Translating peripheral blood biomarkers into Alzheimer’s disease care: an exploratory dual-pathway model of immune and viral dynamics in behavioral and psychological symptoms of dementia

Background Behavioral and psychological symptoms of dementia (BPSD) critically complicate Alzheimer’s disease care, yet the precise biological correlates for highly heterogeneous symptom domains remain largely unexplored. Objective To investigate an exploratory “dual-pathway framework” to map how macroscopic immunosenescence and elevated latent viral antibody titers parallelly correlate with distinct neurobehavioral phenotypes. Methods We evaluated 103 older adults diagnosed with mild cognitive impairment (n = 40) or probable Alzheimer’s disease ( n = 63). The severity and frequency of behavioral domains were assessed using the Neuropsychiatric Inventory (NPI). These profiles were correlated with peripheral blood lymphocyte subsets and serological markers of neurotropic Herpesviridae. Results Macroscopic immunosenescence, reflected by an elevated CD4/CD8 ratio (>1.58), differentiated Alzheimer’s disease from mild cognitive impairment ( p = 0.028), indicating cross-sectional clinical status. To address the highly zero-inflated distribution of BPSD symptoms, we employed a two-step hurdle-like approach. Initial comparisons revealed that elevated EBV-VCA IgM titers were significantly associated with the occurrence of BPSD symptoms ( p = 0.0475). However, subsequent severity analyses exclusively within symptomatic subsets showed that viral titers lacked a continuous linear correlation with symptom severity. Instead, the reduced absolute counts of adaptive immune cells (CD3+, CD4+, and CD19+) exhibited a robust, dose-dependent negative correlation with the global neurobehavioral burden (Total NPI score). Conclusion Behavioral and psychological symptoms of dementia are associated with an exploratory dual-pathway model. Elevated viral antibody titers act as an immunological priming factor associated with symptom occurrence, whereas the reduction of adaptive immune reserves continuously modulates the global neuropsychiatric severity in Alzheimer’s disease.