Co-pathologies modify hippocampal protein accumulation patterns in neurodegenerative diseases

INTRODUCTION: Limited research has extensively analyzed neurodegenerative disease–related protein deposition patterns in the hippocampus. METHODS: This study examined the distribution of proteins in hippocampal subregions across major neurodegenerative diseases and explored their relation to each other. The area density of phosphorylated tau (p-tau), amyloid beta (Aβ), α-synuclein, and phosphorylated TDP-43 protein deposits together with pyramidal cell density in each hippocampal subregion, including CA1-4, prosubiculum (ProS), and subiculum was assessed in 166 cases encompassing various neurodegenerative diseases. RESULTS: Alzheimer's disease-associated p-tau predominated in ProS, Aβ in the CA1, and Lewy body–related α-synuclein in the CA2. The area density of protein deposits increased with the pathological stage until a peak, then decreased in cases with high pathology stages along with pyramidal cell density. Comorbid protein pathology influenced protein deposition patterns. DISCUSSION: This comprehensive evaluation reveals characteristic neurodegenerative disease–related protein accumulation patterns in hippocampal subregions modified by co-pathologies. Highlights: Alzheimer's disease–related phosphorylated tau predominates in the prosubiculum. Amyloid beta predominates in the CA1 and Lewy body–related α-synuclein in the CA2. The area density of protein deposition increases with the disease stage up to a peak. In the high pathology stage, protein deposition and pyramidal cell density decreases. Comorbid protein pathology affects the pattern of protein accumulation.