Glial pathology networks reveal early olfactory vulnerability in post mortem human Alzheimer's disease

INTRODUCTION: The olfactory system is an early target in Alzheimer's disease (AD), yet regional glial pathology interactions remain poorly defined. We examined how glial activation and pathological burden differ between the olfactory cortex (OC) and olfactory bulb (OB) across disease stages. METHODS: Post mortem OC and OB samples from cognitively normal (CN), mild cognitive impairment, and AD cases were analyzed using immunohistochemistry and immunofluorescence for amyloid beta (A beta), phosphorylated tau (pTau), Iba1 (microglia), GFAP (astrocyte), and apolipoprotein E (apoE). RESULTS: Both regions showed stage-dependent increases in A beta and pTau, with regionally distinct glial responses. ApoE signal varied with clinical stage rather than genotype. Co-expression analyses revealed astrocyte-linked networks in the OC and microglia-linked relationships in the OB. DISCUSSION: Findings demonstrate spatially heterogenous glial pathology architectures in the human olfactory system, supporting its role as an early and regionally diverse site of AD vulnerability.