Genome-wide Association Study of Tau PET in the Mayo Clinic Study of Aging
Vijay Ramanan1, Xuewei Wang2, Scott Przybelski1, Sheela Raghavan3, David Knopman1, Jonathan Graff-Radford1, Val Lowe1, Michelle Mielke1, Clifford Jack1, Ronald Petersen1, Owen Ross1, Prashanthi Vemuri1
1Mayo Clinic, 2Health Sciences Research, 3Radiology, Mayo Clinic
To identify genetic factors associated with tau deposition in older adults.

Tau deposition is a key biological feature of Alzheimer’s disease, but the heritable influences on susceptibility and resistance to tau deposition are not well-understood.  The recent availability of tau-PET provides an opportunity to test the hypothesis that common genetic variants would be associated with entorhinal cortex (ERC) tau burden, a sensitive marker of early tau deposition.

Inclusion criteria included individuals over age 50 from the population-based Mayo Clinic Study of Aging with genome-wide genotype and regional tau-PET (AV-1451) data.  Following genotyping with the Illumina GSA array and standard quality control, 515,206 single nucleotide polymorphisms (SNPs) were available for analysis.  A genome-wide association study of ERC tau was performed using an additive genetic model and covarying for age and sex.  Post-hoc stratified analyses utilized amyloid positivity (global PiB>1.48) as a discriminator.

The study sample included 754 individuals (mean age 72.4 years, 54.6% men, 87.4% cognitively unimpaired).  A genome-wide significant association was identified for rs75546066, in an intergenic region on chromosome 9, with the minor (A, frequency=2.7%) allele associated with lower ERC tau (p=2.85x10-8, β=-0.49), and with a stronger effect in amyloid-negative (β=-0.51) versus amyloid-positive (β=-0.23) individuals.  No associations with ERC tau burden were identified for the SNPs defining APOE (apolipoprotein E) ɛ4 or for genotyped SNPs previously associated with AD in large case-control studies.  Three SNPs within MAPT (microtubule-associated protein tau) displayed nominal associations to ERC tau burden, including rs3785883 (p=0.04, β=0.07) which was previously associated with higher cerebrospinal fluid tau in an independent cohort.


This study identified a novel genetic association with resistance to ERC tau deposition in older adults.  Our data also suggests that tau deposition may have a genetic architecture distinct from known AD risk genes, which may have implications for enhanced risk prediction and therapeutic targeting.