Histopathological alterations of deep cervical lymph nodes in Alzheimer's disease and their association with cognitive decline

Abstract Background Alzheimer’s disease (AD) is characterized by progressive cognitive and functional decline with amyloid-beta (Aβ) and tau pathology. In addition to abnormal protein aggregation, impaired clearance of brain-derived solutes through glymphatic and meningeal lymphatic pathways may contribute to disease progression. Deep cervical lymph nodes (DCLNs), as major downstream lymphoid structures of central nervous system drainage, may provide a peripheral histological window into the brain-cervical lymphatic axis. However, whether human DCLNs undergo histopathological remodeling in AD and whether such changes are clinically relevant remain unclear. Methods DCLNs were obtained from 66 participants, including 59 patients with moderate-to-severe AD and 7 cognitively unimpaired controls. Hematoxylin and eosin staining was used to assess lymph node morphology and germinal center (GC) abundance. Multiplex immunofluorescence was performed to evaluate Aβ, tau, alpha-smooth muscle actin (alpha-SMA), CD31, and LYVE-1. Cognitive and functional status were assessed using the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Activities of Daily Living (ADL) scores. AD patients were stratified by GC abundance using a cutoff of 4 GCs. Multivariate logistic regression, receiver operating characteristic analysis, decision curve analysis, and 6-month postoperative follow-up were performed. Results DCLNs from patients with AD showed histopathological remodeling, including reduced GC abundance, structural disruption, fibrosis-related stromal changes, altered vascular and lymphatic marker expression, and detectable Aβ and tau immunoreactivity. Compared with patients with > 4 GCs, those with ≤ 4 GCs had worse baseline cognitive and functional status, including lower MMSE scores and higher CDR-SB and ADL scores. In multivariate analysis, higher alpha-SMA mean fluorescence intensity was associated with a lower likelihood of preserved GC abundance, whereas higher MMSE score was associated with preserved GC abundance. Patients with > 4 GCs also showed greater improvement in MMSE, CDR-SB, and ADL scores at 6 months postoperatively. Conclusions Human DCLNs exhibit histopathological remodeling in AD. Reduced GC abundance is associated with greater clinical impairment, fibrosis-related remodeling, and poorer 6-month postoperative improvement, suggesting that DCLN histopathology may have potential clinical and prognostic relevance in AD.