Detection of Alzheimer's disease (AD) specific tau pathology with conformation-selective anti-tau monoclonal antibody in co-morbid frontotemporal lobar degeneration-tau (FTLD-tau)

Pathological tau aggregates in Alzheimer's disease (AD) and frontotemporal lobar degeneration-tau (FTLD-tau) adopt distinct conformations differentiated by the AD-tau specific monoclonal antibody (mAb) GT-38 that are not readily visualized using phosphorylation-specific anti-tau mAbs. To determine the extent of co-morbid AD-tau pathology in FTLD-tau, we performed immunohistochemical (IHC) staining with GT-38 and assigned Braak stages of AD-tau in a cohort 180 FTLD-tau cases consisting of corticobasal degeneration (CBD; n=49), progressive supranuclear palsy (PSP; n=109), and Pick's disease (PiD; n=22). Nearly two-thirds of patients (n=115 of 180, 63.8%) with FTLD-tau had some degree of comorbid AD-tau pathology and 20.5% of the FTLD-tau cohort had Braak stage B2, consistent with medium-to-high-level AD neuropathological change (ADNPC). The PSP group had the highest frequency of medium-high AD-tau pathology compared to other tauopathies (PSP=31/109, 28.4%; Picks=2/22, 9.1%, CBD=4/49, 8.2%) but neuropathological diagnosis was not found to be a significant independent predictor of medium-high AD Braak stage in a multivariate model after accounting for age at death (OR=1.09; 95% CI=1.03-1.15; p=0.002) and CERAD plaque scores (OR=3.75, 95% CI=1.58-8.89; p=0.003), suggesting there is no predilection for a specific FTLD tauopathy to develop AD-tau co-pathology after accounting for age. Patients with FTLD-tau who had, clinically significant, medium-high AD-tau pathology had significantly higher antemortem CSF levels of both total-tau (t-tau; mean=89.98pg/ml, SD=36.70pg/ml) and phosphorylated-tau (p-tau; mean=20.45pg/ml, SD=9.31pg/ml) compared to patients with negligible-low AD-tau, t-tau (mean=43.04pg/ml, SD=25.40pg/ml) and p-tau (mean=11.90pg/ml, SD=4.48pg/ml) (p0.001 both). Finally, in an exploratory analysis in our largest pathology group (PSP) we find an association of GT-38AD-tau Braak stage with lower baseline MMSE (p=0.03). Together, these finding validate the use of GT-38 to selectively detect AD-tau pathology in the context of FTLD-tau and provides a novel tool to investigate associations of clinical phenotypes amongst co-morbid tauopathies.