FTLD-Tau is a neuropathologic diagnosis for patients with frontal temporal lobar degeneration from a tauopathy. These patients compose about half of frontotemporal dementia (FTD) patients; most other FTD patients have a proteinopathy from TDP-43 (tar DNA binding protein-43) referred to as FTLD-TDP (Irwin et al., 2015). There is no approved therapeutic for FTLD-Tau or FTLD-TDP, and optimal clinical trial design has been impeded by challenges in clinically distinguishing FTLD-Tau, not only from FTLD-TDP, but also from Alzheimer's disease (AD). For example, as many as 30% of patients diagnosed clinically with FTD can have a neuropathologic diagnosis of AD (Irwin et al., 2013; Kertesz et al., 2005; Knibb et al., 2006). While some FDA-approved AD biomarkers are serving useful to detect AD neuropathologic change (ADNC) during life, (Fleisher et al., 2020; Jack et al., 2018) biomarkers specific to FTLD are lacking. Thus, there continues to be a critical need for biomarkers indicative of the underlying molecular pathology to enable patient stratification for therapies aimed at the molecular pathology.

Growing literature has pointed towards the retina as a potential biomarker for dementia as it is an extension of the central nervous system that can be easily imaged at high-resolution (Chan et al., 2018; Kashani et al., 2021; Moinuddin et al., 2021). Spectral-domain optical coherence tomography (OCT) is a non-invasive imaging modality that is widely available, inexpensive, and can image the retina within minutes. Compared to normal controls, we found with OCT that a group of FTD patients with clinical or genetic/autopsy findings suggestive of underlying FTLD-Tau pathology had outer retina thinning driven by loss of the photoreceptor outer nuclear layer (ONL) (Kim et al., 2017). We have previously validated these findings using two different OCT image segmentation algorithms, and longitudinal data has suggested that this ONL thinning persists and progresses among probable FTLD-Tau patients (Kim et al., 2019; Sun et al., 2020). Moreover, we found ONL loss in the retinal tissue of two FTLD-Tau patients who had ONL thinning during life on OCT for important postmortem validation (Kim et al., 2021). Importantly, these findings of ONL (outer retina) thinning contrast with other studies of OCT imaging and histopathology data in AD patients which find predominant inner retina (nerve fiber layer and ganglion cell layer) thinning, but comparative studies with FTLD-Tau are lacking (Chan et al., 2018).

Here, we take a critical step to build on our previous work by addressing this gap. We test the hypothesis that ONL thinning is specific to FTLD-Tau compared to AD, and ONL thinning will relate to measures of disease severity in a prospective cohort of deeply phenotyped patients.