Unraveling the complexity of neurodegeneration: heterogeneous damage patterns of locus coeruleus and substantia nigra in Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) involves complex neurodegeneration in the locus coeruleus (LC) and substantia nigra (SN), critical brain regions affecting cognitive and emotional processes. METHODS: Using the National Alzheimer's Coordinating Center dataset of 11,583 participants, we conducted a multimodal analysis involving descriptive statistics, multifactorial regression, mediation analysis, and receiver operating characteristic curve assessment. RESULTS: LC degenerative changes (18.57%) significantly exceeded SN changes (4.69%). The LC demonstrated stronger correlations with psychiatric symptoms and cognitive impairment. High LC/low SN damage patterns showed the strongest associations with mild cognitive impairment (OR = 2.38) and AD (OR = 3.56). DISCUSSION: Our research reveals the heterogeneous degeneration patterns of LC and SN in AD, providing crucial insights into neurobiological mechanisms and potential strategies for early diagnosis and intervention. HIGHLIGHTS: This study provides a comprehensive framework for understanding the heterogeneous neurodegeneration patterns in AD through a detailed examination of the LC and SN. The research bridges the gap between neuroanatomical changes and neuropsychiatric symptoms, offering a more nuanced perspective on disease progression. Our findings challenge traditional linear models of neurodegeneration, emphasizing the complex and non-uniform nature of neural deterioration in AD. The study underscores the critical importance of investigating multiple neural nuclei to comprehensively understand neurodegenerative processes. By exploring the differential vulnerabilities of LC and SN, we provide new insights into potential targeted therapeutic interventions.