Amygdala-predominant α-synuclein pathology is associated with exacerbated hippocampal neuron loss in Alzheimer's disease.

Misfolded α-synuclein protein accumulates in 43-63% of individuals with symptomatic Alzheimer's disease. Two main patterns of comorbid α-synuclein pathology have been identified: caudo-rostral and amygdala-predominant. α-Synuclein aggregates have been shown to interact with the transactive response DNA-binding protein 43 (TDP-43) and abnormally phosphorylated tau protein. All these proteins accumulate in the amygdala, which is anatomically connected with the hippocampus. However, the specific role of amygdala-predominant α-synuclein pathology in the progression of Alzheimer's disease and hippocampal degeneration remains unclear. In this cross-sectional study, we analysed 291 autopsy brains from both demented and non-demented elderly individuals neuropathologically. Neuronal density in the CA1 region of the hippocampus was assessed for all cases. We semiquantitatively evaluated α-synuclein pathology severity across seven brain regions and calculated a ratio of limbic to brainstem α-synuclein pathology severity, which was used to stratify the cases into two distinct spreading patterns. In the 99 symptomatic Alzheimer's disease cases, we assessed severity of limbic-predominant age-related TDP-43 neuropathological changes and CA1 phosphorylated tau density. We performed triple fluorescence staining of medial temporal lobe samples with antibodies against phosphorylated TDP-43, α-synuclein and phosphorylated tau. Finally, we employed path analysis to determine the association network of various parameters of limbic pathology in Alzheimer's disease cases and CA1 neuronal density. We identified an association between the amygdala-predominant αSyn pathology pattern and decreased neuronal density in the CA1 region. We found that Alzheimer's disease cases with an amygdala-predominant α-synuclein pattern exhibited the highest TDP-43 severity and prevalence of TDP-43 inclusions in the dentate gyrus among all groups, while those with the caudo-rostral pattern had the lowest severity of Alzheimer's disease neuropathological changes. We observed colocalization of TDP-43, aggregated α-synuclein and hyperphosphorylated tau in cytoplasmic inclusions within hippocampal and amygdala neurons of Alzheimer's disease cases. Path analysis modelling suggests that the relationship between amygdala-predominant α-synuclein pathology and CA1 neuron loss is partially mediated by hippocampal tau and TDP-43 aggregates. Our findings suggest that Alzheimer's disease cases with amygdala-predominant α-synuclein pathology may constitute a distinct group with more severe hippocampal damage, a higher TDP-43 burden and potential interactions among α-synuclein, TDP-43 and hyperphosphorylated tau.