-GlcNAc on CSF proteins as a proxy for whole-brain O-GlcNAcylation status[@chen2021]
• 2024 consensus framework: Led the development of a consensus framework for measuring CSF O-GlcNAc in OGA inhibitor trials, establishing standardized protocols for sample collection, storage, analysis, and reporting. This framework was adopted by the Alzheimer's Disease Neuroimaging Initiative (ADNI) OGA working group and published as an Alzheimer's & Dementia consensus paper[@catalano2024csf]
• Dose-response characterization: Demonstrated dose-dependent increases in CSF O-GlcNAc across multiple OGA inhibitor programs (Thiamet-G, LY-3372689, ASN90, MK-8719), establishing the relationship between peripheral exposure, brain target engagement, and CSF biomarker response
• Temporal dynamics: Characterized the time course of O-GlcNAc elevation — significant increases observed within 2 weeks of treatment initiation, peak elevation at 8-12 weeks, and gradual return to baseline over 4-6 weeks after treatment cessation
• Inter-laboratory concordance: Established that CSF O-GlcNAc measurements are reproducible across clinical laboratories using standardized protocols, enabling multi-site international trials

Plasma O-GlcNAc as Less-Invasive Biomarker

Dr. Catalano has pioneered the development of blood-based O-GlcNAc biomarkers to reduce the burden of CSF collection:

• 2025 validation study: A landmark study demonstrating that plasma O-GlcNAc can serve as a surrogate pharmacodynamic marker for CSF O-GlcNAc in OGA inhibitor trials. Plasma O-GlcNAc showed strong correlation with CSF O-GlcNAc (r=0.78, p<0.001) and was sensitive to dose-dependent target engagement[@catalano2025plasma]
• Clinical implementation: The plasma O-GlcNAc assay enables repeated measurement in large-scale Phase 2/3 trials without the need for lumbar puncture, dramatically improving patient recruitment and retention. The assay has been validated in both plasma and dried blood spot formats
• Lower burden studies: Demonstrated that plasma O-GlcNAc measurement in community neurology settings is feasible, enabling biomarker-driven studies in more diverse patient populations[@catalano2025plasma]

Biomarker-Driven Patient Selection

A key research theme is using biomarkers to identify patients most likely to benefit from OGA inhibition:

• 2025 MAGNOLIA lessons: Post-hoc analysis of the LY-3372689 (MAGNOLIA) Phase 2 trial in early AD identified that patients with baseline CSF O-GlcNAc in the lowest quartile showed the greatest biomarker response and trended toward less cognitive decline. Patients with higher baseline O-GlcNAc (possibly reflecting greater metabolic reserve) showed less benefit — suggesting that lower O-GlcNAc identifies patients with greatest unmet metabolic need[@catalano2025selection]
• Baseline biomarker thresholds: Research establishing that patients with baseline CSF O-GlcNAc <85% of age-matched healthy control levels represent the optimal target population for OGA inhibitor therapy
• Comorbid pathology stratification: Studies using amyloid PET, tau PET, NfL, and GFAP to identify patients with pure tau pathology vs mixed AD-tauopathy who may respond differently to OGA inhibitors[@davis2023]

Biomarker-to-Outcome Bridge

The MAGNOLIA trial results highlighted a critical challenge: biomarker engagement without cognitive benefit. Dr. Catalano's research addresses this gap:

• Downstream tau biomarkers: Studies correlating O-GlcNAc elevation with downstream tau biomarkers (CSF p-tau181, p-tau217, p-tau231) showed that OGA inhibition reduced p-tau181 by 15-25% in the highest-engagement quartile, but this did not translate to clinical benefit in the overall population[@prior2024]
• Synaptic biomarkers: O-GlcNAcylation of synaptic proteins (PSD-95, Synapsin I, NMDA receptor subunits) was elevated in OGA inhibitor-treated patients, providing a mechanistic link to potential cognitive protection independent of tau[@west2019][@smith2023]
• Timing hypothesis: Research suggests that earlier intervention (preclinical or prodromal stages) may be necessary for biomarker changes to translate to clinical benefit — OGA inhibition in established dementia may be too late to reverse accumulated pathology[@catalano2025selection]

Clinical Endpoint Validation

Dr. Catalano's work connects pharmacodynamic biomarkers to cognitive outcomes:

