Inflammation-induced amyloid precursor protein (APP) accumulations represent an early neuropathologic feature in the pathogenesis of Alzheimer’s disease (AD). Extracellular APP or soluble (s)APP-containing amyloid plaques in rodents and humans share striking morphological similarities. Tissue sections obtained from (A-B) 15-month-old double immune-challenged (polyriboinosinic-polyribocytidilic acid (PolyI:C) at GD17, PolyI:C at 12 months) wild-type (WT) mice, (C-D) 1-month-old 3xTg-AD mice exposed to PolyI:C at 4 months, and (E-F) an 88-year-old patient with AD. Images were acquired with the same confocal settings in representative areas within the hippocampal formation: layer III-IV in the lateral entorhinal cortex (ECtx, PP), CA1 stratum radiatum (sr, 3xTg-AD mice), and CA1 stratum pyramidale (sp, human subject). Antibody used: anti-N-APP (red) and anti-Aβ1–40/42 (green). (G) Model proposing an AD mutation-independent role of systemic immune challenges, persistent neuroinflammation, and deterioration of innate immunity in the etiology of the age-associated, sporadic form of AD. Scale bars: (A-E) = 10 μm; (F) = 20 μm.