Aberrant aggregation, misfolding, and mislocalization of the microtubule-associated protein tau characterize several neurodegenerative diseases, termed tauopathies. Alzheimer's disease (AD) is the most common tauopathy and most prevalent form of dementia within the global aging population. AD is distinguished from related dementias by the presence of two aggregant protein pathologies: intracellular neurofibrillary tangles (NFTs) composed of aggregated tau protein and extracellular amyloid- beta (A beta ) plaques. While heritable mutations in amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) have considerably advanced our understanding of AD pathogenesis, they account for only a small portion of total AD cases. The majority of AD cases present without known causative mutations. However, human genomic studies have revealed a number of genetic variants contributing significant risk for AD. Genetic analysis by genome wide association studies (GWAS) has led to the identification of several novel genetic risk factors (e.g. ABCA7, PICALM, DSG2, INPP5D, MEF2C, PTK2?, SLC24H4-RIN3, SYK and ABI3). We have observed that a subset of these gene variants modulate the severity of tau pathology in our C. elegans model of tauopathy. In this model, pan-neuronal expression of human tau recapitulates several features of human disease including accumulation of detergent-insoluble phosphorylated tau aggregates, abnormal behavior, neurodegeneration, and shortened lifespan. Loss of function mutations in C. elegans homologs corresponding to GWAS nominated genes
abl-1 (SYK) and
hmr-1 (DSG2) enhance motility defects in human tau expressing worms, while
abt-2 (ABCA7) and
kin-32 (PTK2?) do not. Candidate genes that affect tau-induced motility phenotypes will be further tested for the ability to modulate pathological tau and neurodegeneration. Identification of the molecular mechanisms underpinning genetic risk for AD remains a key unaddressed area and may provide novel therapeutic targets.