Basic Science and Pathogenesis.

Background: APOE is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOE is well known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology.

Method: To elucidate this potential effect, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOE and n = 5 APOE), using a combination of anti-pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry. This proteomic approach was complemented by a neuropathological analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOE and n = 10 APOE).

Result: Our dataset includes 1130 and 1330 proteins enriched in IP samples from APOE and APOE groups (FC ≥ 1.50, IP versus IP). We identified 80 and 68 proteins as pTau interactors in APOE and APOE groups, respectively (SAINT score ≥ 0.80; FDR ≤ 5%). A total of 47/80 proteins were identified as pTau interactors only for APOE cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as pTau interactors only for APOE cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A comprehensive characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE cases.

Conclusion: Our study supports an influence of APOE genotype on pTau subcellular location in the human brain. These results are consistent with a facilitation of pTau progression in Aβ-affected brain regions of APOE carriers, paving the way to the identification of potential new therapeutic targets.