A positive association between phosphorylated Tau217 (pTau217) and neural correlations is prevented by human leukocyte antigen allele DRB1*13:01

Subtle deviations in zero-lag cross correlations (synchronous neural interactions, SNI) differentiate healthy from pathological brain states. Here, we assessed blood biomarkers of dementia and neurodegeneration in relation to SNI in 175 women participating in a longitudinal study for a total of 348 acquisitions. Of seven biomarkers tested (Aβ_1-40, Aβ_1-42, Aβ_1-42/Aβ_1-40 ratio, neurofilament light chain [NFL], total Tau, phosphorylated Tau181 [pTau181], phosphorylated Tau217 [pTau217]), only pTau217 showed a significant positive association with SNI (P = 0.0027) which was negatively associated with cognitive performance. Apolipoprotein E (ApoE) did not influence the pTau217-SNI association, whereas human leukocyte antigen (HLA) DRB1*13:01 reduced the association. The pTau217-SNI association was pronounced in participants seropositive for human herpes virus 1 (HHV1) and human endogenous retrovirus K (HERVK). This effect was abolished in carriers of HLA DRB1*13:01, consistent with the strong predicted binding affinity of this allele with proteins of these viruses. These findings highlight the association of pTau217 with brain function and point to a central role of HLA-mediated immune responses in preserving brain health.