GWAS of Tau‐Neurodegeneration Mismatch Identifies New Risk Loci for Susceptibility to Tau

ABSTRACT Background In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau‐neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies. Methods Here, I perform a genome‐wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4. Results A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome‐wide significance threshold ( p ≤ 5 × 10 −8 ). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10 −8 ; rs9784993, MAF = 0.197, p = 4.92 × 10 −8 ) was associated with lower Tau/Neurodegeneration residuals, indicating higher‐than‐expected neurodegeneration given tau levels. Conclusion GWAS of tau‐related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau‐neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.