Biochemical and Immunohistochemical Associations of TDP-43 and Cryptic RNA With Hippocampal and Amygdala Volumetrics in Alzheimer's Disease.

Abstract

Immunohistochemically (IHC) measured transactive response DNA-binding protein 43 (TDP-43) inclusions are observed in Alzheimer's disease (AD) and are associated with medial temporal lobe atrophy. Accumulation of cryptic exons occurs in AD in response to TDP-43 pathology. We aimed to assess relationships between IHC and biochemically measured insoluble TDP-43 and cryptic exons and assess associations with hippocampal and amygdala volume loss and atrophy rates on magnetic resonance imaging (MRI). Eighty-one neuropathologically diagnosed AD cases were analyzed. For biochemistry, insoluble TDP-43 was quantified using a Meso-scale discovery (MSD) immunoassay. IHC-TDP burden was quantified with digital histopathology. Cryptic RNAs were assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Thirty-eight cases had serial brain MRI. Hippocampal and amygdala volumes were calculated using FreeSurfer. Regression models were used to investigate associations among IHC-TDP-43 status/burden, MSD-TDP status/levels, cryptic RNAs, and hippocampal and amygdala volumes and atrophy rates. IHC-TDP(+) cases exhibited elevated levels of MSD-TDP and cryptic RNAs (KCNQ2, STMN2, and UNC13A) and increased MSD-TDP levels were associated with increased cryptic RNA levels, in the hippocampus and amygdala. IHC-TDP(+) cases had smaller hippocampal and amygdala volumes compared to IHC-TDP(-) cases. MSD-TDP(+) cases had smaller hippocampal volumes and faster amygdala rates of atrophy compared with MSD-TDP(-) cases. Higher KCNQ2 and UNC13A levels were associated with smaller amygdala volumes. MSD-TDP level is a reliable surrogate for IHC-based TDP-43 status. Both TDP-43 and cryptic RNA levels are associated with reduced medial temporal volumes, suggesting cryptic exons may be playing a role in brain volume loss in AD. ANN NEUROL 2026.