Subtyping based on hippocampal cryptic exon burden reveals proteome-wide changes associated with TDP-43 and Alzheimer’s disease pathology

TDP-43 pathology defines limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and frequently co-occurs with Alzheimer's disease neuropathologic change (ADNC), yet the molecular consequences of overlapping pathology remain unclear. We performed biochemical and proteomic analyses of postmortem hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups. Cryptic exon (CE) inclusion was quantified across eight TDP-43-regulated transcripts and related to phosphorylated TDP-43 (pTDP-43), amyloid, and tau pathology. ADNC+LATE-NC cases showed the highest CE levels. Although CE inclusion correlated with pTDP-43, CE measures were more strongly intercorrelated and defined low, intermediate, and high CE subtypes largely independent of amyloid and tau. Proteome-wide analyses revealed reduced abundance of CE-target proteins and disruption of synaptic, endosomal, and RNA-binding pathways in high CE cases. These signatures overlapped with changes in TDP-43-depleted human i 3 Neurons, supporting biological relevance. Overall, CE burden provides a robust molecular classifier of TDP-43 dysfunction across LATE-NC and ADNC.