Objective: To map alpha-synuclein (asyn) and tau markers in amygdala-predominant Lewy body disease (AP-LBD), identifying spread pathways and vulnerable cell populations.

Background: LBD often co-occurs with Alzheimer’s (AD), resulting in more cognitive decline than AD or LBD alone. AP-LBD is prevalent in AD, especially early-onset (EOAD), does not conform with the common staging systems for LBD, and has received little attention. In AP-LBD cases, some show a slight extension of disease from the amygdala to adjacent structures, suggesting the amygdala is a key node, but the factors enabling asyn propagation in some amygdalae remain unknown. We found asyn seeding-competent fibrils in cerebrospinal fluid (CSF) strongly correlate with this extension, supporting the relevance of AP-LBD for understanding pathogenesis and as a potential cohort for intervention.

Method: We identified all postmortem cases with AP-LBD in EOAD to limit other age-related co-pathology from the UCSF Neurodegenerative Disease Brain Bank (n=59), 33 with olfactory bulb available, and 20 with banked CSF for asyn seeding amplification testing. We are using multiplex immunofluorescence to label phosphorylated asyn, truncated tau, and all neurons, and from digital pathology scans, we are training an AI algorithm to quantify labeled neurons by region for the central, basolateral, and cortical nuclei.

Results: LBD was identified exclusively in the amygdala (n=23, type 1) or with slight emergence in the substantia nigra (n=6, type 2), hippocampus (n=8, type 3), or both (n=22, type 4). Of 20 CSF samples, 55% were positive and 5% indeterminate for asyn seeding; 0/5 type 1 and 7/8 type 4 cases were positive. Olfactory LBD was found in 94% of cases. Asyn and tau markers by subnucleus will be compared between CSF-positive and -negative cases. We will report the pattern of LBD across amygdala subnuclei.

Conclusion: Mapping AP-LBD across amygdala subnuclei may yield insights into selectively vulnerable neurons. Better understanding of AP-LBD and its underlying mechanisms may contribute to the development of more targeted diagnostic and therapeutic strategies for some early-stage LBD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/amygdala-predominant-lewy-body-disease-is-a-lens-for-understanding-pathogenesis-and-the-alpha-synuclein-seeding-assay-in-human-postmortem-brain/