Greater locus coeruleus vulnerability in atypical clinicopathologic forms of Alzheimer's disease

INTRODUCTION: The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD). However, the extent of rostrocaudal degeneration across clinicopathologic heterogeneity remains underexplored in AD. METHODS: Using digital pathology, we quantified LC neuronal density and area at three neuroanatomic levels in a large AD series. RESULTS: Analysis of neuropathologic AD subtypes revealed greater middle LC vulnerability in hippocampal sparing AD compared to typical and limbic predominant AD. Regression analyses identified distinct predictor variables associated with the degeneration of rostral and middle LC. Age at onset predicted 24% of the variability in rostral LC neuronal density, whereas Braak stage, brain weight, Lewy body disease, and age at onset accounted for 15% of the variability in middle LC. Analyses of clinical presentations revealed lower rostral LC neuronal density in non-amnestic compared to amnestic AD cases. DISCUSSION: These insights demonstrate greater LC degeneration in atypical clinicopathologic forms of AD, including hippocampal sparing, young-onset, and non-amnestic presentations.