Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease.

Pathological tau isoforms, including hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and AD dementia. These patients exhibit significant retinal ganglion cell (RGC) loss, however the presence of tau isoforms in RGCs and their impact on RGC integrity, particularly in early AD, have not been studied. Here, we analyzed retinal superior temporal cross-sections from 25 MCI or AD patients and 16 age- and sex-matched cognitively normal controls. Using the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining, we found a 46-56% reduction in RBPMS⁺ RGCs and Nissl⁺ neurons in the ganglion cell layer (GCL) of MCI and AD retinas (P < 0.05-0.001). RGC loss was accompanied by soma hypertrophy (10-50% enlargement, P < 0.05-0.0001), nuclear displacement, apoptosis (30-50% increase, P < 0.05-0.01), and prominent expression of granulovacuolar degeneration (GVD) bodies and GVD-necroptotic markers. Both pS396-tau and Oligo-tau were identified in RGCs, including in hypertrophic cells. PS396-tau⁺ and Oligo-tau⁺ RGC counts were significantly increased by 2.1-3.5-fold in MCI and AD retinas versus control retinas (P < 0.05-0.0001). Tauopathy-laden RGCs strongly inter-correlated (r_P=0.85, P < 0.0001) and retinal tauopathy associated with RGC reduction (r_P=-0.40-(-0.64), P < 0.05-0.01). Their abundance correlated with brain pathology and cognitive deficits, with higher tauopathy-laden RGCs in patients with Braak stages (V-VI), clinical dementia ratings (CDR = 3), and mini-mental state examination (MMSE ≤   26) scores. PS396-tau⁺ RGCs in the central and mid-periphery showed the closest associations with disease status, while Oligo-tau⁺ RGCs in the mid-periphery exhibited the strongest correlations with brain pathology (NFTs, Braak stages, ABC scores; r_S=0.78-0.81, P < 0.001-0.0001) and cognitive decline (MMSE; r_S=-0.79, P = 0.0019). Overall, these findings identify a link between pathogenic tau in RGCs and RGC degeneration in AD, involving apoptotic and GVD-necroptotic cell death pathways. Future research should validate these results in larger and more diverse cohorts and develop RGC tauopathy as a potential noninvasive biomarker for early detection and monitoring of AD progression.