Project Overview

Genetic variants in multiple genes increase disease risk and progression in tauopathies. Of the hundreds of annotated variants identified in any single relevant gene, such as Tau, over 90% have no known impact on risk,leaving physicians unable to interpret their clinical significance when encountered. This proposal aims to test a systematic experimental platform in Drosophila for its ability to create a reference database of variant impacts,providing clinicians an evidence-based resource for patient care.

This proof-of-concept study will demonstrate the feasibility of using Drosophila to systematically assess and catalog variant impacts in tauopathy-relevant genes. Beginning with naturally-occurring variants in tau’s critical aggregation domains which remarkably have never been examined for disease relevance, we will establish and validate core platform components needed for high-throughput variant testing. On this successful blueprint, we will thereafter expand this approach to build a comprehensive clinical reference database, similar to those transforming cancer variant interpretation.

We will develop and validate key components needed for scalable variant testing: standardized genetic engineering, consistent expression systems, novel technologies facilitating flexible expansion of reagents, multi-modal analysis of neurotoxicity. As proof-of-concept, we will assess the platform’s toolkit in testing all annotated variants in Tau’s aggregation domains, which remain unexamined to date. This initial dataset will demonstrate our platform’s ability to generate reliable, clinically relevant data, establishing a foundation for comprehensive variant assessment in tauopathy-relevant genes.

Our proof-of-concept platform will immediately deliver clinically relevant data about variants in Tau’s drug-targetable aggregation domains. Long-term, validating this approach will enable systematic assessment of all tauopathy-related variants. For the dementia community, this means transforming genetic test results from sources of anxiety into tools for informed decision-making. The platform will help identify both risk-enhancing variants requiring early intervention and protective variants that could guide new therapeutic strategies.

This study addresses a critical need in tauopathy patient care: when genetic variants are identified, physicians cannot act unless the variant’s pathogenicity and impact on disease risk or progression is known. By demonstrating we can build a reliable experimental platform for scalable variant testing, this work will establish a path toward building a comprehensive variant interpretation database. This would potentially transform clinical decision-making by powering improved single variant and polygenic risk assessment for individual patients.

Principal Investigator

Douglas Allan , University of British Columbia

Partners and Donors

Alzheimer Society of Canada