Novel genetic association with resistance to ERC tau deposition

A novel genetic association with resistance to entorhinal cortex (ERC) tau deposition in older adults has been identified [1]. Results of a genome-wide association study of tau-PET also suggest that tau deposition may have a genetic architecture distinct from known Alzheimer's disease (AD) risk genes.

The study included 754 participants from the Mayo Clinic Study of Aging with genome-wide genotype and regional tau-PET (AV-1451) data. The mean age was 72.4 years, 54.6% were male, and 87.4% were cognitively impaired. A genome-wide association study of tau burden of the ERC (a sensitive marker of early tau deposition) was performed of 515,206 single nucleotide polymorphisms (SNPs) following genotyping with the Illumina GSA array. A post-hoc stratified analysis utilised amyloid-PET positivity (global PiB >1.48) as a discriminator.

A genome-wide significant association was found for rs75546066, in an intergenic region on chromosome 9. The minor allele (A, frequency 2.7%) was associated with lower ERC tau (P=2.85·10^-8; β=-0.49). The effect was stronger in amyloid-negative versus amyloid-positive individuals (β=-0.51 and -0.23, respectively).

The observation that tau deposition may have a genetic architecture distinct from known AD risk genes could have implications for enhanced risk prediction, according to the authors, as well as for therapeutic targeting.

1. Ramanan V, et al. Abstract S4.009, AAN 2020.

Posted on 8 September 202025 March 2024