Amygdala-predominant α-synuclein pathology exacerbates hippocampal neuron loss in Alzheimer’s disease

Misfolded α-synuclein (αSyn) protein accumulates in 43-63% of individuals with symptomatic Alzheimer’s disease (AD). Two main patterns of co-morbid αSyn pathology have been identified: caudo-rostral and amygdala-predominant, with the latter being more common in AD. αSyn pathology has been shown to interact with DNA-binding protein 43 (TDP-43) and abnormally phosphorylated Tau protein (pTau). These proteins tend to accumulate in the amygdala, yet the specific role of amygdala-predominant αSyn pathology in the progression of AD and hippocampal degeneration remains unclear. In this cross-sectional study, we analyzed 291 autopsy brains from both demented and non-demented elderly individuals neuropathologically. Neuronal density in the CA1 region of the hippocampus was assessed using hematoxylin-stained sections for all cases. We semi-quantitatively evaluated αSyn pathology severity in six brain regions and stratified the cases into the two spreading patterns. In 99 AD cases, we assessed limbic-predominant age-related TDP-43 neuropathological changes (LATE-NC), CA1 pTau density, and cerebral amyloid angiopathy (CAA). Structural equation modeling analysis was conducted based on the assessed pathological parameters in AD patients. We identified an association between the amygdala-predominant αSyn pathology pattern and decreased neuronal density in the CA1 region. AD patients with an amygdala-predominant αSyn pattern exhibited the most severe pTDP-43 pathology among all groups, while those with the caudo-rostral pattern had the lowest severity of AD-related pathological changes including CAA type 1. Our model revealed that the relationship between αSyn pathology and CA1 neuron loss is mediated through pTau and LATE-NC. Our results indicate that amygdala-predominant αSyn pathology, in contrast to αSyn pathology with a caudo-rostral pattern, significantly contributes to hippocampal neuron loss, potentially by accelerating TDP-43 and pTau pathologies. This finding, along with observed neuropathological differences between AD patients with these two αSyn spreading patterns, underscores the need for precise stratification of patients. The stratification should consider not only the molecular and morphological identity of co-pathologies but also the distribution pattern of the respective co-pathologies.