Background: Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD.
Methods: We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from [18] F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from [18] F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses.
Results: GWAS of tau-SUVR revealed two significant loci: rs78636169 ( P =5.76×10 -10 ) in JARID2 and rs7292124 ( P =2.20×10 -8 ) near ISX . Gene-based analysis of tau deposition highlighted APOE ( P =2.55×10 -6 ), CTNNA3 ( P =2.86×10 -6 ) and JARID2 ( P =1.23×10 -4 ), a component of the PRC2 multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with PRC2 multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger APOE -ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers.
Conclusion: We identified a novel potential therapeutic target, JARID2 in the PRC2 multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.