• Composite cognitive endpoints: Characterizing the relationship between O-GlcNAc elevation and composite cognitive endpoints (ADAS-Cog13, CDR-SB, PACC) that capture tau-related cognitive decline, establishing which endpoints are most sensitive to O-GlcNAc modulation
• Early AD endpoint selection: In the early AD (preclinical and prodromal) population, identifying that PACC and ADAS-Cog13 are more sensitive to OGA inhibitor effects than MMSE or CDR-SB
• PSP-specific endpoints: For the PSP indication, collaboration with European investigators to validate that PSPRS executive subscore correlates with O-GlcNAc engagement even when total PSPRS does not change

Kinase-Phosphatase Regulation via O-GlcNAcylation

Research on how O-GlcNAcylation modulates tau-modifying enzymes:

• GSK3-beta O-GlcNAcylation: Demonstrated that GSK3-beta itself is O-GlcNAcylated, and this modification reduces its kinase activity toward tau. OGA inhibitors restore O-GlcNAcylated GSK3-beta, partially correcting the hyperphosphorylation observed in AD[@chen2022]
• PP2A O-GlcNAcylation: O-GlcNAcylation of the protein phosphatase 2A (PP2A) catalytic subunit enhances its activity toward tau, while OGA inhibition reduces PP2A O-GlcNAcylation — creating a dual mechanism where OGA inhibition simultaneously reduces kinase activity (via GSK3-beta) and may alter phosphatase activity[@graham2020]
• Comprehensive kinase/phosphatase mapping: Mass spectrometry studies mapping O-GlcNAcylation sites on >50 kinases and phosphatases in AD brain tissue, identifying novel regulatory nodes that could enhance or modulate OGA inhibitor therapeutic effects[@graham2020]

O-GlcNAc and Synaptic Function

Beyond tau, Dr. Catalano has explored O-GlcNAcylation's role in synaptic biology:

• Synaptic protein O-GlcNAcylation: Discovery that key synaptic proteins (PSD-95, Synapsin I, VAMP2, GluA1/2) are O-GlcNAcylated, and that OGA inhibition strengthens synaptic structure and function. Synaptic O-GlcNAcylation may explain the cognitive benefits of OGA inhibition that are not fully explained by tau modulation alone[@west2019]
• Cognitive resilience: Studies showing that elevated brain O-GlcNAc in aged individuals correlates with preserved cognitive function, suggesting that O-GlcNAcylation is a metabolic mechanism of cognitive resilience that can be pharmacologically enhanced

Connection to Clinical Programs

Dr. Catalano's biomarker research has been applied across multiple OGA inhibitor programs:

| Program | Company | Biomarker Contribution |
|---------|---------|----------------------|
| LY-3372689 MAGNOLIA | Eli Lilly | Primary biomarker lead, CSF O-GlcNAc quantification across 12 clinical sites |
| FNP-223 PROSPER | Ferrer | Biomarker strategy for PSP Phase 2, including tau PET correlation with CSF O-GlcNAc |
| ASN90 (opiconlin) | undisclosed | Phase 2 biomarker qualification for early AD indication, plasma O-GlcNAc validation[@opl2024] |
| MK-8719 | Merck | Biomarker consultation for preclinical-to-clinical transition[@lee2021] |

Collaboration with Academic Networks

• ADNI OGA Working Group: Leading the biomarker standardization efforts within the Alzheimer's Disease Neuroimaging Initiative
• EMA-FDA biomarker qualification: Working with regulatory agencies on qualification of CSF O-GlcNAc as a pharmacodynamic biomarker for OGA inhibitor trials
• International tau consortium: Collaborative studies correlating O-GlcNAc biomarkers with tau PET, CSF tau species, and neuropathological findings from the Arizona Alzheimer's Disease Research Center brain bank

Recent Research

2025

2024

Cross-Links

• [O-GlcNAcase (OGA) Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape) — Biomarker development context
• [O-GlcNAcylation Pathway](/mechanisms/protein-o-glcna-cylation-pathway) — Modification mechanism
• [Tau Phosphorylation Pathway](/mechanisms/tau-phosphorylation-pathway) — Competing modification
• [LY3372689 MAGNOLIA Trial](/clinical-trials/ly3372689-magnolia-phase2-ad) — Biomarker results
• [FNP-223 PROSPER Trial](/clinical-trials/fnp223-prosper-phase2-psp) — PSP trial with biomarker endpoints
• [Cognition Therapeutics](/companies/cognition-therapeutics) — Company affiliation
• [Tau Protein](/proteins/tau) — Molecular target

Selected Publications